Synthesis, characterization, catalytic and antiamoebic activity of vanadium complexes of binucleating bis(dibasic tridentate ONS donor) ligand systems

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FULL PAPER

DOI: 10.1002/ejic.201200012

Synthesis, Characterization, Catalytic and Antiamoebic Activity of Vanadium

Complexes of Binucleating Bis(dibasic tridentate ONS donor) Ligand Systems

Mannar R. Maurya,*^[a]Chanchal Haldar,^[a]Aftab Alam Khan,^[a]Amir Azam,^[b]

Attar Salahuddin,^[b]Amit Kumar,^[c]and Joao Costa Pessoa*^[c]

Keywords: Vanadium / Enzyme models / Antiprotozoal agents / Hydrazones / EPR spectroscopy / NMR spectroscopy

[V^IVO(acac)₂] (acac = acetylacetonate) was treated with li-

gands CH₂(H₂L)₂in methanol heated at reflux to yield two

neutral binuclear V^IVcomplexes with the formula

ethane, 1-phenylethane-1,2-diol and 2-bromo-1-phenyl-

ethane-1-ol, and of salicylaldehyde to yield 5-bromosalicylal-

dehyde, 3,5-dibromosalicylaldehyde and 2,4,6-tribromo-

phenol; they therefore act as functional models of vanadium-

dependent haloperoxidases. It is also shown that

Cs₂[CH₂{V^VO₂(sal-sbdt)}₂]·2H₂O (4) and Cs₂[CH₂{V^VO₂(sal-

smdt)}₂]·2H₂O (6) are catalyst precursors for the catalytic oxi-

[CH₂{V^IVOL(H₂O)}₂], namely, 1 and 2. Ligands CH₂(H₂L)₂

I

and II were derived from 5,5Ј-methylenebis(salicylaldehyde)

and S-benzyldithiocarbazate [CH₂(H₂sal-sbdt)₂, I] or S-meth-

yldithiocarbazate [CH₂(H₂sal-smdt)₂, II]. Aerial oxidation of

1 and 2 in the presence of KOH or CsOH·H₂O resulted in the dation of styrene by peroxide to yield styrene oxide, benzal-

formation of dioxidovanadium(V) complexes, K₂[CH₂-

dehyde, 1-phenylethane-1,2-diol, benzoic acid and phenyl-

acetaldehyde. Plausible intermediates involved in these cata-

lytic processes were established by UV/Vis, EPR and ⁵¹V

NMR spectroscopic studies. The V^VO₂complexes along with

ligands I and II were also screened against HM1:1MSS

strains of Entamoeba histolytica; the IC₅₀values of com-

pounds 3, 4 and 5 were significantly lower than that of metro-

nidazole, thereby suggesting that they may be promising

drugs for the treatment of amoebiasis.

{V^VO₂(sal-sbdt)}₂]·2H₂O Cs₂[CH₂{V^VO₂(sal-sbdt)}₂]·

(3),

2H₂O (4), K₂[CH₂{V^VO₂(sal-smdt)}₂]·2H₂O (5) and Cs₂[CH₂-

{V^VO₂(sal-smdt)}₂]·2H₂O (6). The compounds were charac-

terized in the solid state and in solution, namely, by spectro-

scopic techniques (IR, UV/Vis, EPR, ¹H, ¹³C and ⁵¹V NMR

spectroscopy). It is demonstrated that the V^VO₂complexes

3–6 are efficient and selective towards the oxidative bromin-

ation by H₂O₂of styrene to yield 1,2-dibromo-1-phenyl-

substrates.^[5–8]Homogeneous vanadium (IV and V) com-

plexes as well as their immobilized analogues also catalyze

other organic reactions such as the epoxidation of alk-

enes,^[11–14]the hydroxylation of hydrocarbons,^[15]hydro-

and oxidative amination^[16]and the oxidation of alcohols to

aldehydes and ketones,^[17,18]thus showing their influence on

the yield and selectivity in chemical transformations.

Prospective therapeutic applications of vanadium com-

pounds, particularly in the treatment of Diabetes mellitus

and cancer, and more recently in vitro antiamoebic activity

against Entamoeba histolytica and antitrypanosomal ac-

tivity against Trypanosoma cruzi, have also stimulated fur-

ther developments in the coordination chemistry of vana-

dium.^[3,19]Among all parasites, the intestinal parasite Enta-

moeba histolytica, which affects millions of people world-

wide and especially those in tropical developing countries,

is responsible for amoebic colitis and amoebic liver ab-

scesses. The World Health Organization in its most recent

estimates has placed the death toll from amoebiasis at

40000–100000 lives annually. Approximately 90% of

patients with mild to moderate amoebic dysentery respond

to metronidazole (MNZ), an important drug that is applied

in treatments.^[20–22]However, this drug causes several side

Introduction

Interest in the coordination chemistry of vanadium, with

particular emphasis on its biological,^[1–3]structural^[2,4]and

catalytic properties^[5–8]has increased over the past two

decades. Vanadate-dependent haloperoxidase enzymes

(VHPO)^[9]and the covalent bonding of the imidazole moi-

ety of a histidine residue through N^εto vanadate in the

active site have stimulated the design of structural mod-

els.^[10]These structural models have been extended to func-

tional similarities in that vanadium complexes also model

the oxidative halogenation and sulfoxidation of organic

[a] Department of Chemistry, Indian Institute of Technology

Roorkee,

Roorkee 247667, India

Fax: +91-1332-273560

E-mail: rkmanfcy@iitr.ernet.in

[b] Department of Chemistry, Jamia Millia Islamia,

Jamia Nagar, New Delhi 100025, India

[c] Centro de Química Estrutural, Instituto Superior Técnico,

Technical University of Lisbon,

Av Rovisco Pais, 1049-001 Lisboa, Portugal

Fax: +351-21-8464455

E-mail: joao.pessoa@ist.utl.pt

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejic.201200012.

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M. R. Maurya, J. Costa Pessoa et al.

FULL PAPER

effects in patients. MNZ also induces certain tumours in

rodents and is mutagenic towards bacteria.^[23–27]Therefore,

research on the new drugs for the treatment is a relevant

therapeutic demand.

(1)

Dioxidovanadium(V) complexes of ONO, ONN and

ONS donor ligands have shown very convincing results on

the in vitro activity against Entamoeba histolytica.^[28,29]We

recently described binuclear V^IVO and V^VO₂complexes of

binucleating bis(dibasic tridentate ONO donor) ligands and

have studied their reactivity and catalytic and antiamoebic

activity.^[29]Their good reactivity patterns and catalytic and

antiamoebic activity encouraged us to consider binucleating

bis(dibasic tridentate ONS donor) ligands, and we now de-

scribe the synthesis and characterization of binuclear V^IVO

and V^VO₂complexes of ligands I and II derived from 5,5Ј-

methylenebis(salicylaldehyde) [CH₂(Hsal)₂] and S-benzyldi-

thiocarbazate (sbdt) or S-methyldithiocarbazate (smdt;

Scheme 1).

