Rhenium and Technetium Complexes with Pentadentate Thiocarbamoylbenzamidines: Steps toward Bioconjugation

Article abstract of DOI:10.1021/acs.inorgchem.5b00769

Thiocarbamoylbenzimidoyl chlorides, PhC(Cl)=N-(C=S)-NR¹R², react with 2-(iminodiacetic acid)benzylamine under formation of the potentially pentadentate ligands H₃L (R¹, R² = Et) and H₃L-COOEt (R¹ = Me, R² = C₆H₄-4-COOEt) in high yields. Hydrolysis of H₃L-COOEt in NaOH/MeOH gives quantitatively another benzamidine ligand H₃L-COOH. The novel ligands readily react with (NBu₄)[MOCl₄] (M = Re, Tc) under formation of stable complexes with the general composition [MO(L)], in which they are triply deprotonated and fully occupy the remaining five coordination positions of the {MO}³⁺ cores. In a "proof-of-principle" reaction for possible bioconjugations, the complex [ReO(L-COOH)] has been labeled with triglycine ethyl ester in high yields.

Full text of DOI:10.1021/acs.inorgchem.5b00769

Article
pubs.acs.org/IC
Rhenium and Technetium Complexes with Pentadentate
Thiocarbamoylbenzamidines: Steps toward Bioconjugation
Hung Huy Nguyen,*,† Chien Thang Pham,†,‡ and Ulrich Abram*,‡
†Department of Chemistry, Hanoi University of Science, 19 Le Thanh Tong, Hanoi, Vietnam
‡Institute of Chemistry and Biochemistry, Freie Universitat Berlin, Fabeckstrasse 34-36, D-14195 Berlin, Germany
̈
S
* Supporting Information
ABSTRACT: Thiocarbamoylbenzimidoyl chlorides, PhC-
(Cl)N−(CS)−NR1R2, react with 2-(iminodiacetic acid)-
benzylamine under formation of the potentially pentadentate
ligands H3L (R1, R2 = Et) and H3L−COOEt (R1 = Me, R2 =
C6H4-4-COOEt) in high yields. Hydrolysis of H3L−COOEt in
NaOH/MeOH gives quantitatively another benzamidine ligand
H3L−COOH. The novel ligands readily react with (NBu4)-
[MOCl4] (M = Re, Tc) under formation of stable complexes
with the general composition [MO(L)], in which they are
triply deprotonated and fully occupy the remaining five
coordination positions of the {MO}3+ cores. In a “proof-of-
principle” reaction for possible bioconjugations, the complex
[ReO(L−COOH)] has been labeled with triglycine ethyl ester
in high yields.
their periphery.12,13 This fact may play a role when the obtained
technetium and rhenium complexes shall be used as chelating
sites in conjugates with biologically targeting molecules, which
rapidly and efficiently transport the radionuclides to the
biological target.
In the present work, we describe the syntheses of novel
pentadentate dialkylamino(thiocarbonyl)benzamidine ligands
(Chart 1) and some of their rhenium and technetium
complexes. The modification of the ligand sphere with an
additional carboxylic group and the examination of a coupling
reaction of the rhenium complex using triglycine ethyl ester are
also demonstrated.
INTRODUCTION
■
Technetium and rhenium are important in the field of nuclear
medicine due to the availability of radioisotopes suitable for
diagnostic radiopharmaceuticals (99mTc: γ-emitter, Eγ = 140
keV, t1/2 = 6.0 h),1,2 or potential therapeutic agents for various
forms of cancer or arthritis (186Re and 188Re: both β−-emitters
with t1/2 of 89.3 and 17.0 h, respectively).3 Thus,
thermodynamically stable and/or kinetically inert technetium
and rhenium complexes, which do not undergo easy ligand
exchange reactions in the plasma, are of constant interest for
the development of new radiopharmaceuticals.4 In this scene,
pentadentate ligand systems would be perfectly suitable for the
complexation of the common {ReVO}3+ and {TcVO}3+ cores,
which can easily be obtained by the reduction of [MO4]− ions
available from the commercial generator systems. Surprisingly,
only a few examples of oxidotechnetium(V) or -rhenium(V)
complexes with pentadentate ligands are hitherto structurally
well characterized.5−9 This may be understood by the facts that
the syntheses of pentadentate ligands are frequently time-
consuming procedures and the targeted oxido cores request
systems with preferably oxygen donors for coordination in trans
position of the normally trans-labilizing O2− ligands.
Chart 1. Ligands Used in This Work
Recently, we have reported a series of multidentate
benzamidine ligands, which are formed in relatively simple
reactions between benzimidoyl chlorides and functionalized
primary amines.10,11 Thus, the synthesis of pentadentate
systems via reactions of benzimidoyl chlorides and potentially
tetradentate ligands having a terminal primary amine group
could be a very facile approach. Additionally, our interests in
this type of ligand are due to the flexibility of modifications in
Received: April 6, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.inorgchem.5b00769
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148.73 (Caryl−N), 156.41 (CONH), 172.65 (NCH2CO). ESI+ MS
(m/z): 339.0, 50%, [M + H ]+; 361.1, 70%, [M + Na ]+; 377.1, 20%,
[M + K ]+. ESI− MS (m/z): 337.3, 100%, [M − H ]−.
2-(Aminodiacetic acid)benzylammonium Bis-trifluoroacetate
Salt (4). Compound 3 (4.737 g) and CF3COOH (15 mL) were
stirred in dry CH2Cl2 (15 mL) at room temperature for 2 h. The
organic solvents were removed under vacuum to give quantitatively
compound 4 as a colorless powder.
EXPERIMENTAL SECTION
■
Materials. All chemicals used in this study were reagent grade and
used without further purification. Solvents were dried and used freshly
distilled unless otherwise stated. (NBu4)[ReOCl4] and (NBu4)-
[TcOCl4] were prepared by standard procedures.14,15 The synthesis
of the N,N-[(diethylamino)(thiocarbonyl)]benzimidoyl chloride was
performed by the standard procedure of Beyer et al.16 N-(tert-
Butoxycarbonyl)-2-aminobenzylamine (1) was synthesized following
the literature procedure,17 except that the purification was carried out
by recrystallization from CH2Cl2/n-hexane.
Anal. Calcd for C15H16F6N2O8: C, 38.6; H, 3.5; N, 6.0. Found: C,
38.2; H, 3.4; N, 6.1. IR (KBr, cm−1): 3144 (br, s), 1782 (vs), 1720
(vs), 1608 (s), 1492 (m), 1458 (m), 1404 (w), 1250 (s), 1218 (s),
1196 (s), 1168 (s), 1068 (w), 968 (w), 786 (w), 721 (w), 698 (w),
605 (w). 1H NMR (400 MHz, DMSO-d6, ppm): 3.92 (s, 4H,
NCH2CO), 4.10 (d, J = 5.1 Hz, 2H, CH2NH), 7.16 (t, J = 7.3 Hz, 1H,
C6H4), 7.35 (m, 2H, C6H4), 7.44 (d, 1H, 7.4 Hz, C6H4), 8.27 (s, br,
4H, OH). 13C NMR (400 MHz, CDCl3, ppm): 41.13 (NCH2Ph),
55.12 (NCH2CO), 116.39 (q, JCF = 290.0 Hz, CF3), 124.11 (Caryl),
124.59 (Caryl), 130.11 (Caryl), 130.42 (Caryl), 131.53 (Caryl), 149.48
(Caryl−N), 159.00 (q, JCF = 35.0 Hz, CF3CO), 173.27 (NCH2CO).
ESI+ MS (m/z): 239.1, 100%, [M + H ]+; 261.0, 10%, [M + Na ]+.
ESI− MS (m/z): 237.3, 100%, [M − H ]−, 113.1, 80%, [CF3COO−].
4-(N-Methylamino)benzoic Acid Ethylester (5). Compound 5 was
prepared by the method of Kadin.18 A solution of ethyl 4-
aminobenzoate (16.52 g), succinimide (11.90 g), and 9.1 mL of
37% aqueous formaldehyde in 100 mL of ethanol was heated on reflux
for 3 h. After cooling to room temperature, the formed colorless
precipitate of ethyl 4-(aminomethylsuccinimide)benzoate was col-
lected by suction filtration. It was dissolved in 50 mL of DMSO, and
NaBH4 (3.33 g) was added in small portions over a period of 15 min.
After being heated to 80 °C for 15 min, the reaction mixture was
poured into cold water. The resulting mixture was extracted three
times with ether. The combined ether extracts were dried, and the
solvent was removed in vacuum. The remaining solid was recrystal-
lized from CH2Cl2/MeOH, which gave colorless crystals of 5. Yield:
62.0% (11.10 g).
