DSpace at VNU: (ReO)-O-V and (ReNPh)-N-V complexes with pentadentate benzamidines - Synthesis, structural characterization and DFT evaluation of isomeric complexes

DSpace at VNU: (ReO)-O-V and (ReNPh)-N-V complexes with pentadentate benzamidines - Synthesis, structural characterizati...

Accepted Manuscript

ReVO and ReVNPh Complexes with Pentadentate Benzamidines – Synthesis,

Structural Characterization and DFT Evaluation of Isomeric Complexes

Hung Huy Nguyen, Pham Chien Thang, Ulrich Abram

To appear in: Polyhedron

Received Date: 28 June 2015

Accepted Date: 31 July 2015

Please cite this article as: H Huy Nguyen, P Chien Thang, U Abram, ReVO and ReVNPh Complexes withPentadentate Benzamidines – Synthesis, Structural Characterization and DFT Evaluation of Isomeric Complexes,

Polyhedron (2015), doi: http://dx.doi.org/10.1016/j.poly.2015.07.079

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Re O and Re NPh Complexes with Pentadentate Benzamidines – Synthesis,

Structural Characterization and DFT Evaluation of Isomeric Complexes

Hung Huy Nguyen,a)* Pham Chien Thang,b) Ulrich Abramb)*

a)Department of Chemistry, Hanoi University of Science, 19 Le Thanh Tong, Hanoi, Vietnam

procedure They can be prepared by reactions of 2-aminobenzyliminodiacetic acid

diethylester with N,N-[(dialkylamino)(thiocarbonyl)]benzimidoyl chlorides and subsequent

hydrolysis The ligands react with [ReOCl3(PPh3)2] or [Re(NPh)Cl3(PPh3)2] under triple deprotonation and form compounds of the general compositions [ReO(L)] and [Re(NPh)(L)], respectively The organic ligands occupy the remaining five coordination positions of the {ReO}3+ and {Re(NPh)}3+ cores in all compounds studied The phenylimido complexes hydrolyze in basic media under formation of their oxidorhenium(V) analogs

Keywords: Rhenium, Pentadentate ligands, Oxido complexes, Imido complexes, X-ray structure, DFT

Corresponding Autors: nguyenhunghuy@hus.edu.vn (Hung Huy Nguyen)

ulrich.abram@fu-berlin.de (Ulrich Abram)

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1 Introduction

Beside several other applications, rhenium compounds currently attract interest because

of potential applications of complexes of the isotopes 186Re and 188Re in radiotherapy [1-6] Additionally, coordination compounds of rhenium are frequently used as non-radioactive models for development of technetium radiopharmaceuticals [7] In this context, there is a permanent need for efficient chelating systems, which form stable and/or kinetically inert complexes with rhenium or technetium [8] Such a robust coordination sphere is a

‘chemical pre-requisite’ for resisting the competition of other potential ligand systems, which are present in all biological fluids in a huge amount and will meet them on their way

to the target organ Pentadentate ligands should be ideal chelators for the stabilization of the frequently formed {ReO}3+ core and its analogous phenylimido {ReNPh}3+ core Nevertheless, hitherto there is only a limited number of structurally well-characterized rhenium or technetium complexes with pentadentate ligands reported and particularly such compounds were not in the focus of related nuclearmedical research [9-13] This may possibly be understood by the fact that the syntheses of pentadentate ligands are frequently related to multi-step procedures, which are too time-consuming for the preparation of only one single molecule with uncertain biodistribution features In the light of another strategy, which focuses on the synthesis of a ‘bioconjugation kit’ [14], however, any effort in the synthesis of a robust ‘multi-use ligand’ seems to be justified Following this approach, first

99mTc or 186,188Re complexes with a strong chelator (having an anchor group in its periphery) are produced This pre-formed radioactive label can then be coupled in a second step with arbitrary peptide-based biomolecules

Recently, we reported about such a pentadentate ligand system based on thiocarbamoylbenzamidines, which provides an anchor for the coupling of peptides, and its

rhenium and technetium complexes (H3L and [M(L*)] in Scheme 1) [14] Such multidentate ligands can be prepared from benzimidoyl chlorides and functionalized primary amines [14-17]

In the present work, we report about the syntheses of similar pentadentate dialkylamino(thiocarbonyl)benzamidines (H3LMorph, and H3LEt), which are expected to form more stable complexes with {ReO}3+ and {ReNPh}3+ cores

2 Results and Discussion

2.1 Computational Studies

In order to optimize the coordination abilities of the pentadentate benzamidines by a further increase of the stability of the formed chelates, we searched for alternative ligands With regard to the time-consuming syntheses, we decided to estimate the potential of another promising candidate of a pentadentate ligand (H3L) first by DFT calculations [18]