(2)

(3)

All complexes are soluble in methanol, DMSO and

DMF. Complexes 1 and 2 exhibit magnetic moment values

of 1.73 and 1.71 μ_B, respectively, which is within the ex-

pected range reported for magnetically dilute d¹systems.

Proposed structures of these complexes (Scheme 2) are

based on their spectroscopic characterization (IR; elec-

tronic; EPR; H and ⁵¹V NMR spectroscopy) and elemen-

1

tal analyses. The ligands coordinate through each of their

dianionic (ONS)^2–thioenolate tautomeric forms.

Scheme 1. Structure of the ligands designated by I and II used in

this work.

The haloperoxidase activity was confirmed by studying

the oxidative bromination of salicylaldehyde and styrene

when using the V^VO₂complexes as catalyst precursors. In

addition, the activity for catalytic oxidations was demon-

strated through the oxidation of styrene by peroxide. The

V^VO₂complexes have also been screened against

HM1:1MSS strains of Entamoeba histolytica.

Results and Discussion

[V^IVO(acac)₂] (acac = acetylacetonate) was treated with

the binucleating ligands CH₂(H₂sal-sbdt)₂(I) or

CH₂(H₂sal-smdt)₂(II) in a 2:1 molar ratio in methanol

heated at reflux to give the binuclear oxidovanadium(IV)

complexes [CH₂{V^IVO(sal-sbdt)(H₂O)}₂] (1) and [CH₂-

{V^IVO(sal-smdt)(H₂O)}₂] (2), respectively. Oxidation of 1

and 2 in the presence of KOH or CsOH·H₂O gave the corre-

sponding V^VO₂species K₂[CH₂{V^VO₂(sal-sbdt)₂}]·2H₂O

(3), Cs₂[CH₂{V^VO₂(sal-sbdt)₂}]·2H₂O (4), Cs₂[CH₂{V^VO₂-

(sal-smdt)₂}]·2H₂O (5) and Cs₂[CH₂{V^VO₂(sal-smdt)₂}]·

2H₂O (6). These complexes were also isolated directly by

the reaction of [V^IVO(acac)₂] with I or II in a 2:1 ratio in

methanol heated at reflux followed by aerial oxidation in

the presence of the corresponding hydroxides. Here the re-

action probably proceeds through the formation of the

V^IVO complexes 1 and 2. Equations (1), (2) and (3) summa-

rize the synthetic procedures by using CH₂(H₂sal-sbdt)₂as

a representative ligand.

Scheme 2. Schematic structural formulae of the V^IVO and V^VO₂

complexes that were prepared.

2

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Vanadium Complexes of Binucleating Ligand Systems

IR Spectral Studies

probably involved in binding to K⁺/Cs⁺in the crystal struc-

ture; such binding was confirmed in anionic dioxidovanadi-

um(V) complexes.^[31,32]

The IR spectra of a representative ligand and of the cor-

responding V^VO₂complex are presented in Figure S1 in the

Supporting Information, and a partial list of IR spectro-

scopic data for ligands and complexes is presented in

Table 1. The ligands exhibit a sharp band at 1030 (I) and

1039 cm^–1(II) due to ν(C=S) and a broad weak band in the

region 3090 to 3250 cm^–1due to ν(NH). The disappearance

of these bands in the spectra of complexes indicates the

thioenolization of the ϾC=S group and coordination of

sulfur to vanadium. The presence of medium-intensity

bands at 325 (1) and 330 (2) cm^–1due to ν(V–S) gives fur-

ther evidence for the coordination of sulfur to vanadium in

Electronic Spectral Studies

Ligands I and II exhibit absorption bands at around 206,

255, 328 and 360 nm, which are assigned to φ Ǟ φ*, π Ǟ

π₁*, π Ǟ π₂*, and n Ǟ π* transitions, respectively. Similar

slightly shifted bands are also observed in the correspond-

ing complexes (Table S1 in the Supporting Information). In

addition, a new band of medium intensity appears at ap-

proximately 405 nm, which is assigned to a ligand-to-metal

charge transfer (LMCT) band.

these complexes in the solid state. The ν(C=N_azomethine

)

bands of the ligands appear at 1625 (in I) and 1624 cm^–1

(in II). These bands show up at 1609–1613 cm^–1in com-

plexes 1–6, thereby suggesting the coordination of the azo-

methine nitrogen atom. Bands that appear at 948 (in I) and

936 cm^–1(in II) are assigned to the ν(N–N) stretch. Upon

complex formation, a shift to higher frequency of the ν(N–

N) band is expected because of the diminished repulsion

between the lone pairs of adjacent nitrogen atoms,^[30]and

we assign this band to a peak that appears in the range

1027–1034 cm^–1(Table 1). The V^IVO complexes exhibit

bands at 994 (1) and 996 cm^–1(2) due to the ν(V=O)

stretch. The V^VO₂complexes exhibit one sharp band in the

884–887 cm^–1region and a weaker one at approximately

Upon dissolution, the V^IVO complexes have a tendency

to hydrolize and oxidize (see below). Three bands at 575,

680 and 845 nm (in 1) and at 565, 675 and 875 nm (in 2),

observed at higher concentration, are assigned to d–d tran-

sitions. However, it is probable that these bands might be

due to the presence of more than one type of V^IVO complex

in solution. For the V^VO₂complexes no such bands were

detected.

¹H NMR Spectroscopic Studies

1

Table 2 summarizes data of the H NMR spectra of the

928–939 cm^–1due to ν_sym(O=V=O) and ν_asym(O=V=O). ligands and V^VO₂complexes, whereas Figure S2 in the Sup-

These bands confirm the cis-V^VO₂structure in the com- porting Information presents the representative H NMR

1

plexes.^[4]The weakening of one of the bands may be consid- spectra of II and of complex 6. The H NMR spectra of

1

ered to suggest that the O atoms of the V^VO₂units are ligands exhibit singlets at δ = 13.35 ppm (I) and at δ =

13.32 ppm (II) due to phenolic protons. The absence of this

signal in the complexes indicates the coordination of the

phenolate oxygen atoms. Similarly, the disappearance of the

signals that appear at δ = 10.10 ppm (I) and δ = 10.11 ppm

Table 1. IR data of the compounds prepared (ν in cm^–1) and the

corresponding assignments.