Anal. Calcd for C10H13NO2: C, 67.0; H, 7.3; N, 7.8. Found: C, 67.2;
H, 7.2; N, 7.8. IR (KBr, cm−1): 3385 (s), 2975 (w), 2935 (w), 2900
(w), 1685 (s), 1605 (vs), 1535 (s), 1475 (m), 1370 (m), 1310 (w),
1275 (s), 1175 (s), 1105 (m), 770 (m). 1H NMR (400 MHz, CDCl3,
ppm): 1.29 (t, J = 7.2 Hz, 3H, CH2CH3), 2.82 (s, 3H, NCH3), 4.12 (s,
1H, NH), 4.24 (q, J = 7.2 Hz, 2H, CH2CH3), 6.48 (d, J = 6.8 Hz, 2H,
Ph), 7.82 (d, J = 6.8 Hz, 2H, Ph).
N-(4-Ethoxycarbonylphenyl)-N-(methyl)-N′-benzoylthiourea (6).
The synthesis of 6 was performed by the standard procedure using
5 as starting material.19 Benzoyl chloride (7.00 g, 50 mmol) in 5 mL of
dry acetone was added dropwise to a solution of NH4SCN (3.80 g, 50
mmol) in 10 mL of dry acetone. After the addition was completed, the
mixture was kept at 40 °C for 1 h and the formed precipitate of NH4Cl
was filtered off. Compound 5 (8.96 g, 50 mmol) in 5 mL of dry
acetone was slowly added to the resulting yellow solution, which then
was stirred at room temperature for 3 h. After the volume of the
solvent was reduced to about 10 mL, the mixture was kept at 0 °C and
the formed precipitate was filtered off, washed with cold MeOH and
diethyl ether, and dried in vacuum. Yield: 73.0% (12.50 g).
Radiation Precautions. 99Tc is a weak β−-emitter. All
manipulations with this isotope were performed in a laboratory
approved for the handling of radioactive materials. Normal glassware
provides adequate protection against the low-energy beta emission of
the technetium compounds. Secondary X-rays (bremsstrahlung) play
an important role only when larger amounts of 99Tc are used.
Physical Measurements. Infrared spectra were measured as KBr
pellets on a Shimadzu FTIR spectrometer between 400 and 4000
cm−1. NMR spectra were taken with JEOL 400 MHz and Bruker 500
MHz multinuclear spectrometers. ESI mass spectra were measured
with Agilent 6210 ESI-TOF (Agilent Technology) and LTQ Orbitrap
XL (Thermo Scientific) mass spectrometers. All MS results are given
in the form: m/z, assignment. Elemental analyses of carbon, hydrogen,
nitrogen, and sulfur were determined using a Heraeus vario EL
elemental analyzer. The 99Tc values were determined by standard
liquid scintillation counting.
Syntheses of the Ligands. N-(tert-Butoxycarbonyl)-2-(amino-
diacetic acid diethyl ester)benzylamine (2). N-(tert-Butoxycarbonyl)-
2-aminobenzylamine (1) (8.891 g, 40 mmol), ethyl bromoacetate
(13.8 mL, 125 mmol), i-Pr2EtN (27.8 mL, 160 mmol), and finely
powdered KI (1 g) in toluene (150 mL) were heated under reflux for
48 h. After being cooled to room temperature, water (50 mL) was
added. The two layers were separated. The aqueous phase was
extracted with toluene (50 mL). The combined organic phases were
dried over MgSO4, filtered, and concentrated under reduced pressure.
The residual was heated at ca. 80 °C under a pressure of 20 mmHg for
4 h to remove the remaining ethyl bromoacetate. The obtained yellow
oil, which contained mainly the diester 2 and traces of ethyl
bromoacetate, was used in the next step without further purification.
Yield is about 95% (14.989 g).
Anal. Calcd for C20H30N2O6: C, 60.9; H, 7.7; N, 7.1. Found: C,
1
61.5; H, 7.7; N, 7.0. H NMR (400 MHz, CDCl3, ppm): 1.13 (t, J =
7.1 Hz, 6H, OCH2CH3), 1.36 (s, 9H, CH3), 3.90 (s, 4H, NCH2CO),
4.05 (q, J = 7.1 Hz, 4H, OCH2CH3), 4.31 (d, J = 5.9 Hz, 2H, CH2NH)
6.12 (s, br, 1H, NHCO), 7.01 (t, J = 7.5 Hz, 1H, C6H4), 7.14 (t, J =
7.7 Hz, 1H, C6H4), 7.22 (d, J = 7.7 Hz, 1H, C6H4), 7.25 (d, J = 8.0 Hz,
1H, C6H4).
N-(tert-Butoxycarbonyl)-2-(aminodiacetic acid)benzylamine (3).
Compound 2 (7.889 g, 20 mmol) and NaOH (2.400 g, 60 mmol) in
50 mL of MeOH were stirred at room temperature for 24 h, and then
the reaction mixture was evaporated to dryness in vacuum. The
remaining solid was dissolved in 50 mL of cold brine solution, and
cold HCl (6 M) was slowly added. The temperature was kept at 5−10
°C during this procedure until a pH of 6 was obtained. The product
was extracted with THF (3 × 30 mL). The combined organic phases
were dried over MgSO4, filtered, and evaporated in vacuo to dryness.
The obtained residue was recrystallized from CHCl3 to give the pure
product as a colorless solid. Yield 70% (4.737 g).
Anal. Calcd for C16H22N2O6: C, 56.8; H, 6.5; N, 8.3. Found: C,
56.2; H, 6.5; N, 8.1. IR (KBr, cm−1): 3394 (s), 3124 (br, s), 1755 (vs),
1705 (vs), 1662 (vs), 1523 (s), 1488 (m), 1454 (m), 1392 (m), 1369
(m), 1303 (m), 1253 (s), 1212 (s), 1184 (s), 1049 (m), 972 (m), 856
(m), 779 (m), 682 (m), 590 (m). 1H NMR (400 MHz, CDCl3, ppm):
0.900 (s, 9H, CH3), 3.41 (s, 4H, NCH2CO), 3.80 (s, 2H, CH2NH),
6.20 (s, br, 1H, NHCO), 6.52 (t, J = 7.4 Hz, 1H, C6H4), 6.66 (t, J =
7.6 Hz, 1H, C6H4), 6.73 (d, J = 7.6 Hz, 1H, C6H4), 6.80 (d, J = 7.9 Hz,
1H, C6H4). 13C NMR (400 MHz, CDCl3, ppm): 28.76 (C(CH3)3),
40.45 (NCH2Ph), 55.01 (NCH2CO), 78.19 (C(CH3)3), 123.32
(Caryl), 124.32 (Caryl), 127.55 (Caryl), 128.43 (Caryl), 135.25 (Caryl),
Anal. Calcd for C18H18N2O3S: C, 63.1; H, 5.3; N, 8.2; S, 9.4. Found:
C, 62.9; H, 5.1; N, 8.3; S, 9.3. IR (KBr, cm−1): 3225 (m), 3190 (w),
3060 (w), 2985 (w), 2940 (w), 2905 (w), 1710 (s), 1690 (s), 1605
(m), 1510 (s), 1450 (w), 1430 (m), 1365 (s), 1315 (m), 1275 (vs),
1180 (m), 1110 (s), 720 (s). 1H NMR (400 MHz, CDCl3, ppm): 1.34
(t, J = 7.1 Hz, 3H, CH2CH3), 3.77 (s, 3H, NCH3), 4.31 (q, J = 7.1 Hz,
2H, CH2CH3), 7.38 (d, 4H, Ph), 7.50 (t, J = 7.3 Hz, 1H, Ph), 7.57 (d,
J = 7.4 Hz, 2H, Ph), 8.01 (d, J = 8.7 Hz, 2H, Ph), 8.36 (s, 1H, NH).
13C NMR (400 MHz, CDCl3, ppm): 14.42 (OCH2CH3), 43.37
(NCH3), 61.38 (OCH2CH3), 124.54 (Caryl), 128.23 (Caryl), 128.79
(Caryl), 129.52 (Caryl), 129.63 (Caryl), 132.28 (Caryl), 136.17 (Caryl),
140.64 (Caryl−N), 165.73 (COO), 168.51 (CO), 175.26 (CS).
ESI+ MS (m/z): 343.1, 100%, [M + H ]+; 365.2, 40%, [M + Na ]+.