H3L* and H3L are related ligand systems They provide the same donor atom constellations,

but with a replaced CH spacer in their backbone (Scheme 1) Thus, we calculated the

over-Scheme 1. Pentadentate benzamidines and their ReO complexes

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all energies for optimized geometries of the diethyl derivatives [ReO(L*Et)] and [ReO(LEt)] The results of the geometrical optimization obtained for [ReO(L*Et)] can directly be compared with the X-ray data of the compound, which are contained contained in ref 14 The optimized parameters are in good agreement with the experimental ones The bond lengths differ by less than 0.04 Å, whereas the angles by 4 o or less A Table with details of the experimental and calculated structural data is contained in the Supplementary Material

On the basis of the good agreement between the experimental and calculated data for [ReO(L*Et)], we extended the calculations to the complex [ReO(LEt)] in order to estimate stabilizing or destabilizing effects due to the modifications in the coordination sphere of the metal A comparison of the energies of optimized structures of the two structural isomers [ReO(L*Et)] and [ReO(LEt)] strongly suggests that the latter compound is more stable by a

value of about 22 – 23 kJ/mol This energetic difference is nearly independent of the employed DFT methods as well as of the basis set combinations (Table 1) These facts together with the slight discrepancy between the experimental and optimized bonding parameters in [ReO(L*Et) underlines the reliability of performed DFT calculations and

Table 1. Energies of optimized geometries of [ReO(LEt)] and [ReO(L*Et)] at different levels of DFT

Re C,H,N,O,S method [ReO(LEt)] [ReO(L*Et)] kJ/mol LANL2DZ 6-31G* PBE0

B3LYP -1961.73297 -1961.72425 -1963.57025 -1963.56175 -22.89 -22.31 LANL2DZ 6-31G** PBE0

B3LYP

-1961.76982 -1961.76122 -1963.60699 -1963.59860

-22.57 -22.04 LANL2TZ 6-31G** PBE0

B3LYP -1961.79351 -1961.78475 -1963.63174 -1963.62318 -22.99 -22.46 [a] ∆E = E[ReO(L)] – E[ReO(L*)]

2-nitroben-of 1 The disubstituted product is formed almost quantitatively within 10 h when an excess

of 25% bromoacetic acid ethylester is used It should be mentioned that a similar procedure with aromatic amines requires more drastic conditions [14]

The reduction of the nitro group of 1 can be performed either by H2 gas with a Pd/C catalyst or with Raney nickel in an ethylacetate/methanol mixture The first reaction must

be quenched after 5 h in order to minimize the formation of side-products due to the

cleavage of the N-benzyl bond and gives an overall yield of 55% after purification by

column chromatography (silica gel) with ethyl acetate/n-hexane (1:1) More effective is the

Scheme 2. The synthesis of the pentadentate ligand H3L

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use of the Raney nickel The reduction proceeds slowly but is much cleaner under the same conditions After 24 h, the reaction is complete and no side-products can be detected by NMR spectroscopy The final ligands H3L are best prepared by reactions of 2 with the corresponding benzimidoyl chlorides to form 3 and subsequent hydrolysis of these

compounds with NaOH in methanol Neutralization of the products of such reactions with citric acid gives the pentadendate ligands H3L in high yields An alternative route, which contains the hydrolysis of the ester in the first step produces a number side products due to the low solubility of the dicarboxylic acid in non-alcoholic solvents such as THF or acetone, which are normally used for preparation of benzamidine ligands [14,19,20]

The IR spectra of H3L show strong, broad bands for the νOH stretches in the region between

3500 cm-1 and 2500 cm-1 Very strong absorptions around 1720 cm-1 are assigned to νC=O

vibrations, which are well separated from the strong absorptions of the νC=N stretches in the

1616 cm-1 region [21-24] The 1H NMR spectra of H3L are characterized by two singlets around 3.45 ppm and 4.00 ppm, which are assigned to the methylene protons of NCH2CO and PhCH2N, respectively Broad singlets at 9.40 ppm and 11.50 ppm belong to NH and COOH resonances The hindered rotation around the CS-NR1R2 bonds, which is found for many thiocarbamoylbenzamidines, is also observed for H3L This results in magnetic

inequality of the two residues R, and consequently the 1H NMR spectrum of H3LMorph

shows two overlapping signals with complex coupling patterns of two NCH2 groups and two OCH2 groups of the morpholine residue In the case of H3LEt, two set of well resolved signals corresponding two ethyl groups of -NEt2 residue are observed The +ESI mass spectra of the ligands show clear patterns with expected molecular ion [M+H]+ peaks and confirm their composition unambiguously

2.3 Oxidorhenium(V) complexes

Representatives of the novel ligand system H3L react with the sparingly soluble starting material [ReOCl3(PPh3)2] in MeOH/CH2Cl2 under formation of red crystalline solids of the

composition [ReO(L)] (4) in high yields (Scheme 3) The reactions are slow at ambient

temperature, but can be accelerated by the addition of a supporting base such as Et3N and

heating The products are readily soluble in DMSO or DMF, less soluble in CH2Cl2 or CHCl3 and almost insoluble in alcohols