˜

Compounds

ν(C=S) ν(C=N) ν(V=O) ν(N–N)

(II) due to –NH protons is in agreement with the thioenoliz-

ation of the thione group in ligands and subsequent replace-

ment of hydrogen atoms by the metal ion. A significant

downfield shift [CIS (Δδ) = 0.51–0.53 ppm] (CIS = chemi-

cal-induced shift) of the azomethine (–CH=N–) proton sig-

nal of the complexes with respect to the corresponding free

ligands confirms the coordination of the azomethine nitro-

gen. The signal, which is due to the –CH₂– group attached

CH₂(H₂sal-sbdt)₂(I)

CH₂(H₂sal-smdt)₂(II)

1030

1039

1625

1624

1609

1613

1612

1609

1612

948

936

1034

[CH₂{V^IVO(sal-sbdt)(H₂O)}₂] (1)

K₂[CH₂{V^VO₂(sal-sbdt)}₂]·2H₂O (3)

Cs₂[CH₂{V^VO₂(sal-sbdt)}₂]·2H₂O (4)

[CH₂{V^IVO(sal-smdt)(H₂O)}₂] (2)

K₂[CH₂{V^VO₂(sal-smdt)}₂]·2H₂O (5)

Cs₂[CH₂{V^VO₂(sal-smdt)}₂]·2H₂O (6)

994

884, 935 1027

887, 928 1027

1034

886, 939 1030

887, 927 1033

996

1

Table 2. H NMR spectroscopic data (δ in ppm) of ligands and complexes recorded in [D₆]DMSO.

Compd.^[a,b]–CH=N–

Aromatic H

–CH₂–

–OH

–NH

–SCH₂–

–CH₃

I

3

(Δδ)

4

(Δδ)

II

8.50(s, 2 H) 6.80 (d, 2 H), 7.50 (d, 2 H), 7.35 (m, 12 H) 3.75 (s, 2 H) 13.35 (s, 2 H) 10.10 (s, 2 H) 4.50 (s, 4 H)

9.02(s, 2 H) 6.78(d, 2 H), 7.0–7.80(m, 14 H)

(0.52)

3.89(s, 2 H)

(0.14)

4.39(s, 4 H)

(–0.11)

9.03 (s, 2 H) 6.77 (d, 2 H), 7.35–7.75 (m, 14 H)

(0.53)

3.89 (s, 2 H)

(0.14)

4.39 (s, 4 H)

(–0.11)

8.45 (s, 2 H) 6.8 (d, 2 H), 7.4 (d, 2 H), 7.55 (d, 2 H)

3.80 (s, 2 H) 13.32 (s, 2 H) 10.11 (s, 2 H)

2.5 (s, 6 H)

2.50 (s, 6 H)

(0.03)

2.50 (s, 6 H)

(0.03)

5

(Δδ)

6

8.96 (s, 2 H) 6.77 (d, 2 H), 7.26 (d, 2 H), 7.51 (d, 2 H)

(0.51)

8.96 (s, 2 H) 6.7 (d, 2 H), 7.26 (d, 2 H), 7.50 (d, 2 H)

(0.52)

3.87 (s, 2 H)

(0.07)

3.86 (s, 2 H)

(0.08)

(Δδ)

[a] Letters given in parentheses indicate the signal structure: s = singlet, br. = broad (unresolved), m = multiplet. [b] Δδ = δ(complex) –

δ(ligand).

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to two aromatic rings in ligands as well as in complexes, donors, otherwise probably the peak would be detected at

appears at nearly the same position (Δδ = 0.08–0.14 ppm), lower fields. The minor resonance at δ = –495 ppm is tenta-

and this suggests that the two Schiff base units remain at- tively assigned to species CIII in which the S_thiolateis not

tached in solution as well. Other resonances due to –SCH₂– coordinated to the V^Vcentre; the chemical shift corre-

protons (singlet), –SCH₃protons (singlet) and aromatic sponds to ONO coordination. Upon the stepwise addition

protons (complex multiplets) in the complexes also appear of an aqueous 30% solution of H₂O₂to the solution of 4

in almost the same positions as in the respective ligands. in DMSO (ca. 4 mm), the resonance at δ = –463 ppm pro-

1

The H NMR spectroscopic data are thus consistent with gressively decreases its intensity and a resonance at δ =

the ONS dibasic tridentate binding mode of each unit of –521 ppm progressively develops (Figure 1, b–e), which we

ligands I and II.

tentatively assign to [CH₂{V^VO(O₂)(sal-sbdt)(Sv)}₂]^2–(CV;

at least one of the V^Vcentres has a coordinated peroxide

ligand).

¹³C NMR Spectroscopic Studies

The ¹³C NMR spectra recorded for complexes 3 and 4

contain ten signals that correspond to the 31 carbon atoms

of the molecules and, also on account of their symmetry,

the spectra for complexes 5 and 6 contain eight signals that

correspond to 19 carbon atoms of the molecules. The peaks

observed and their assignments are included in the Sup-

porting Information (Tables S2 and S3), as they are com-

patible with the structures proposed.

⁵¹V NMR Spectroscopic Studies

Complexes 3, 4, 5 and 6 were further characterized in

solution by recording their ⁵¹V NMR spectra in [D₆]DMSO

(see Table 3). The line widths at half-height are approxi-

mately 200 Hz. The ⁵¹V NMR spectra of complexes

[CH₂{V^VO₂(ONS)}₂]^2–(4 mm) in DMSO show a major res-

onance at δ = –462/–463 ppm and a minor one at δ = –494/–

497 ppm. The ⁵¹V nucleus is thus less shielded than com-

monly observed with V^VO₂complexes with O,N-donor

atoms. However, the chemical shifts are well within the

range expected for vanadium(V) complexes where a soft S

atom participates in coordination in addition to the O- and

N-donor atoms.^[33]

Figure 1. ⁵¹V NMR spectra for solutions (ca. 4 mm) of

Cs₂[CH₂{V^VO₂(sal-sbdt)}₂]·2H₂O (4): (a) in DMSO and (b–d) after

stepwise additions of an aqueous solution of 30% H₂O₂; (b)

1.0 equiv. H₂O₂added; (c) 2 equiv. H₂O₂(total) added; (d)

4.0 equiv. H₂O₂(total) added; (e) solution of (d) after leaving the

tube open for 2 h; (f) solution of (e) after leaving the tube open for

36 h.

Table 3. Summary of the ⁵¹V NMR spectroscopic data and assign-

ment of the vanadium complexes studied in this work (see text and

Scheme 3).

The solution that corresponds to the spectrum of Fig-

ure 1 (d) was then divided in two portions. Portion (i): The

tube was left open for around 36 h. The resonance at δ =

–521 ppm almost disappeared, thereby indicating that, as

far as V^Vspecies are concerned, these were converted back

to CII, with a signal at δ = –463 ppm indicating the revers-

ibility of the process. Additionally the ⁵¹V NMR spectro-

scopic signals show broadening that indicates the probable

presence of V^IVO species in the solution. This was con-

firmed by recording the EPR spectra for both solutions

(Figure 1, f, e). The spectra are reasonably intense with rea-

sonably sharp lines, and the spin-Hamiltonian parameters

Chemical shifts [ppm]

CII

CIII

CIV

CV

CVI

3

4

5

6

–463.0

–462.0

–463.0

–495

–497

–495

–445

–448

–525

–521

–525

–553

–440

Solution Behaviour of Cs₂[CH₂{V^VO₂(sal-sbdt)}₂]·2H₂O (4)

The ⁵¹V NMR spectrum of 4 dissolved in DMSO has a obtained for the solution of Figure 1 (f) are g_ʈ= 1.974, g_Ќ

major resonance at δ = –463 ppm and a minor one at δ = = 1.934, A_Ќ= 59ϫ10^–4cm^–1and A_ʈ= 178ϫ10⁴cm^–1. This

–495 ppm (Figure 1a). The resonance at δ = –463 ppm is indicates partial hydrolysis relative to the A_ʈvalues expected

assigned to [CH₂{V^VO₂(sal-sbdt)(Sv)}₂]^2–(CII, Sv = H₂O for complex 1.

or DMSO; Scheme 3); the two V^VO₂centres are equivalent.