B i s - [ N - ( 4 - e t h o x y c a r b o n y l p h e n y l ) - N - m e t h y l - N ′ -
benzoylthioureato]nickel(II) (7). The synthesis of 7 from 6 was
adopted from the general procedure.16 Compound 6 (10.27 g, 30
B
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mmol) was dissolved in boiling EtOH (50 mL) and slowly added to a
hot solution of Ni(CH3COO)2·4H2O (3.72 g, 15 mmol) in 30 mL of
MeOH, which resulted in the precipitation of a red-brown solid of 7.
The reaction mixture was refluxed for additional 30 min and then
cooled to room temperature. Compound 7 was collected by suction
filtration and dried in vacuo. Yield: 93.0% (10.32 g).
H3L−COOEt. The synthesis of H3L−COOEt was adopted from the
procedure described for H3L except that the benzimidoyl chloride 8
was used.
Anal. Calcd for C29H30N4O6S: C, 61.9; H, 5.4; N, 10.0; S, 5.7.
Found: C, 61.6; H, 5.2; N, 9.8; S, 5.8. IR (KBr, cm−1): 3348 (br, s),
1712 (br, s), 1605 (s), 1542 (s), 1493 (m), 1446 (s), 1276 (s), 1202
1
(s), 1138 (s), 1099 (s), 1018 (m), 972 (w), 775 (m). H NMR (400
Anal. Calcd for C36H34N4NiO6S2: C, 58.3; H, 4.6; N, 7.6; S, 8.7.
Found: C, 58.3; H, 4.8; N, 7.3; S, 8.5. IR (KBr, cm−1): 3065 (w), 2975
(w), 2925 (w), 2855 (w), 1720 (s), 1605 (w), 1525 (s), 1420 (s), 1375
MHz, DMSO-d6, ppm): 1.40 (t, J = 7.1 Hz, 3H, CH2CH3), 3.56 (s,
3H, NCH3), 3.83 (s, 4H, NCH2CO), 4.37 (q, J = 7.1 Hz, 2H,
CH2CH3), 4.49 (s, 2H, PhCH2NH), 6.86 (t, br, 1H, Ph), 6.93 (d, br,
1H, Ph), 7.14 (t, br, 1H, Ph), 7.19 (d, br, 1H, Ph), 7.47 (m, 7H, Ph),
7.91 (d, J = 8.6 Hz, 2H, Ph), 8.67 (s, br, 1H, NH) 12.13 (s, br, 2H,
COOH). 13C NMR (400 MHz, DMSO-d6, ppm): 14.34 (OCH2CH3),
42.89 (NCH3), 61.15 (OCH2CH3), 59.20 (NCH2Ph), 66.54 (N-
CH2CO), 120.01 (Caryl), 124.43 (Caryl), 125.51 (Caryl), 126.70 (Caryl),
128,99 (Caryl), 129.12 (Caryl), 130.68 (Caryl), 130.97 (Caryl), 131.03
(Caryl), 131.48 (Caryl), 133.20 (Caryl), 135.76 (Caryl), 148.57 (Caryl−N),
152.95 (Caryl−N), 165.30 (PhCOO), 166.93 (CN), 172.62(COO),
180.77 (CS). ESI+ MS (m/z): 563.2, 100%, [M + H ]+; 585.2, 60%,
[M + Na]+; 601.1, 20%, [M + K]+. ESI− MS (m/z): 561.2, 100%, [M
− H ]−.
H3L−COOH. H3L−COOEt (562 mg, 1 mmol) was added to a
solution of NaOH (400 mg, 10 mmol) in MeOH (5 mL). The
reaction mixture was stirred at room temperature for 12 h, and then
the solvent was removed under vacuum. The resulting residue was
dissolved in brine solution (5 mL). After being neutralized with 10
mmol of HCl, the mixture was extracted with THF (2 × 5 mL). The
organic phases were collected, dried over MgSO4, and the solvent was
removed under vacuum to give compound H3L−COOH as a slightly
yellow powder. Yield: 80% (427 mg).
1
(s), 1285 (s), 1110 (m), 1020 (m), 910 (m), 710 (m), 705 (m). H
NMR (400 MHz, CDCl3, ppm): 1.41 (t, J = 7.0 Hz, 6H, CH2CH3),
3.60 (s, 6H, NCH3), 4.40 (q, J = 7.0 Hz, 4H, CH2CH3), 7.3−8.1 (m,
18H, Ph). 13C NMR (400 MHz, CDCl3, ppm): 14.40 (OCH2CH3),
41.94 (NCH3), 61.23 (OCH2CH3), 124.55 (Caryl), 127.11 (Caryl),
128.02 (Caryl), 129.38 (Caryl), 130.68 (Caryl), 131.93 (Caryl), 136.02
(Caryl), 149.44 (Caryl−N), 165.72 (COO), 165.93 (CO), 175.44
(CS). ESI+ MS (m/z): 741.0, 50%, [M + H ]+; 762.9, 10%, [M + Na
]+.
N-(4-Ethoxycarbonylphenyl)-N-methyl-N′-benzimidoyl Chloride
(8). The synthesis of 8 was adopted from the general procedure.16
A
solution of SOCl2 (1.60 mL, 22.0 mmol) in 20 mL of dry CH2Cl2 was
added dropwise into a stirred solution of compound 7 (8.16 g, 11.0
mmol). The reaction mixture was stirred at room temperature for an
additional 2 h and then heated on reflux for 30 min. The formed
precipitate of NiCl2 was filtered off, and the filtrate was evaporated
under reduced pressure. Compound 8 was obtained as yellow,
microcrystalline solid. Yield: 65.0% (5.16 g).
Anal. Calcd for C18H17ClN2O2S: C, 59.9; H, 4.8; N, 7.8; S, 8.9.
Found: C, 59.9; H, 4.8; N, 7.8; S, 8.9. IR (KBr, cm−1): 3055 (w), 2981
(w), 2935 (w), 2900 (w), 1716 (s), 1639 (s), 1600 (m), 1505 (m),
1454 (m), 1365 (s), 1273 (s), 1164 (s), 1103 (s), 1014 (m), 910 (m),
775 (m), 690 (m). 1H NMR (400 MHz, CDCl3, ppm): 1.36 (t, J = 7.1
Hz, 3H, CH2CH3), 3.80 (s, 3H, NCH3), 4.33 (q, J = 7.1 Hz, 2H,
CH2CH3), 7.34 (d, J = 8.2 Hz, 4H, Ph), 7.45 (t, J = 7.3 Hz, 1H, Ph),
7.74 (d, J = 7.8 Hz, 2H, Ph), 8.01 (d, J = 8.3 Hz, 2H, Ph). 13C NMR
(400 MHz, CDCl3, ppm): 14.27 (OCH2CH3), 43.38 (NCH3), 61.36
(OCH2CH3), 125.25 (Caryl), 128.48 (Caryl), 129.12 (Caryl), 130.10
(Caryl), 130.79 (Caryl), 132.92 (Caryl), 133.62 (Caryl), 144.39 (Caryl−N),
147.68 (C−Cl), 165.49 (COO), 188.06 (CS). ESI+ MS (m/z):
361.0, 70%, [M + H ]+.
H3L. N-[(Diethylamino)(thiocarbonyl)]benzimidoyl chloride (686
mg, 2.7 mmol), compound 4 (1.409 g, 2.5 mmol), and NEt3 (2.02 g,
20 mmol) were stirred in 20 mL of dry EtOH for 6 h at room
temperature and then at 40 °C for 1 h. The organic solvent was
evaporated under reduced pressure to dryness. The residue was
dissolved in 20 mL of THF, and brine solution (20 mL) was added.
The organic layer was separated, dried over MgSO4, filtered, and the
solvent was removed in vacuo. The residue was washed with diethyl
ether and dried in vacuum to give H3L as a colorless solid. Yield: 65%
(742 mg).
Anal. Calcd for C27H26N4O6S: C, 60.7; H, 4.9; N, 10.5; S, 6.0.