The IR spectra of 4 show no bands of OH or NH stretches, which reflects the presence of

the triply deprotonated forms of the ligands Additionally, the shift of the νC=N band from about 1615 cm-1 in the spectra of the uncoordinated compounds to the region around

1535 cm-1 indicates the formation of a benzamidinate chelate ring Two different absorptions of νC=O stretches are observed around 1713 cm-1 and 1696 cm-1 and can be assigned to the two nonequivalent carboxylate groups in the molecules The presence of Re=O bonds is confirmed by strong absorptions at 964 cm-1 for 4 Morph and at 962 cm-1 for

4 Et They appear in the expected range for octahedral ReVO complexes with trans O=Re-O arrangement [7,25,26]

The 1H NMR spectra of 4 in DMSO-d6 are characterized by three pairs of doublets with typical geminal coupling constants corresponding to the protons of three methylene groups

in the chelate rings While the two PhCH2N protons resonate at 3.65 and 3.71 ppm, the

Scheme 3. Reaction of H3L with [ReOCl3(PPh3)2]

resonances of the four COCH2N protons appear in the range between 4.6 ppm to 5.6 ppm The rigid structure of NR1R2 residues in corresponding thiocarbamoylbenzamidine

complexes has previously been reported and is also observed in 4 [14,25].In the 1H NMR

spectrum of 4 Morph, four signals, two broadened doublets at 3.89 ppm and 3.97 ppm and another two overlapped in a multiplet at 3.84 ppm, corresponding to the four NCH2

protons are observed Those of the four OCH2 protons give two broadened doublets at 4.30 and 4.51 ppm and a multiplet at 4.58 ppm Similarly, the rigid structure of NEt2 results in four magnetically unequalent CH2 protons, which correspond to four well-resolved double

quartets with a geminal coupling constant of J 1 = 14 Hz and a vicinal coupling constant of

J2 = 7.0 Hz The 1H NMR spectra of 4 recorded in DMSO-d6 are quite different from those recorded in CDCl3 with respect to the chemical shift of the NR1R2 residues and the CH2

protons in the chelate rings In the case of complex 4 Morph, the spectrum in CDCl3 shows an overlapped multiplet at 3.92 ppm, which is assigned to four NCH2 protons, and two well separated multiplets at 4.22 ppm, 4.36 ppm and one overlapping multiplet at 4.51 ppm, which are assigned to the four OCH2 protons in the morpholinyl residue

Figure 1 depicts the molecular structure of 4 Morph Some important bond lengths and angles are summarized in Table 2 The rhenium atom has adopted a distorted octahedral

Figure 1. Molecular structure of [ReO(LMorph)] (4 Morph) [32] Hydrogen atoms are omitted for clarity

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coordination environment, in which five positions of the coordination sphere are occupied

by the donor atoms of the ligand {LMorph}3- and the remaining position is occupied by a

terminal oxido ligand The molecular structure of 4 Morph confirms the presence of the triply

deprotonated form of the organic ligand One of the carboxylic groups (O68) is in trans position to the oxido ligand, while O64 occupies a cis position This is consistent with the

two C=O bands observed in the IR spectrum of 4 Morph The Re-O68 bond length is slightly shorter than the Re-O64 distance, reflecting some transfer of electron density from the rhenium oxygen double bond to this bond [26,27].The partial double bond character of the C4–N5 bond may make the six-membered chelate ring containing the aminobenzylamine

unit rigid and, thus, it is prevented from switching between boat and chair conformation as

is suggested by the splitting of PhCH2N signals of the ring in the 1H-NMR spectrum of the compound

2.3 Phenylimidorhenium(V) complexes with H3L

The rhenium(V) phenylimido core, which is isoelectronic with the rhenium(V) oxido core,

is expectedly also stabilized by the H3L chelator system However, reactions of H3L with

Table 2. Selected experimental bond lengths (Å) and angles (deg) in [ReO(LMorph)] (4 Morph)

O10–Re– S1 103.4(2) O10–Re–O64 94.8(3) N5–Re–O64 166.2(3) O10–Re–N5 95.8(3) O10–Re–O68 164.4(3) S1–Re–N5 94.6(2) O10–Re–N8 88.2(3) S1–Re–N8 165.4(2) N8–Re–N5 93.0(3)