Portion (ii): Addition of styrene resulted in the disap-

A soft S atom participates in coordination in addition to pearance of the signal at δ = –521 ppm. The only resonance

the O and N donor atoms possibly trans to one of the O_oxidoclearly detected was found at δ = –463 ppm, thus giving

4

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Vanadium Complexes of Binucleating Ligand Systems

evidence for the involvement/consumption of the peroxo

species during the catalytic process.

Addition of acid (HCl, 11.6 m), that is, 1, 2, 3 and

4 equiv. to a solution of 4 (in DMSO, ca. 4 mm) led to a

shift of the δ = –463 ppm resonance to δ = –448 ppm (see

Figure 2); the solution turned red and the pH was approxi-

mately 4.5–5.0. The addition of acid might protonate the

oxo group and the resonance at δ = –463 ppm would pro-

gressively shift to –448 ppm (broad, ca. 98%) (Figure 2, d),

which probably corresponds to an oxido/hydroxido species

(CIV). An alternative plausible explanation for CIV is the

protonation of one of the coordinated donor atoms of the

ligand. Addition of 4 equiv. KOH to a portion of the solu-

tion of Figure 2 (d) yielded a ⁵¹V NMR spectrum with a

main signal at δ = –463 ppm, which indicated the reversibil-

ity of the processes. The other portion was left standing and

spectrum (e) was recorded.

Scheme 3. Summary of speciation of V^V-containing species in solu-

tions of 3–6. In CIV, CV and CVI either half of the V^Vcentres or

both may be present as specified. For example, CIV might corre-

spond to either [{V^VO₂(L)(Sv)}CH₂{V^VO(OH)(L)(Sv)}] or

[{V^VO(OH)(L)(Sv)}CH₂{V^VO(OH)(L)(Sv)}] (Sv = solvent). The

formation of a species involving protonation of one of the coordi-

nated donor atoms might also be a plausible assignment for CIV.

Depending on the pH, CVII (a hypobromite-containing species)

might include (or not) donor atoms from the ligand present in solu-

tion.

EPR and UV/Vis Studies

Figure 2. ⁵¹V NMR spectra for solutions of Cs₂[CH₂{V^VO₂(sal-

sbdt)}₂]·2H₂O (4): (a) in DMSO (ca. 4 mm), (b) solution of (a) after

addition of 1.0 equiv. of an aqueous solution of HCl (11.6 m), pH

≈ 5.8; (c) solution of (b) after addition of 2.0 equiv. (total) HCl; (d)

after addition of 4.0 equiv. (total) HCl (pH ≈ 3.5); (e) solution of

spectrum (d) after leaving the sample standing for about 24 h.

The EPR spectra of “frozen” solutions (77 K) in DMSO

of compounds 1 and 2 are depicted in Figure 3. The lines

show broadening due to both incomplete rotational averag-

ing of the g and A tensors and probable partial precipi-

tation of the complexes upon freezing the solutions. Appar-

ently, two sets of lines that show hyperfine splitting due to

the ⁵¹V nucleus were obtained. The spectra were simulated,

Additionally, the spectra in Figure 2 (d, e) show a broad- and the spin-Hamiltonian parameters obtained by simula-

ening of the ⁵¹V NMR spectroscopic signals, which indi- tion of the spectra are included in Table 4. EPR spectra

cates the probable presence of V^IVO species in the solution. were also recorded by passing He through the solutions of

This was confirmed by recording the EPR spectra of both 1 and 2 in DMSO in the presence of ascorbic acid, but the

solutions. Both EPR spectra are reasonably intense and the positions of the lines remained the same.

spin-Hamiltonian parameters obtained are g_ʈ= 1.974, g_Ќ

=

The values of A_ʈcan be estimated using the additivity

1.954, A_Ќ= 59ϫ10⁴cm^–1and A_ʈ= 178ϫ10⁴cm^–1for a relationship [A_ʈ^est= ΣA_ʈ,i(i = 1 to 4)] (A_ʈ,i= contribution

solution of (e). The parameters are similar to those of solu- of each of the four donor atoms coordinated equatorially)

tions of 1 in DMSO (see below), thus indicating an O₃N or proposed by Wüthrich^[34]and Chasteen^[35]with an esti-

O₄binding mode around the V^IVcentre due to the partial mated accuracy of Ϯ3ϫ10^–4cm^–1. The A_ʈvalues obtained

reduction/hydrolysis.

for 1 and 2 (Table 4) agree with the A_ʈ^estvalues calculated

Similar results were obtained in case of complexes 3, 5 from the partial contributions of the equatorial donor

and 6 (Scheme 3). The peaks observed and their assign- groups^{[29,32,35–37]}relevant in the present case [H₂O

ments are included in the Table 3 and Supporting Infor- (45.7ϫ10^–4cm^–1), O_phenolate(38.9ϫ10^–4cm^–1), N_imine(38.1

mation (Figures S3–S7), and they are compatible with the to 43.7ϫ10^–4cm^–1), O_DMSO(41.9ϫ10^–4cm^–1), S_thiolate

structural formulae proposed.

(31.9ϫ10^–4cm^–1)] either assuming an NO₃(species II) or

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Figure 3. First-derivative EPR spectra of frozen (77 K) solutions

(ca. 4 mm) (a) [CH₂{V^IVO(sal-sbdt)(H₂O)}₂] (1) in DMSO (b)

[CH₂{V^IVO(sal-smdt)(H₂O)}₂] (2) in DMSO. The solutions were

frozen after around 15 min of mixing of the solid and solvent.

Figure 4. First-derivative EPR spectra of 4 mm [CH₂{V^IVO(sal-

sbdt)(H₂O)}₂] (1) (a) in DMSO; (b) after addition of 1.0 equiv. of

H₂O₂(aqueous 30% solution), (c) after addition of a total of

2.0 equiv. of H₂O₂, (d) after addition of a total of 3.0 equiv. of

H₂O₂and (e) after addition of a total of 10 equiv. of styrene to the

solution of (d).

Table 4. Spin-Hamiltonian parameters obtained by simulation^[38]of

the experimental first-derivative EPR spectra recorded for solutions

of complexes 1 and 2 in DMSO at 77 K.