Found: C, 60.4; H, 4.8; N, 10.3; S, 6.1. IR (KBr, cm−1): 3368 (br, s),
1717 (s), 1605 (s), 1562 (s), 1423 (s), 1492 (m), 1423 (m), 1381
1
(m), 1272 (s), 1176 (s), 775 (m), 698 (m). H NMR (400 MHz,
DMSO-d6, ppm): 3.58 (s, 3H, NCH3), 3.98 (s, 4H, NCH2CO), 4.55
(s, 2H, PhCH2NH), 6.87 (t, br, 1H, Ph), 6.96 (d, br, 1H, Ph), 7.21 (t,
br, 1H, Ph), 7.29 (d, br, 1H, Ph), 7.40 (m, 7H, Ph), 7.94 (d, J = 8.2
Hz, 2H, Ph), 8.70 (s, br, 1H, NH), 12.74 (s, 3H, COOH). 13C NMR
(400 MHz, DMSO-d6, ppm): 43.70 (NCH3), 56.37 (NCH2Ph), 66.03
(N−CH2CO), 119.90 (Caryl), 125.01 (Caryl), 125.95 (Caryl), 126.66
(Caryl), 127.05 (Caryl), 128.31 (Caryl), 128.84 (Caryl), 129.60 (Caryl),
130.56 (Caryl), 131.39 (Caryl), 132.31 (Caryl), 134.76 (Caryl), 146.01
(Caryl−N), 149.32 (Caryl−N), 166.03 (PhCOO), 168.12 (CN),
173.13 (COO), 180.21 (CS). ESI+ MS (m/z): 535.2, 40%, [M + H
]+; 557.2, 100%, [M + Na]+; 573.1, 80%, [M + K]+. ESI− MS (m/z):
533.2, 100%, [M − H ]−.
Syntheses of the Complexes. [ReO(L)] (9). H3L (46 mg, 0.1
mmol) and Et3N (50 μL) were added to a stirred solution of
(NBu4)[ReOCl4] (58 mg, 0.1 mmol) in 5 mL of MeOH. The reaction
mixture was heated under reflux for 30 min. After being cooled to
room temperature, the formed purple solid of 9 was filtered off,
washed with cold MeOH, and dried under vacuum. Yield: 67% (44
mg).
Anal. Calcd for C23H28N4O4S: C, 60.5; H, 6.2; N, 12.3; S, 7.0.
Found: C, 60.3; H, 6.3; N, 12.2; S, 7.2. IR (KBr, cm−1): 3250 (br, s),
1720 (br, s), 1631 (br, s), 1573 (s), 1539 (s), 1489 (m), 1454 (s),
1423 (s), 1311 (m), 1257 (s), 1199 (s), 1138 (s), 1076 (m), 968 (w),
Compound 9 can also be synthesized from other precursors such as
[ReVNCl2(PPh3)2], [ReV(NPh)Cl3(PPh3)2], or [ReIIICl3(MeCN)-
(PPh3)2] by heating them with H3L in the presence of a base
(Et3N), water, and air.
1
883 (w), 779 (m), 698 (m). H NMR (400 MHz, DMSO-d6, ppm):
1.07 (t, J = 7.0 Hz, 3H, CH3), 1.13 (t, J = 7.0 Hz, 3H, CH3), 3.52 (q, J
= 7.0 Hz, 2H, NCH2CH3), 3.78 (q, J = 7.0 Hz, 2H, NCH2CH3), 3.99
(s, 4H, NCH2CO), 4.64 (d, J = 5.2 Hz, 2H, CH2NH), 7.12 (t, J = 7.3
Hz, 1H, C6H4), 7.25 (t, J = 7.2 Hz, 1H, C6H4), 7.30 (d, J = 8.0 Hz, 1H,
C6H4), 7.36 (d, J = 7.6 Hz, 1H, C6H4), 7.47 (m, 5H, Ph), 8.35 (s, br,
1H, NHCO), 12.76 (s, br, 1H, COOH). 13C NMR (400 MHz,
DMSO-d6, ppm): 12.34, 13.45 (CH2CH3), 46.42, 46.98 (NCH2CH3),
56.56 (NCH2), 67.51 (NCH2CO), 118.21 (Caryl), 125.23 (Caryl),
127.48 (Caryl), 127.90 (Caryl), 128.87 (Caryl), 129.55 (Caryl), 130.04
(Caryl), 132.68 (Caryl), 135.34 (Caryl), 149.54 (Caryl−N), 166.24 (C
N), 172.50 (COO), 180.18 (CS). ESI+ MS (m/z): 457.1, 100%, [M
+ H ]+; 479.2, 60%, [M + Na ]+. ESI− MS (m/z): 455.1, 100%, [M −
H ]−.
Anal. Calcd for C23H25N4O5ReS: C, 42.1; H, 3.8; N, 8.5; S, 4.9.
Found: C, 42.0; H, 3.6; N, 8.3; S, 4.7. IR (KBr, cm−1): 3055 (w), 2963
(m), 2926 (m), 1720 (vs), 1666 (vs), 1512 (s), 1442 (m), 1404 (m),
1350 (m), 1311 (m), 1041 (w), 964 (m), 941 (m), 910 (m), 771 (m),
702 (m). 1H NMR (400 MHz, CDCl3, ppm): 1.30 (t, J = 7.2 Hz, 3H,
CH3), 1.33 (t, J = 7.1 Hz, 3H, CH3), 3.77 (m, 1H, NCH2CH3), 3.84
(m, 1H, NCH2CH3), 3.89 (s, 2H, PhCH2N), 4.03 (m, 1H,
NCH2CH3), 4.09 (m, 1H, NCH2CH3), 4.53 (d, J = 15.5 Hz, 1H,
NCH2CO), 4.83 (d, J = 14.0 Hz, 1H, NCH2CO), 5.06 (d, J = 13.8 Hz,
1H, NCH2CO), 5.68 (d, J = 15.6 Hz, 1H, NCH2CO), 7.00 (d, J = 7.6
Hz, 1H, C6H4), 7.22 (t, J = 7.5 Hz, 1H, C6H4), 7.33 (m, 2H, C6H4),
1
7.44 (m, 3H, Ph), 7.48 (d, J = 7.5 Hz, 2H, Ph). H NMR (400 MHz,
DMSO-d6, ppm): 1.26 (t, J = 7.2 Hz, 3H, CH3), 1.29 (t, J = 7.2 Hz,
C
DOI: 10.1021/acs.inorgchem.5b00769
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
Table 1. X-ray Structure Data Collection and Refinement Parameters
[ReO(L)] (9)
[TcO(L)] (10)
[ReO(L−COOEt)]·1.25 MeOH (11)
formula
MW
C23H25N4O5ReS
655.73
C23H25N4O5STc
567.53
C30.25H32N4O8.25ReS
801.86
crystal system
a/Å
monoclinic
32.448(3)
7.160(1)
20.521(2)
90
monoclinic
32.213(2)
7.187(1)
20.453(2)
90
triclinic
9.949(1)
b/Å
10.980(1)
16.796(2)
100.54(1)
92.32(1)
c/Å
α/deg
β/deg
γ/deg
100.69(1)
90
100.29(1)
90
113.36(1)
1643.0(3)
V/Å3
4684.8(9)
C2/c
4659.2(8)
C2/c
space group
crystal size
Z
P1
̅
0.5 × 0.2 × 0.04
8
0.2 × 0.15 × 0.03
8
0.1 × 0.067 × 0.05
2
D
calc/g cm−3
1.859
1.618
1.621
μ/mm−1
5.320
0.751
3.816
no. of reflns
no. of indep, Rint
no. of parameters
R1/wR2
14 462
20 479
17 975
6207, 0.1002
326
6270, 0.1119
326
8768, 0.1067
380
0.0477/0.0776
0.872
0.0505/0.1109
0.907
0.0668/0.1695
1.068
GOF
CSD
CCDC 1058104
CCDC 1058105
CCDC 1058106
3H, CH3), 4.00 (m, 4H, NCH2CH3), 4.10 (d, J = 18.3 Hz, 1H,
PhCH2N), 4.40 (d, J = 18.2 Hz, 1H, PhCH2N), 4.78 (d, J = 15.2 Hz,
1H, NCH2CO), 4.82 (d, J = 14.1 Hz, 1H, NCH2CO), 5.37 (d, J = 14.5
Hz, 1H, NCH2CO), 5.63 (d, J = 15.6 Hz, 1H, NCH2CO), 7.13 (d, J =
7.6 Hz, 1H, C6H4), 7.29 (t, J = 7.4 Hz, 1H, C6H4), 7.43 (m, 2H,
C6H4), 7.57 (m, 3H, Ph), 7.67 (d, J = 8.0 Hz, 2H, Ph). 13C NMR (400
MHz, DMSO-d6, ppm): 13.01, 13.23 (NCH2CH3), 46.75, 47.13
(NCH2CH3), 64.03 (NCH2Ph), 65.37, 66.71 (NCH2CO), 119.38
(Caryl), 127.84 (Caryl), 128.57 (Caryl), 128.78 (Caryl), 129.56 (Caryl),
130.83 (Caryl), 131.54 (Caryl), 132.67 (Caryl), 137.02 (Caryl), 153.81
(Caryl−N), 170.44 (CN), 173.34 (COORe), 173.67 (COORe),
183.61 (CS). ESI+ MS (m/z): 657.2, 100%, [M + H ]+.