Heating of the reaction mixture for a prolonged reaction time results in a complete

hydrolysis of 5 and the formation of 4 as the sole product Despite the fact that the addition

of a base like Et3N accelerates the hydrolysis of 5, its addition was required for the

deprotonation of H3L in a reasonable time While compound 5 Et seems to hydrolyze very quickly and could only be detected in the reaction mixture by MS spectroscopy, the

hydrolysis of 5 Morph was slow The pure complex 5 Morph can be obtained by a chromatographic purification (silica gel, CHCl3/hexane) of the product mixture obtained at ambient temperatures A similar hydrolysis has been observed before for reactions of [Re(NPh)Cl3(PPh3)2] with ligands of the type H3L* (Scheme 1) In this case, any attempts

to isolate the phenylimido species failed, and only the oxido complexes were obtained in good yields [14] It is worth to notice that without a base, no hydrolysis of the complex

5 Morph could be detected in the solution

The IR spectrum of 5 Morph is characterized by very strong, broad absorptions at 1700 cm-1, which are typical for coordinated carboxylate groups A strong bathochromic shift of the

νC=N band is also observed The 1H NMR spectrum of 5 Morph has principally the same

Scheme 4. Reaction of H3L with [Re(NPh)Cl3(PPh3)2]

pattern as that of 4 except the additional aromatic signals, which belong to the phenylimido ligand

Single crystals of 5 Morph suitable for an X-ray study were obtained by slow evaporation

of CH2Cl2/n-hexane mixtures Figure 2 illustrates the molecular structure of this compound Selected bond lengths and angles are given in Table 3 The structure reveals a distorted octahedral environment around the rhenium atom containing the coordinated

Figure 2. Molecular structure of [Re(NPh)(LMorph)] (5 Morph) [32] Hydrogen atoms are omitted for clarity

Table 3. Selected experimental bond lengths (Å) and angles (deg) in [Re(NPh)(LMorph)]

(5 Morph)

N10–Re– S1 97.8(4) N10–Re–O64 88.9(4) N5–Re–O64 166.2(4) N10–Re–N5 101.3(4) N10–Re–O68 168.6(4) S1–Re–N5 93.6(3) N10–Re–N8 94.4(4) S1–Re–N8 165.1(3) N8–Re–N5 92.4(4)

{LMorph}3- as triply deprotonated, pentadentate ligand as discussed for the corresponding

oxido complex 4 Morph The remaining position in the octahedral sphere is occupied by a

phenylimido ligand, which is coordinated in trans position to one of the carboxylate groups

The Re–N–C bond of the phenylimido ligand is almost linear with a value of 167.3(9)o The

Re-N10 bond length of 1.69(1) Å in 5 Morph is in the expected range of rhenium-nitrogen double bonds [7].The bonding situation inside the ligand {L}3- of the complexes 5 Morph is generally similar to that of the oxido compound

3 Conclusions

The pentadentate ligand H3L, which has been developed by a computer-aided procedure

is well suitable for the formation of stable complexes with the {ReO}3+ core It could be demonstrated that minor modifications in the skeleton of such pentadentate ligands may have marked influence on the stability of the formed complexes

The optimized ligands are good candidates as chelating units for ‘bioconjucation kits’ on the basis of {ReO}3+ or {TcO}3+ complexes A possible position for the bioconjugation is shown in Scheme 5 Corresponding studies for the synthesis of such ligands, which possess

a suitable anchor group for the coupling of a peptide-based biomolecule, and their rhenium and technetium complexes are planed for the future in our laboratories

Scheme 5. Derivative of H3L with an anchor group for bioconjugation

N,N-[(diethylamino)(thiocarbonyl)]benzimidoyl chloride and nyl)]benzimidoyl chloride were performed by the procedure of Beyer et al [30]

[(morpholinyl)(thiocarbo-4.2 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 Positive ESI mass spectra were measured with an Agilent 6210 ESI-TOF (Agilent Technology) mass spectrometer All MS results are given in the form: m/z, assignment Elemental analysis of carbon, hydrogen, nitrogen and sulfur were determined using a Heraeus vario EL elemental analyzer

4.3 Syntheses of the ligands

4.3.1 2-Nitrobenzyliminodiacetic acid diethylester (1)

2-Nitrobenzylamine (6.086 g, 40 mmol), ethyl bromoacetate (11.0 mL, 99 mmol), a mixture of finely powdered K2CO3 (16.8 g, 122 mmol), KI (1.0 g) and 100 mL of dry MeCN were heated under reflux for 10 h After being cooled to room temperature, the mixture was filtered and the solvent was removed under reduced pressure The excess of ethyl bromoacetate was removed by heating the mixture to 80oC under a pressure of about

20 mmHg The product was obtained as a slightly yellow oil Yield 96 % (12.45 g) Elemental analysis: Calcd for C15H20N2O6: C, 55.55; H, 6.22; N, 8.64% Found: C, 55.36;

H, 6.31; N, 8.51% 1H NMR (400 MHz, CDCl3, ppm): 1.25 (t, J = 7.1 Hz, 6H, CH2CH3),