Complexes

(5 mm, DMSO)

g_ʈ

A_ʈ

g_Ќ

A_Ќ

[ϫ10^–4cm^–1]

1

2

species I

1.936 178.1

species II 1.942 164.9

species I 1.937 177.4

species II 1.942 165.4

1.976 65.0

1.977 64.9

1.976 65.1

1.976 65.2

an O₄(species I) equatorial binding set. If S_thiolateis consid-

ered to be an equatorial donor atom, the A_ʈ^estare much

lower (ca. 157ϫ10^–4cm^–1). Thus, at least in DMSO solu-

tion the S_thiolateis not bound to the V^IVcentre (at least

equatorially).

Addition of 1, 2 and 3 equiv. H₂O₂to solutions of 1 or

2 in DMSO acidifies the solutions, and V^IVO species form

(see Figure 4) with almost identical spin-Hamiltonian pa-

rameters (g_ʈ= 1.939, A_ʈ= 177.8ϫ10^–4cm^–1for 1; and g_ʈ

= 1.935, A_ʈ= 178.0ϫ10^–4cm^–1for 2). The V^IVO is also

progressively oxidized to V^V. According to the g_ʈand A_ʈ

values obtained for these partially oxidized solutions, in

these V^IVO species the equatorial binding set is probably

O₄, thus indicating the substitution of donor atoms of the

ligand by DMSO and/or H₂O molecules in the coordination

sphere.

Figure 5. ⁵¹V NMR spectra for solutions (ca. 4 mm) of complex

[CH₂{V^IVO(sal-sbdt)(H₂O)}₂] (1) (a) in DMSO and (b–d) after

stepwise additions of an aqueous solution of 30% H₂O₂: (b)

1.0 equiv. H₂O₂added, (c) 2 equiv. H₂O₂(total) added, (d)

4.0 equiv. H₂O₂(total) added and (e) solution of (d) after the ad-

dition of 10 equiv. of styrene.

The EPR spectra thus indicate that upon dissolving 1 in

Similar changes in the EPR and ⁵¹V NMR spectra have

DMSO, the V^IVcomplex partly hydrolyzes and oxidizes; in also been observed for solutions of complex 2 (4 mm) in

solution the binding set (O_phenolate

,

N_imine

,

S_thiolate

,

DMSO upon addition of H₂O₂. The spectra recorded are

O_{water equatorial}

is not detected by EPR for the V^IVO com- presented in the Supporting Information (Figures S8 and

)

plexes formed upon dissolution. The ⁵¹V NMR spectrum S9).

of this solution depicts a resonance at δ = –463 ppm (Fig-

The formation of peroxo complexes in methanol by treat-

ure 5a). The resonance at δ = –463 ppm is assigned to ment of 1 and 2 with H₂O₂was also studied by electronic

[CH₂{V^VO₂(sal-sbdt)(Sv)}₂]^2–(CII, S = H₂O or DMSO absorption spectroscopy. Thus, the addition of two drops

Scheme 3). Typically, the ⁵¹V NMR spectra of the solutions of a dilute solution of H₂O₂(3.21 g, 28.3 mmol of 30%

of either complex 1 or 2 were measured after approximately aqueous H₂O₂dissolved in 30 mL of MeOH) to a

1 h of mixture of the solids with the solvent. Upon the step- 6.43ϫ10^–5m solution of 1 in methanol (ca. 20 mL) and re-

wise addition of an aqueous 30% solution of H₂O₂to the cording the spectra after every 15 min interval resulted in

solution of 3 (in DMSO, ca. 4 mm), the resonance at δ = the spectral changes presented in Figure 6. The band at

–520 ppm appears. It corresponds to the mono-peroxo spe- 417 nm slightly decreases in intensity and the λ_maxslowly

cies.

shifts to 400 nm. Simultaneously, the weak shoulder that

6

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Vanadium Complexes of Binucleating Ligand Systems

appears at approximately 350 nm slowly sharpens with a formation of species CV and CVI, which decrease the con-

slight gain in intensity. The band at 297 nm gains intensity tribution of the band that involves the C=N group and pre-

while maintaining the position, and bands at 210 and cludes the observation of an increase in the absorption

240 nm sharply gain intensity. The three d–d bands that ap- around 400–450 nm.

pear at 575, 680 and 845 nm (in 1) and at 565, 675 and

875 nm (in 2) recorded with more concentrated solutions

slowly decrease their intensities and finally become indistin-

guishable (Figure 7). Changes in the UV/Vis spectra similar

to those presented here have been interpreted as involving

the progressive oxidation of V^IVO species followed by for-

mation of a oxidoperoxidovanadium(V) compound.^[17,39]

However, peroxo-to-vanadium charge-transfer transitions

have been reported at λ_max≈ 450 nm.^[40]In the present sys-

tems, the electronic spectra of both complexes exhibit rather

strong broad bands at approximately 410 nm, probably in-

volving the C=N group,^[37,41]thus in the same range of the

peroxo-to-vanadium charge-transfer transition, which

makes the detection of the latter band difficult. It is possible

that there are several processes taking place, namely, the

Figure 7. Spectral changes obtained during titration of (A) 20 mL

of a 5.76ϫ10^–3m solution of [CH₂{V^IVO(sal-sbdt)(H₂O)}₂] (1) in

DMSO, (B) 20 mL of a 8.76ϫ10^–3m solution of [CH₂{V^IVO(sal-

smdt)(H₂O)}₂] (2) in DMSO, with a dilute solution of H₂O₂

(1.26 g, 11.1 mmol of 30% aqueous H₂O₂in 5 mL of DMSO). The

spectra were recorded after the successive addition of one-drop

portions, at 2 min time intervals. The three d–d bands recorded

progressively decrease their intensity as V^IVO complexes are oxid-

ized to V^Vspecies.

Similar changes in the UV region of the absorption spec-

tra of 2 could also be observed when using lower concentra-

tions (Figure S10 in the Supporting Information). Thus, ad-

dition of two drops of a dilute aqueous/MeOH solution of

H₂O₂(3.21 g, 28.46 mmol of 30% aqueous H₂O₂dissolved

in 30 mL of MeOH) to a 6.33ϫ10^–5m solution of

[CH₂{V^IVO(sal-smdt)(H₂O)}₂] in methanol (20 mL) yielded

an increase in the intensity of the band at 215 nm, along

with only a small gain in the intensity of the 305 nm band

with a marginal shift towards a lower wavenumber. Further

additions of H₂O₂resulted in the slow decrease in intensity

of the 405 nm band along with broadening, whereas the

weak shoulder that appeared at approximately 350 nm

Figure 6. Spectral changes obtained after adding two drops of a

dilute aqueous/MeOH solution of H₂O₂(3.21 g, 28.3 mmol 30%

aqueous H₂O₂dissolved in 30 mL of MeOH) to a solution of

[CH₂{V^IVO(sal-sbdt)(H₂O)}₂] (1) in methanol (ca. 6.43ϫ10^–5m,

20 mL). The spectra were recorded every 15 min. The expanded

region of 300 to 500 nm is shown in B.