NMR (400 MHz, DMSO-d6, ppm): 14.64 (OCH2CH3), 43.04
(NCH3), 61.59 (OCH2CH3), 64.21 (NCH2Ph), 65.61 (N−
CH2CO), 67.00 (N−CH2CO), 119.91 (Caryl), 128.08 (Caryl), 128.34
(Caryl), 129.30 (Caryl), 129,59 (Caryl), 130.23 (Caryl), 131.07 (Caryl),
131.10 (Caryl), 131.73 (Caryl), 131.82 (Caryl), 133.30 (Caryl), 136.93-
(Caryl), 147.88 (Caryl−N), 154.33 (Caryl−N), 165.38 (PhCOO), 171.35
(CN), 173.90 (COORe), 174.74 (COORe), 184.08 (CS). ESI+
MS (m/z): 763.1, 100%, [M + H ]+; 784.9, 10%, [M + Na]+.
[TcO(L−COOEt)] (12). The technetium complex 12 was prepared
from (NBu4)[TcOCl4] by the procedure described for its rhenium
analogue 11. Compound 12 was isolated as a green solid. Yield: 67%
(45 mg).
Anal. Calcd for C29H27N4O7TcS: Tc, 14.6. Found: Tc, 14.6. IR
(KBr, cm−1): 2977 (w), 1701 (vs), 1523 (vs), 1454 (m), 1388 (m),
1276 (s), 1218 (m), 1114 (m), 1018 (w), 956 (m), 910 (m), 779 (m),
705 (m). 1H NMR (400 MHz, CDCl3, ppm): 1.18 (s, 3H,
OCH2CH3), 3.68 (d, J = 17.7 Hz, 1H, PhCH2N), 3.96 (s, 3H,
NCH3), 4.36 (m, 3H, OCH2CH3 + PhCH2N), 4.49 (d, J = 18.0 Hz,
1H, NCH2CO), 4.74 (d, J = 15.4 Hz, 1H, NCH2CO), 4.93 (d, J = 15.4
Hz, 1H, NCH2CO), 5.15 (d, J = 18.0 Hz, 1H, NCH2CO), 7.1−7.4 (m,
11H, Ph), 8.08 (d, J = 7.6 Hz, 2H, Ph).
[TcO(L)] (10). The technetium complex 10 was prepared from
(NBu4)[TcOCl4] by the procedure described above as for its rhenium
analogue 9. Compound 10 was isolated as a green solid. Yield: 75%
(43 mg).
Anal. Calcd for C23H25N4O5TcS: Tc, 17.4. Found: Tc, 17.5. IR
(KBr, cm−1): 3066 (w), 2954 (w), 2923 (w), 1701 (vs), 1654 (vs),
1500 (s), 1442 (m), 1407 (m), 1350 (m), 1311 (s), 1288 (m), 1045
1
(w), 944 (m), 910 (m), 771 (m). H NMR (400 MHz, DMSO-d6,
ppm): 1.29 (m, 6H, CH3), 3.79 (m, 2H, NCH2CH3), 3.84 (s, 2H,
PhCH2N), 3.93 (m, 2H, NCH2CH3), 4.43 (d, J = 15.3 Hz, 1H,
NCH2CO), 4.79 (d, J = 14.1 Hz, 1H, NCH2CO), 5.01 (d, J = 14.1 Hz,
1H, NCH2CO), 5.11 (d, J = 15.3 Hz, 1H, NCH2CO), 7.04 (d, J = 7.5
Hz, 1H, C6H4), 7.23 (t, J = 7.6 Hz, 1H, C6H4), 7.45 (m, 7H, Ph).
[ReO(L−COOEt)] (11). H3L−COOEt (56 mg, 0.1 mmol) and Et3N
(50 μL) were added to a stirred solution of (NBu4)[ReOCl4] (58 mg,
0.1 mmol) in 5 mL of MeOH. The reaction mixture was heated under
reflux for 30 min. After being cooled to room temperature, the formed
purple solid of 11 was filtered off, washed with cold MeOH, and dried
under vacuum. Yield: 63% (48 mg).
Anal. Calcd for C29H27N4O7ReS: C, 45.7; H, 3.6; N, 7.4; S, 4.21.
Found: C, 45.6; H, 3.6; N, 7.2; S, 4.1. IR (KBr, cm−1): 2985 (w), 2931
(w), 2851 (w), 1717 (vs), 1527 (s), 1496 (m), 1388 (m), 1280 (s),
1226 (w), 1114 (w), 1096 (m), 1018 (w), 988 (w), 936 (w), 910 (m),
779 (m), 706 (w). 1H NMR (400 MHz, DMSO-d6, ppm): 1.33 (t, J =
6.9 Hz, 3H, OCH2CH3), 3.85 (s, 3H, NCH3), 4.14 (d, J = 18.1 Hz,
1H, PhCH2N), 4.34 (q, J = 6.9 Hz, 2H, OCH2CH3), 4.44 (d, J = 18.0
Hz, 1H, PhCH2N), 4.78 (d, J = 15.5 Hz, 1H, NCH2CO), 4.90 (d, J =
15.5 Hz, 1H, NCH2CO), 5.32 (d, J = 13.5 Hz, 1H, NCH2CO), 5.69
(d, J = 16.1 Hz, 1H, NCH2CO), 7.20 (s, br, 1H, Ph), 7.28 (t, J = 7.4
Hz, 1H, Ph), 7.4−7.6 (m, 9H, Ph), 8.11 (d, J = 7.9 Hz, 2H, Ph). 13C
[ReO(L−COOH)] (13). H3L−COOH (54 mg, 0.1 mmol) and Et3N
(50 μL) were added to a stirred solution of (NBu4)[ReOCl4] (58 mg,
0.1 mmol) in 5 mL of MeOH. The reaction mixture was heated under
reflux for 30 min. After standing at room temperature for 24 h, the
formed purple solid was filtered off, washed with cold MeOH, and
dried under vacuum. Yield: 52% (38 mg).
Anal. Calcd for C27H23N4O7ReS: C, 44.1; H, 3.4; N, 7.6; S, 4.4.
Found: C, 44.2; H, 3.3; N, 7.5; S, 4.3. IR (KBr, cm−1): 3166 (br, m),
1705 (vs), 1685 (vs), 1535 (s), 1496 (m), 1389 (m), 1354 (m), 1307
(m), 1230 (m), 1172 (w), 1118 (w), 1080 (w), 984 (m), 941 (w), 914
1
(m), 864 (m), 783 (m), 698 (m). H NMR (400 MHz, DMSO-d6,
ppm): 3.85 (s, 3H, NCH3), 4.09 (d, J = 18.3 Hz, 1H, PhCH2N), 4.44
(d, J = 18.3 Hz, 1H, PhCH2N), 4.78 (d, J = 14.4 Hz, 1H, NCH2CO),
4.89 (d, J = 15.6 Hz, 1H, NCH2CO), 5.32 (d, J = 14.4 Hz, 1H,
NCH2CO), 5.69 (d, J = 15.6 Hz, 1H, NCH2CO), 7.20(d, J = 7.6 Hz,
1H, Ph), 7.28 (t, J = 7.4 Hz, 1H, Ph), 7.4−7.6 (m, 9H, Ph), 8.09 (d, J
= 8.4 Hz, 2H, Ph), 13.24 (s, 1H, COOH). 13C NMR (400 MHz,
DMSO-d6, ppm): 42.57 (NCH3), 63.71 (NCH2Ph), 65.11 (N−
CH2CO), 66.49 (N−CH2CO), 119.43 (Caryl), 127.39 (Caryl), 127.84
(Caryl), 128.69 (Caryl), 129,10 (Caryl), 129.71 (Caryl), 131.02 (Caryl),
131.22 (Caryl), 131.35 (Caryl), 132.01 (Caryl), 132.81 (Caryl), 135.70
D
DOI: 10.1021/acs.inorgchem.5b00769
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
Scheme 1. Synthesis of the Potentially Pentadentate Ligand H3L
(Caryl), 144.06 (Caryl−N), 153.85 (Caryl−N), 166.44 (PhCOO), 170.93
(CN), 173.41 (COORe), 174.05 (COORe), 183.58 (CS). ESI+
MS (m/z): 735.1, 100%, [M + H ]+; 757.2, 60%, [M + Na]+. ESI− MS
(m/z): 733.1, 100%, [M − H ]−.
unsatisfactory R values. For this reason details of the crystallographic
results obtained for 12 will not be discussed in this Article. The
molecular structure of the complex, however, could be derived from
the data set unambiguously and is in full agreement with the
spectroscopic results.
Additional information on the structure determinations has been
deposited with the Cambridge Crystallographic Data Centre.
[ReO(L−TriGlyCOOEt)] (14). Compound 13 (37 mg, 0.05 mmol),
N,N′-dicyclohexylcarbodiimide (14 mg, 0.07 mmol), and N-hydro-
benzotriazole (9 mg, 0.07 mmol) were dissolved in 3 mL of dry DMF.
The reaction mixture was stirred at room temperature for 30 min.
Triglycine ethylester (17 mg, 0.07 mmol) then was added, and the
mixture was stirred at room temperature for an additional 12 h. The
solvent was removed under vacuum, and the residue was suspended in
THF (5 mL). The insoluble urea was filtered off, and the filtrate was
washed with 5 mL of brine solution. After the organic phase was dried
over MgSO4, the solvent was removed under vacuum. The residue was
washed with cold MeOH and the red product was filtered off and
dried under vacuum. Yield: 95% (45 mg).
RESULTS AND DISCUSSION
■
The pentadentate benzamidine ligand H3L can be obtained
from 2-aminobenzyl amine in a multistep synthesis, which is
shown in Scheme 1. The nonsymmetric diamine was chosen to
allow a selective protection of one amine group and to
functionalize the other one, which gives access to ligands with
high denticity. Thus, in the first step, the aliphatic amine group
of 2-aminobenzyl amine is selectively protected by the reaction
with 1 equiv of di-tert.-butyl dicarbonate in dry CH2Cl2 to form
o-NH2C6H4CH2NHBOC (1). The aromatic amine group then
is converted to the iminodi(ethyl acetate) (2) by treatment
with an excess amount of BrCH2COOEt in the presence of a
supporting base. The reaction between 1 and BrCH2COOEt
(with KI as catalyst) proceeds very slowly. Refluxing 1 with a
large excess of BrCH2COOEt (ca. 6 equiv) in MeCN and with
solid K2CO3 used as a supporting base for 6 days resulted in a
mixture of 2 (60%) and monosubstituted product (40%).
However, with the use of toluene as solvent and a
homogeneous supporting base such as i-Pr2EtN instead of
solid K2CO3, the formation of 2 proceeds almost quantitatively
with only 3 equiv of BrCH2COOEt and a reflux period of 2
days. Hydrolysis of the ester 2 with NaOH in MeOH at room
temperature, followed by acidification with cold diluted HCl,
gives the carboxylic acid 3. The aliphatic amine of 3 is then
deprotected by CF3COOH/CH2Cl2 (1:1), giving the tetra-
dentate amine 4 as trifluoroacetate salt. Because of the poor
solubility of 4 in acetone or THF, the synthesis of the
pentadentate benzamidine H3L from N,N-diethylthiocarbonyl-
N′-benzimidoyl chloride and 4 was carried out in dry EtOH.
The ligand is obtained as a light yellow microcrystalline solid in
high yields. No significant amount of side products by potential
reactions of the benzimidoyl chloride and EtOH was
detected.21,22
Anal. Calcd for C35H36N7O10ReS: C, 45.1; H, 3.9; N, 10.5; S, 3.4.
Found: C, 45.2; H, 3.8; N, 10.7; S, 3.4. IR (KBr, cm−1): 3325 (m),
3062 (w), 2928 (m), 2850 (w), 1713 (vs), 1655 (vs), 1535 (s), 1497
(m), 1446 (w), 1384 (m), 1307 (m), 1219 (m), 1130 (w), 1084 (w),
1
980 (m), 941 (w), 910 (m), 864 (w), 787 (m), 605 (m). H NMR
(400 MHz, DMSO-d6, ppm): 1.17 (t, J = 7.1 Hz, 3H, OCH2CH3),
3.75 (d, J = 5.9 Hz, 2H, NHCH2CO), 3.85 (m, 5H, NCH3
+
NHCH2CO), 3.93 (d, J = 5.7 Hz, 2H, NHCH2CO), 4.07 (m, 3H,
OCH2CH3 + NCH2Ph), 4.43 (d, J = 18.4 Hz, 1H, NCH2Ph), 4.79 (d,
J = 14.5 Hz, 1H, NCH2CO), 4.89 (d, J = 15.7 Hz, 1H, NCH2CO),
5.30 (d, J = 14.5 Hz, 1H, NCH2CO), 5.68 (d, J = 15.7 Hz, 1H,
NCH2CO), 7.20 (d, J = 7.4 Hz, 1H, Ph), 7.28 (t, J = 7.4 Hz, 1H, Ph),
7.4−7.6 (m, 9H, Ph), 8.03 (d, J = 8.4 Hz, 2H, Ph), 8.24 (t, br, 1H,
NH), 8.29 (t, br, 1H, NH), 8.98 (t, br, 1H, NH). 13C NMR (400
MHz, DMSO-d6, ppm): 14.07 (OCH2CH3), 40.64 (CONHCH2),
41.76 (CONHCH2), 42.01 (CONHCH2), 42.98 (NCH3), 60.44
(OCH2CH3), 63.64 (NCH2Ph), 65.23 (N−CH2CO), 66.50 (N−
CH2CO), 120.03 (Caryl), 126.36 (Caryl), 127.35 (Caryl), 128.67 (Caryl),
129.01 (Caryl), 129.27 (Caryl), 131.10 (Caryl), 131.56 (Caryl), 131.99
(Caryl), 132.32 (Caryl), 132.93 (Caryl), 136.42 (Caryl), 143.55 (Caryl−N),
152.87 (Caryl−N), 167.44 (PhCONH), 168.03 (CH2COOEt), 169.40
(CH2CONH), 169.69 (CH2CONH), 171.02 (CN), 173.56
(COORe), 174.15 (COORe), 183.60 (CS). ESI+ MS (m/z):
956.1718, 100%, [M + Na ]+, 972.1576, 90%, [M + K ]+.
X-ray Crystallography. The intensities for the X-ray determi-
nations were collected on a STOE IPDS 2T instrument at 200 K with
Mo Kα radiation (λ = 0.71073 Å) using a graphite monochromator.
Standard procedures were applied for data reduction and absorption
correction. Structure solution and refinement were performed with
SHELXS97 and SHELXL97.20 Hydrogen atom positions were
calculated for idealized positions and treated with the “riding model”
option of SHELXL. More details on data collections and structure
calculations are contained in Table 1. Disordered solvent methanol is
contained in the lattice of 11. It has been modeled as three molecules
with partial occupation. A similar situation has been found for the
solid-state structure of the analogous technetium complex 12, which
The IR spectrum of H3L exhibits very strong broad bands in
the region between 3500 and 2800 cm−1, which are
characteristic for the νOH stretches of free carboxylic groups.
The absorption of the νCO vibrations is very strong and broad
and appears at 1720 cm−1. It is partially overlapped with the
1
strong absorption of the νCN stretch at 1631 cm−1. The H
NMR spectrum of H3L shows two well-separated signal sets of
two ethyl groups due to the hindered rotation of the NEt2
moiety around the C(S)−NEt2 bond.10,11,23,24 While a singlet
at 3.99 ppm is assigned to the methylene protons of CH2CO, a
also crystallizes in the triclinic space group P1 (a = 9.993(1), b =
̅
11.505(2), c = 16.440(2) Å, α = 100.31(1), β = 89.21(1), γ =
118.66(1)°). Because the disorder in the latter structure could not be
resolved with an appropriate model, the refinement resulted in
E
DOI: 10.1021/acs.inorgchem.5b00769
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
Scheme 2. Reactions of H3L with (NBu4)[MOCl4]
doublet at 4.64 with J = 5.2 Hz is typical for the methylene
protons of CH2NH. The chemical shifts of the aromatic
protons belonging to the aminobenzylamine appear in the
range from 6.8 to 7.3 ppm, which is at higher field as compared
to those of the other phenyl group. Broad singlets at 8.35 and
12.76 ppm are assigned to the NH and COOH resonances,
respectively.
nitrogen atom coordinate to the metal centers under formation
of two five-membered chelate rings. Two methylene protons in
each ring are magnetically nonequivalent due to their different
positions, up and down with respect to the ring plane. Because
of the dissociation of the protons of the neighboring nitrogen
atoms, the resonances of the methylene protons of the
benzylamine groups are high-field shifted by about 0.8 ppm
and appear as singlets at about 3.89 ppm (Figure 1a).