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slowly sharpened with a slight gain in intensity. The 215

and 305 nm bands only showed a marginal increase in in- tion of V^IVspecies, we interpret these results by assuming

tensity. the formation of oxidohydroxido species with the formula

As reported for other systems,^[29,40,42]besides the forma-

The reactivity of Cs₂[CH₂{V^VO₂(sal-sbdt)}₂]·2H₂O (4) [CH₂{V^VO(OH)(HL)}₂]²⁺via [CH₂{V^VO₂(HL)}₂] and/or

and Cs₂[CH₂{V^VO₂(sal-smdt)}₂]·2H₂O (6) with H₂O₂was [CH₂{V^VO₂(OH)(HL)}₂] (see Scheme 4). It is also possible

also tested and spectral changes were monitored by elec- that complexes [CH₂{VO₂(HL)(Sv)}₂] might also form.

tronic absorption spectroscopy. The spectral changes ob- Protonation of the hydrazone nitrogen has been reported

tained upon adding successive one-drop portions of an {e.g., for the structurally characterized [VO(Hsal-bhz)]

aqueous/MeOH solution of H₂O₂(3.21 g, 28.3 mmol of (H₂sal-bhz derives from salicylaldehyde and benz-

30% aqueous H₂O₂dissolved in 30 mL of MeOH) to a oylhydrazide)}, which forms upon treatment of the corre-

solution of 4 in methanol (ca. 5.63ϫ10^–5m, 20 mL) are pre- sponding anionic dioxido complex with HCl.^[43]EPR and

sented in Figure S11 in the Supporting Information. A con- electron spin echo envelope modulation (ESEEM) spectra

siderable increase in the intensity of the 210 nm band and recorded for [VO(salim)(acac)] (salim = a Schiff base ligand

an increase in the intensity of the 297 nm band was ob- that contains imidazole) upon addition of acid were ex-

served at the beginning (i.e., after addition of about 20 plained by the protonation of the imine N atom.^[44]Very

drops of H₂O₂), whereas the band at 410 nm remained ne- similar results were obtained for related binucleating li-

arly constant. Upon further addition of H₂O₂, the weak gands^[29]that involve an ONO binding set and were inter-

shoulder that appeared at around 345 nm started to emerge, preted similarly. Scheme 4 may be considered to summarize

along with weakening of the band at around 410 nm (Fig- the processes that take place, with one of the =N–N= nitro-

ure S11). Similar spectral changes were obtained for 6 (Fig- gen atoms being the site of protonation.

ure S12 in the Supporting Information). The final spectra

in both cases were similar to those obtained by the reaction

of the corresponding V^IVO complexes with H₂O₂.

The behaviour of the solutions of the V^VO₂complexes

in methanol upon addition of HCl was also monitored by

electronic absorption spectroscopy. Thus the dropwise ad-

dition of HCl dissolved in methanol (3.9ϫ10^–3m) to a solu-

tion of Cs₂[CH₂{V^VO₂(sal-sbdt)}₂]·2H₂O (4) (ca.

2.85ϫ10^–5m, 20 mL) caused the darkening of the solution

along with slow broadening of bands. The spectral changes

are depicted in Figure 8.

Scheme 4. Formation of [CH₂{V^VO(OH)(HL)}₂]²⁺by successive

protonations starting with complexes [CH₂{V^VO₂(L)}₂]^2–. All in-

cluded species are in equilibria. Each V^VO₂(L), V^VO₂(HL),

V^VO(OH)(L) and V^VO(OH)(HL) core will probably correspond to

a different chemical shift in the ⁵¹V NMR spectra.

Catalytic Activity

Oxidation of Styrene

Oxidation of styrene has been reported by several re-

searchers using homogeneous as well as heterogeneous cata-

lysts, and the major oxidation products obtained are styrene

oxide, benzaldehyde, benzoic acid, phenylacetaldehyde and

1-phenylethane-1,2-diol (Scheme 5).^[12,39a,45]We carried out

the oxidation of styrene using Cs₂[CH₂{V^VO₂(sal-sbdt)}₂]·

Figure 8. Spectral changes obtained during titration of

a

2H₂O (4) and Cs₂[CH₂{V^VO₂(sal-smdt)}₂]·2H₂O (6) as cat-

alyst precursors and using an aqueous hydrogen peroxide

solution as oxidant. All these expected products were ob-

tained as well as minor amounts of unidentified products.

The following parameters were studied by taking

2.85ϫ10^–5m solution of Cs₂[CH₂{V^VO₂(sal-sbdt)}₂]·2H₂O (4) in

methanol (20 mL) upon dropwise additions of HCl dissolved in

MeOH (3.9ϫ10^–3m). Each spectrum was recorded upon successive

additions of one-drop portions.

Very similar features were also observed with solutions Cs₂[CH₂{V^VO₂(sal-smdt)}₂]·2H₂O (6) as a representative

of 3, 5 and 6. The spectral changes in the case of catalyst precursor with the objective being to obtain the

Cs₂[CH₂{V^VO₂(sal-smdt)}₂]·2H₂O (6) are presented in Fig- maximum oxidation of styrene: (i) amount of catalyst, (ii)

ure S13 in the Supporting Information.

amount of oxidant and (iii) amount of solvent.

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Vanadium Complexes of Binucleating Ligand Systems

namely, 0.0010, 0.0035 and 0.0050 g, were used with a sty-

rene (10 mmol)/aqueous 30% H₂O₂molar ratio of 1:1 dis-

solved in methanol (5 mL), and the reaction was carried

out at 80 °C. As shown in Figure 9, 0.0010 g of 6 gave 99%

conversion of styrene in 8 h of reaction time. Increasing the

amount of catalyst precursor lowered the conversion. Thus,

0.0010 g of catalyst may be considered sufficient to run the

reaction under the above conditions. Variable solubility of

the catalyst in limited methanol is possibly the reason for

less conversion of substrate with a higher amount of cata-

lyst.

Similarly, three different molar ratios of aqueous 30%

H₂O₂to styrene (e.g., 1:0.5, 1:1 and 1:2) were considered

under similar reaction conditions (i.e., 0.0010 g of 6 in 5 mL

of methanol and carrying out the reaction at 80 °C for 8 h).

The increase in the H₂O₂-to-styrene ratio from 1:0.5 to 1:1

improved the conversion from 66 to 99%, whereas the 1:2

ratio did not significantly improve the conversion (Figure 9,

b). The volume of solvent also affected the net conversion

of styrene. Thus, varying the methanol amount from 5 to

7 mL improved the rate of conversion and the reaction ac-

quired a steady state in a shorter period of time, though it

did not affect the overall conversion of styrene (Figure 9, c).