The ligand H3L reacts with the (NBu4)[MOCl4] (M = Tc,
Re) precursors in MeOH after addition of the supporting base
Et3N under formation of complexes of the composition
[MO(L)] [M = Re (9), Tc (10)] (Scheme 2). While the
rhenium complex is formed slowly and heating under reflux is
required to complete the formation of the violet-purple powder,
the technetium compound is readily precipitated from the
reaction mixture at an ambient temperature as a green
microcrystalline solid. Compounds 9 and 10 are stable as
solids and in solution. Interestingly, compounds 9 and 10 are
also obtained when H3L is heated on reflux under aerobic
conditions and without exclusion of water with other starting
materials possessing different cores and contain the metal ions
at different oxidation states such as [MVNCl2(PPh3)2],
[MV(NPh)Cl3(PPh3)2], or [MIIICl3(MeCN)(PPh3)2] in almost
quantitative yields. This strongly suggests that the formation of
the oxidometal(V) complexes of H3L is thermodynamically
preferred and {MN}2+, {MNPh}3+, or {M}3+ (M = Re, Tc)
complexes are readily converted when oxidation/hydrolysis is
possible.
Figure 1. A part of the 1H NMR spectrum of [ReO(L)] (a) in CDCl3
and (b) in DMSO-d6.
In the IR spectra of complexes 9 and 10, no absorptions in
the region above 3100 cm−1, which correspond to νN−H and
νO−H stretches in the free ligand, are observed. This is a strong
hint for the triply deprotonated form of the ligand. While the
νCO bands of two nonequivalent carboxylate groups in 9
appear at 1720 and 1666 cm−1, the corresponding stretches in
10 reveal strong bands at 1701 and 1654 cm−1. For both
compounds, the formation of a benzamidinato chelate, which is
normally accompanied by a large delocalization of π electrons,
is indicated by a strong bathochromic shift of the νCN to the
1500 cm−1 region.10,11,24 The medium absorption bands at 964
and 944 cm−1 are assigned to the νReO and νTcO stretches,
1
Interestingly, in the H NMR spectrum of 1 measured in
DMSO-d6, this singlet is split into two doublets at 4.10 and 4.40
ppm with typical germinal coupling constants (J = 18.2 Hz)
(Figure 1b). This can be explained by a restricted equilibrium
between the chair and the boat conformations of the six-
membered chelate ring in DMSO.
Single-crystal X-ray diffraction studies on complexes 9 and 10
confirm the conclusions drawn from the spectroscopic studies.
An ellipsoid representation of the molecular structure of 10 is
depicted in Figure 2. The equivalent molecular structure of the
rhenium complex 9 is virtually identical and, thus, not
presented as an extra figure. However, selected bond lengths
and angles of both compounds are compared in Table 2, where
the atomic labeling scheme for compound 9 is adopted from
that of the technetium complex shown in Figure 2. The metal
atoms reveal a distorted octahedral coordination environment
with a terminal oxido ligand. The remaining five coordination
positions are occupied by the donor atoms of {L}3−. One of the
carboxylate oxygen atoms is expectedly in trans position to the
respectively.25 The H NMR spectra of 9 and 10 in CDCl3
1
show no signals of O−H or N−H protons. The spectra reflect
the rigid arrangement around the tertiary nitrogen atoms of the
(CS)−NEt2 moieties. This results in magnetic nonequivalence
of its four methylene protons as is indicated by four separated
signals with ABX3 splitting patterns as previously mentioned.26
The signals of the four methylene protons of NCH2CO appear
in two pairs of doublets at 4.53/5.68 ppm, 4.83/5.06 ppm for 9
and 4.79/5.01 ppm, 4.43/5.11 ppm for 10 with typical geminal
spin coupling constants (J = 14.0−15.5 Hz). This observation
indicates that the two carboxylates and the tertiary aromatic
F
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of the poor solubility of the nickel complex 7 in CCl4, dry
CH2Cl2 was used as solvent for the synthesis of the
corresponding benzimidoyl chloride 8. The synthesis of
H3L−COOEt is similar to that of H3L except using
benzimidoyl chloride 8 instead of N,N-diethylthiocarbonyl-N′-
benzimidoyl chloride. The reaction was also carried out in dry
EtOH, and ligand H3L−COOEt can be isolated in high yields.
The IR spectrum of H3L−COOEt is characterized by a broad
strong absorption ranging from 3450 to 2500 cm−1, which is
related to the carboxylic OH stretches. The νCO stretches of
protonated carboxylic acid groups appear as a broad strong
band at 1712 cm−1. Another strong absorption band at 1605
cm−1 is assigned to the νCN vibration, which is typical for
benzamidine-type compounds. The 1H NMR spectrum of
H3L−COOEt shows the expected signal pattern. A triplet at
1.40 ppm and a quartet at 4.37 ppm, respectively, belong to the
resonances of the methyl and methylene protons of the ethyl
ester. No hindered rotation effects, which are normally
discussed for thiourea moieties, are observed for this
compound. This is reflected by a sharp singlet at 3.56 ppm
corresponding to the resonance of the N−CH3 protons. The
signals corresponding to the methylene groups of NCH2CO
and NCH2Ph are found as singlets at 3.83 and 4.49 ppm,
respectively. Two broad signals at 8.67 and 12.13 ppm can be
assigned to the NH and COOH resonances.
Figure 2. Molecular structure of [TcO(L)] (10). Hydrogen atoms
were omitted for clarity.
oxido ligand. The distances from the metal atoms to the oxygen
atoms trans to the oxido ligands are slightly shorter than the
distances to the oxygen atoms in the equatorial coordination
sphere. However, all of these distances fall into the range of
rhenium−oxygen and technetium−oxygen single bonds found
in some other carboxylato complexes.27,28 The M−N bonds to
the tertiary nitrogen atoms N8 are longer by about 0.25 Å than
the M−N5 bonds. Nevertheless, the M−N5 bond lengths are in
the same range observed before for other technetium or
rhenium thiocarbamoylbenzamidinato complexes.29 The M−
O10 bond lengths of 1.662(6) Å in 9 and 1.659(3) Å in 10 are
unexceptional.
For the use of ligands of the type H3L in bioconjugation, an
additional anchor like a carboxylic or an amino group should be
introduced to the periphery of the ligands. Generally, the ligand
skeleton of H3L can be modified in three different positions: (i)
the phenyl group of the benzamidine, (ii) the aromatic ring of
aminobenzylamine, or (iii) the thiourea (CS)−NR1R2 moiety.
The latter is the most convenient one and shall be used as a
demonstration for the ready variability of the novel ligand
system.12,13 The desired pentadentate ligand H3L−COOEt can
be obtained by a multistep synthesis as is shown in Scheme 3.
The syntheses of the benzoylthiourea 6 and its nickel complex
7, which contains an ester group, were carried out similar to the
standard procedure,16 except using the secondary amine 5,
which was prepared from 4-aminobenzoic ethyl ester. Because
H3L−COOEt readily reacts with (NBu4)[MOCl4] (M = Re,
Tc) in refluxing MeOH with the addition of base under
formation of a purple solid of the composition [ReO(L−
COOEt)] (11) or the green technetium analogue [TcO(L−
COOEt)] (12) (Scheme 4). Both compounds were isolated as
pure crystalline solids in high yields.
The information, which can be derived from the IR spectra of
11 and 12, is similar to that discussed for compounds 9 and 10:
coordinated carboxylato groups and the formation of the
benzamidine chelate rings with delocalized π-electrons.
Medium absorption bands at 988 and 956 cm−1 are assigned
to the νReO and νTcO vibrations.25 Like the 1H NMR
spectrum of the uncoordinated ligand, those of 11 and 12 do
not reveal a hindered rotation around the (CS−-NMe(p-
C6H4COOEt) bonds. This is indicated by only one set of well-
resolved signals corresponding to protons of the NMe(p-
C6H4COOEt) moiety. The absence of NH and COOH
resonances suggests {L−COOEt}3− being coordinated as a
triply deprotonated ligand. The coordination of the ligand {L−
COOEt}3− in the expected fashion is also clearly confirmed by
the appearance of six doublet signals with geminal coupling
Table 2. Selected Bond Lengths (Å) and Angles (deg) in [ReO(L)] (9) and [TcO(L)] (10)
9
10
9
10
Bond Lengths
M−O10
M−S1
M−N5
M−N8
1.662(6)
2.290(2)
2.022(7)
2.253(6)
2.078(6)
2.030(7)
1.659(3)
2.296(1)
2.000(4)
2.253(4)
2.063(4)
2.031(3)
S1−C2
C4−N5
C62−O63
C62−O64
C66−O67
C66−O68
1.75(1)
1.35(1)
1.22(1)
1.309(9)
1.20(1)
1.31(1)
1.746(5)
1.349(6)
1.222(6)
1.285(6)
1.220(6)
1.292(6)
M−O64
M−O68
Angles
O10−M− S1
O10−M−N5
O10−M−N8
O10−M−O64
104.1(2)
104.5(1)
O10−M−O68
S1−M−N8
N5−M−O64
S1−M−N5
162.5(2)
162.4(1)
97.5(3)
86.8(3)
93.6(3)
97.0(1)
87.2(1)
93.7(1)
166.2(2)
166.7(3)
93.1(2)
165.5(1)
167.8(1)
92.8(1)
G
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Scheme 3. Syntheses of H3L−COOEt and H3L−COOH
Scheme 4. Reactions of H3L−COOEt with (NBu4)[MOCl4] (M = Re, Tc)
patterns belonging to the six methylene protons as previously
discussed for complexes 9 and 10.
Table 3. Selected Bond Lengths (Å) and Angles (deg) in
[ReO(L−COOEt)] (11)
Single crystals of 11 suitable for X-ray diffraction were
obtained by slow diffusion of MeOH into solutions of the
complex in DMSO. Figure 3 illustrates the molecular structure
of 11. Selected bond lengths and angles are contained in Table
3. The structure of the analogous technetium complex is
virtually the same. The metal atoms possess distorted
octahedral environments; in each, one position is taken by a
terminal oxido ligand and the five remaining positions are
occupied by the donor atoms of {L−COOEt}3−. The bond
Re−O10
Re−S1
Re−N5
Re−N8
O10−M−S1
O10−M−N5
O10−M−N8
O10−M−O64
1.651(8)
2.294(2)
2.047(7)
2.219(7)
Re−O64
Re−O68
S1−C2
C4−N5
O10−M−O68
S1−M−N8
N5−M−O64
S1−M−N5
2.059(6)
2.065(6)
1.76(1)
1.32(1)
105.0(3)
163.4(3)
96.9(3)
87.8(3)
98.3(3)
163.7(2)
163.4(3)
95.1(2)
lengths and angles in their molecular structures are very similar
to those of 9 and 10 with minor differences in the substituted
group of the thiourea moiety.
Hydrolysis of the ester H3L−COOEt in a MeOH solution of
NaOH gave the salt Na4L−COO, which was subsequently
treated with the exact amount of aqueous HCl required to
obtain the acidic form of the ligand, H3L−COOH. The yield of
the hydrolysis is almost quantitative, and no side-reactions were
detected. The IR spectrum of H3L−COOH is similar to that
discussed for H3L−COOEt except for a slight bathochromic
shift of about 5 cm−1 for the absorption band of the CO
1
vibrations. In the H NMR spectrum of H3L−COOH, the
absence of resonances of the ethyl ester group is observed. The
other signals appear in the same region as those in the spectrum
of H3L−COOEt.
Figure 3. Molecular structure of [ReO(L−COOEt)] (11). Hydrogen
atoms were omitted for clarity.
H
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1
Figure 4. H NMR spectrum of (a) [ReO(L−COOEt)] (11) and (b) [ReO(L−COOH)] (13).
Scheme 5. Coupling Reaction of [ReO(L−COOH)] with Triglycine Ethyl Ester and Formation of 14
Like the H3L−COOEt ligand, H3L−COOH readily reacts
with (NBu4)[ReOCl4] in MeOH after addition of Et3N. This is
indicated by an immediate change of the color of the reaction
mixture from which a violet solid of the composition [ReO(L−
COOH)] (13) was directly isolated. The amount of base,
which is added, must not exceed 3 equiv of (NBu4)[ReOCl4],
to minimize the formation of the anion [ReO(L−COO)]−,
which is soluble in MeOH. Many attempts to obtain high-
quality single crystals of 13 for an X-ray structure study failed.
However, the structure of 13, which is similar to that of 11, can
readily be derived from the spectroscopic data.
The additional carboxylic group in the periphery of ligand
H3L−COOH is intended to act as a linker to couple its
rhenium or technetium complexes to bioactive compounds
such as peptides. For this purpose, we can consider two
alternative routes. In the first approach, the free ligand is
coupled to a targeting compound before being treated with the
(radioactive) metal ions. This approach follows the classical kit-
preparation of 99mTc radiopharmaceuticals and will give “one
kit−one target” solutions. In the second approach, a two-step
solution, the radioactive chelate is prepared first as a
“bioconjucation kit” and treated with the suitable biomolecule
in a subsequent step. This, however, requires a chemically
robust chelate and ideally the opportunity of an even rough
separation of the preformed chelate from the bulk chelator to
ensure an effective bioconjugation in the carrier-free tracer
chemistry. On the other hand, such a “bioconjugation kit”
would deliver a “one complex−many targets” solution on the
basis of an optimized metal chelate.
A very broad band between 3450 and 2500 cm−1 remains in
the IR spectrum of 13 and confirms the existence of the free
carboxylic group of the thiourea site. The other structural
features are similar to those of compound 11. The individual
assignments of the bands are given in the Experimental Section.
1
A part of the H NMR spectra of 11 and 13 are compared in
1
Figure 4. The H NMR spectrum of 13 expectedly does not
The ligand system introduced in this Article is not
particularly suitable for the first approach of bioconjugation,
because the presence of three carboxylic groups in H3L−
COOH would require a complicated protection of those of the
iminodiacetic acid site before conjugation to, for example, a
peptide. For the second approach, however, the very stable
show any signals of ethyl ester protons, but reveals a broad
signal at 13.24 ppm, which is typical for OH protons of
carboxylic groups. The other resonances of 13 have almost the
same chemical shifts as those in 11. This strongly confirms the
analogous structures of the two compounds.
I
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1
Figure 5. H NMR spectrum of [ReO(L−TriGlyCOOEt)] (14).
metal chelate seems to be well suitable, because the
iminodiacetic moiety is blocked by the formation of
coordination bonds and the remaining carboxylic group of
phenyl residue can selectively react with biomolecules. Thus,
we undertook a “proof-of-principle” experiment. For this, a
small peptide such as triglycine ethyl ester was used. The
reaction of 13 and triglycine ethyl ester was done in dry DMF
at room temperature with the addition of a slight excess of
N,N′-dicyclohexylcarbodiimide (DCC) and N-hydroxybenzo-
triazole (HOBT) to give the coupling product [ReO(L−
TriGlyCOOEt)] (14) with yields of over 95% (Scheme 5).
Compound 14 is sparingly soluble in alcohol, CH2Cl2, or
CHCl3, but soluble and stable in DMF or DMSO solutions.
Good quality single crystals of 14 could not be obtained, but
the structure of 14 is clearly elucidated by means of
spectroscopic methods.
centers. The use of this new class of compounds in further
experiments, particularly such as the synthesis of bioconjugates
with 186,188Re or 99mTc, is planned for the future in collaboration
with partner researchers, because such studies are presently not
possible in our laboratories.
ASSOCIATED CONTENT
* Supporting Information
■
S
X-ray crystallographic data in CIF format. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/acs.inorgchem.5b00769.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: nguyenhunghuy@hus.edu.vn.
*E-mail: ulrich.abram@fu-berlin.de.
■
The IR spectrum of 14 exhibits a strong absorption at 3325
cm−1 corresponding to the NH stretches of the triglycine
residue. The spectral features belonging to the skeleton of the
Notes
The authors declare no competing financial interest.
1
rhenium complex are identical to those in 13. The H NMR
ACKNOWLEDGMENTS
■
spectrum of 14 (Figure 5) additionally confirms the presence of
the triglycine ethyl ester by a triplet at 1.17 ppm and a quartet
at 4.07 ppm belonging to ethyl ester protons, and three
doublets at 3.75, 3.84, and 3.93 ppm and three triplets at 8.24,
8.29, and 8.99 ppm corresponding to the CH2 and NH
resonances, respectively. Moreover, the complex formation is
clearly indicated by the presence of six doublets of the CH2
protons of the chelate ring, which appear at 4.06 (overlapped
with OCH2 of the ethyl ester group), 4.43, 4.77, 4.89, 5.27, and
5.71 ppm with characteristic geminal coupling patterns.
Additionally, the high-resolution mass spectrum of 14 shows
only intense peaks at 956.1718 and 972.1576 corresponding to
ions [M + Na]+ (calcd 956.1699) and [M + K]+ (calcd
972.1439).
We gratefully acknowledge financial support from DAAD
(Deutscher Akademischer Austauschdienst, Germany) and
NAFOSTED (Vietnam’s National Foundation for Science
and Technology Development) through project 104.02-
2012.76.
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CONCLUSIONS
■
The pentadentate H3L is the first representative of a novel,
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of stable complexes with rhenium(V) and technetium(V)
J
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