Scheme 5. Various oxidation products of styrene obtained and

identified in the catalytic reactions reported in this work.

The effect of the amount of catalyst on the oxidation of When using 10 mL of methanol, the reaction took longer to

styrene was studied as a function of time and the results acquire the steady state, probably due to dilution of the

are presented in Figure 9 (a). Three different amounts of 6, reactants.

Figure 9. (a) Effect of the amount of catalyst on the oxidation of styrene. (b) Effect of H₂O₂amount (H₂O₂/styrene molar ratio) on

oxidation of styrene. (c) Effect of volume of solvent (methanol) on the oxidation of styrene. (d) Effect of amount of catalyst precursor,

Cs₂[CH₂{V^VO₂(sal-sbdt)}₂]·2H₂O (4), on the oxidation of styrene. For reaction conditions, see text.

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After setting the optimized reaction conditions (i.e., Oxidative Bromination of Styrene

10 mmol of styrene, 10 mmol of 30% H₂O₂and 0.0010 g of

Oxidative bromination of styrene under a two-phase sys-

catalyst in 7 mL of methanol at 80 °C) for 6, another cata-

lyst precursor, 4, was also tested under the same reaction

conditions. Thus, 10 mmol of styrene, 10 mmol of 30%

H₂O₂and 0.0010 g of 4 were dissolved in methanol (7 mL)

and the reaction was carried out at 80 °C. A maximum of

around 32% conversion was only obtained after 8 h of reac-

tion time. However, by increasing the amount of 4 the con-

version also increased, and as high as 88% conversion of

styrene was achieved with 0.0030 g of catalyst in 8 h of reac-

tion time. The reaction was completed in approximately 5 h

upon increasing the amount of 4 to 0.0040 g, but the final

conversion is almost same (90%) (Figure 9, d). The conver-

sion and selectivity of different products are presented in

Table 5. Thus, the performance of catalyst precursor 6 is

much better (TOF = 1148 h^–1) relative to 4 (TOF =

396 h^–1). A blank reaction under the above conditions gave

approximately 3% conversion of styrene.

tem by using Cs₂[CH₂{VO^V(sal-sbdt)}₂]·2H₂O and

Cs₂[CH₂{VO^V(sal-smdt)}₂]·2H₂O as catalyst precursors in

the presence of KBr, HClO₄and H₂O₂gave mainly three

products, namely, (a) 1,2-dibromo-1-phenylethane, (b) 2-

bromo-1-phenylethane-1-ol and (c) 1-phenylethane-1,2-diol

(Scheme 6). Some minor products (benzaldehyde, styrene

epoxide, benzoic acid and 4-bromostyrene) were also de-

tected but their overall percentage is approximately 7% of

the total of the main products. The obtained products are

the same as those reported by Conte et al.^[5,6a]Addition of

HClO₄in four equal portions was required to obtain better

oxidative bromination. All products were separated/isolated

by column chromatography and the content of each frac-

1

tion was confirmed by H NMR spectroscopy as well as

GC–MS.

Table 5. Product selectivity and percent conversion of styrene after

8 h of reaction time.

Scheme 6. Main products obtained by oxidative bromination of

styrene: (a) 1,2-dibromo-1-phenylethane (dibromide), (b) 2-bromo-

1-phenylethane-1-ol (a bromohydrin) and (c) 1-phenylethane-1,2-

diol.

Cat. Conv. TOF [h^–1]^[a]Selectivity [%]^[b]

[%]

so

Bza Phed bzac phaa other

4

6

7

8

88

99

56

60

396

1148

308

274

4.4

3.7

6

10.8 40.3 30.4 13.8 0.3

4.6

15

14

11.2 77.2 3.0

22

20

0.3

12

13

36

37

9

The following parameters were studied to optimize the

reaction conditions for the maximum oxidative bromination

of styrene by taking 6 as catalyst precursor: (i) catalyst

amount, (ii) oxidant amount and (iii) catalyst precursor.

Three different amounts of 6 (0.0010, 0.0020 and

0.0030 g) were used as catalyst precursor while keeping

fixed the amounts of styrene (1.04 g, 10 mmol), KBr

7

[a] Higher TOF for catalyst 6 is due to its better performance (with

lower amount) in catalytic reaction. [b] so: styrene oxide, bza: benz-

aldehyde, phed: 1-phenylethane-1,2-diol, bzac: benzoic acid, phaa:

phenylacetaldehyde.

From Table 5 it is clear that both the turnover frequency (4.76 g, 40 mmol), 30% H₂O₂(6.81 g, 60 mmol) and aque-

(TOF) and selectivity values presented differ significantly ous 70% HClO₄(5.72 g, 40 mmol) in a CH₂Cl₂/water (50%

for both complexes, and that Cs₂[CH₂{V^VO₂(sal-smdt)}₂]· v/v) mixture (40 mL) at room temperature. As presented in

2H₂O has excellent catalytic activity for the oxidation of Figure 10 (a), a maximum of 99% conversion was obtained

styrene, with benzoic acid being the more important prod- after 1 h of reaction with 0.0010 g of catalyst precursor, and

uct. Under the optimized reaction conditions for maximum 0.0020 and 0.0030 g of catalyst precursor gave nearly the

conversion of styrene, the selectivity of the products formed same conversion. Therefore, 0.0010 g of 6 was set as opti-

using 4 as catalyst precursor follows the order 1-phenyl- mum. Additions of HClO₄were made in four portions, one

ethane-1,2-diol Ͼ benzoic acid Ͼ phenylacetaldehyde Ͼ immediately after the catalyst precursor (reaction time = 0)

benzaldehyde Ͼ styrene oxide, whereas in case of 6 the or- and the three other portions with 15 min intervals.

der is benzoic acid Ͼ 1-phenylethane-1,2-diol Ͼ benzalde-

To optimize the amount of HClO₄, three different

hyde Ͼ styrene oxide Ͼ phenylacetaldehyde. Formation of amounts of 70% HClO₄were used for fixed amounts of

styrene (ep)oxide in low amount indicates its conversion to styrene (1.04 g, 10 mmol), catalyst precursor (0.0010 g),

other products. Indeed the experimental conditions were KBr (4.76 g, 40 mmol), 30% H₂O₂(6.81 g, 60 mmol) and

not optimized for the formation of the epoxide.

CH₂Cl₂/H₂O (40 mL, 50% v/v) at room temperature for

We have also obtained the oxidation of styrene by using 1 h. Increasing the perchloric acid amount from 1.43 g

0.0010 g each of the corresponding mononuclear complexes (10 mmol) to 2.86 g (20 mmol) increased the conversion

K[V^VO₂(sal-sbdt)(H₂O)] (7) and Na[V^VO₂(sal-smdt)(H₂O)₂] from 61 to 99%. Only a slight improvement in conversion

(8) and the results are also presented in Table 5. It is clear was obtained upon further increasing this amount to 4.29 g

from the table that both show catalytic activity but binu- (30 mmol). Therefore, 2.86 g of 70% HClO₄was considered

clear complexes are more active than their corresponding to be the more adequate one (Figure 10, b), thus making

mononuclear complexes. In fact, the complexes reported additions in four equal portions.

here perform much better than several other reported vana-

The effect of the amount of H₂O₂, added as an aqueous

30% H₂O₂solution, was studied with substrate-to-oxidant

dium compounds.^[6c]

10

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Vanadium Complexes of Binucleating Ligand Systems

Figure 10. (a) Effect of catalyst amount on oxidative bromination of styrene. Reaction conditions: styrene (1.04 g, 10 mmol), amount of

catalyst precursor (0.0010, 0.0020 or 0.0030 g), KBr (4.76 g, 40 mmol), aqueous 30% H₂O₂(6.81 g, 60 mmol) and 70% HClO₄(5.72 g,

40 mmol) added in four equal portions at t = 0, 15, 30 and 45 min of reaction time (marked with arrows in the figure), and CH₂Cl₂/H₂O

(40 mL, 50% v/v) at room temperature for 1 h. (b) Effect of the amount of perchloric acid, added in four equal portions in 15 min

intervals, on the oxidative bromination of styrene. (c) Effect of the amount of H₂O₂on the oxidative bromination of styrene. (d) Effect

of the amount of KBr on the oxidative bromination of styrene. See text for other conditions for plots (b), (c) and (d).

ratios of 1:2, 1:3, 1:4 and 1:5 for a fixed amount of styrene sumption of styrene and the selectivity of the formation of

(1.04 g, 10 mmol), amount of catalyst precursor (0.0010 g), major products with time for these experimental conditions.

KBr (4.76 g, 40 mmol) and HClO₄(2.86 g, 20 mmol) in

CH₂Cl₂/H₂O (40 mL, 50% v/v), and the reaction was moni-

tored at room temperature for 1 h. The conversion in-

creased upon increasing the substrate-to-oxidant ratio, and

a 1:3 ratio was sufficient to convert 98% styrene. Increasing

this ratio further did not improve the final conversion, ex-

cept to complete the reaction in a shorter time (ca. 50 min;

Figure 10, c).

Similarly, three different substrate-to-KBr ratios were

used. Upon increasing the amount of KBr from 1:2 to 1:3,

the obtained conversion increased from approximately 84

to 99%, but a further increase in the KBr amount gave

almost the same conversion (Figure 10, d).

Table S4 in the Supporting Information summarizes all

conditions applied to optimize the reaction conditions for

the maximum oxidative bromination of styrene when using

6 as catalyst precursor. Entry 10 of this table presents the

Figure 11. Percentage consumption of styrene and selectivity of the

formation of products with time using Cs₂[CH₂{VO^V(sal-smdt)}₂]·

optimized reaction conditions, which are styrene (1.04 g,

2H₂O (6) as catalyst precursor and the optimized conditions speci-

fied in the text.

10 mmol), amount of catalyst precursor 0.0010 g, 30%

aqueous H₂O₂(3.40 g, 30 mmol), 3.56 g (30 mmol) of KBr,

HClO₄(2.86 g, 20 mmol) added in four equal portions in

The formation of all three products starts with the con-

15 min intervals, and CH₂Cl₂/H₂O (40 mL, 50% v/v) at sumption of styrene. However, among the three products

room temperature for 1 h. Figure 11 represents the con- formed, the selectivity of 1-phenylethane-1,2-diol reaches

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75% at the end of 1 h, whereas that of 1,2-dibromo-1-phen- Table 6. Results of oxidative bromination of salicylaldehyde cata-

lyzed by 3–8. Conversion and relative amounts of products ob-

tained after 7 h of reaction.

ylethane is only 6%. The selectivity of the formation of 2-

bromo-1-phenylethane-1-ol (bromohydrin) initially in-

Entry Catalyst

Substr. Conv. TOF Selectivity of product

creases, reaching approximately 23%, and after around

40 min of reaction decreases. It is around 18% at the end

of 1 h. Increasing the reaction time beyond 1 h increased

the formation of the dibromide but decreased that of the

bromohydrin, whereas 1-phenylethane-1,2-diol remained al-

most constant. It should be noted here that for the catalytic

oxidation of styrene the experimental conditions were set

up for maximum conversion of styrene, and the product

obtained in higher relative amounts was 1-phenylethane-

1,2-diol, not the bromohydrin.

precursor /H₂O₂[%]

[h^–1]

mono dibromo tribromo

1

2

3

4

5

6

7

8

9

10

6

5

4

3

7

8

1:2

1:3

1:4

1:5

1:6

89

87

88

89

86

91

89

98

99

393

386

388

390

391

365

403

378

176

172

81.3

76.2

68.4

55.2

40.3

38.8

36.2

28.8

33

17.4

21.9

28.5

39.6

51.8

59.3

55.3

61.4

66

1.3

1.9

3.1

5.2

7.9

6.9

8.5

9.8

1

34

65

1

We have also obtained oxidative bromination of styrene

by using mononuclear complexes K[V^VO₂(sal-sbdt)(H₂O)]

(7) and Na[V^VO₂(sal-smdt)(H₂O)₂] (8) (0.0010 g of each)

under the above optimized conditions. Conversions ob-

tained after 1 h of reaction time were 98 and 97%, respec-

tively. Using 0.0010 g of mononuclear complexes approxi-

mately corresponded to the same number of moles of metal

centres as for binuclear complexes; hence their catalytic po-

tential is almost the same as that of the binuclear com-

plexes.

icylaldehyde (17.4%); only about 1.3% of 2,4,6-tribromo-

phenol was formed. Increasing the H₂O₂/substract molar

ratio did not improve the conversion of salicylaldehyde sig-

nificantly, but the degree of bromination of the substrate

increased (i.e., the degree of formation of 3,5-dibromosali-

cylaldehyde and 2,4,6-tribromophenol was significantly

higher). The corresponding mononuclear complexes

K[V^VO₂(sal-sbdt)(H₂O)] (7) and Na[V^VO₂(sal-smdt)(H₂O)₂]

(8) exhibited 98 and 99% conversion, respectively, with 65

and 66% selectivity towards major product 3,5-dibromosal-

icylaldehyde. A maximum of 54 and 50% conversion of sal-

icylaldehyde with 87 and 85% selectivity, respectively, was

reported with mononuclear complexes K[VO₂(sal-inh)]·

H₂O and K[VO₂(sal-bhz)]·H₂O.^[46]

The catalytic potential of these complexes in the oxidat-

ive bromination of salicylaldehyde also compares well with

similar binuclear complexes that have ONO-donor ligands.

For example, complexes K₂[CH₂{VO^V(sal-nah)}₂]·2H₂O,

K₂[CH₂{VO^V(sal-bhz)}₂]·2H₂O, K₂[CH₂{VO^V(sal-fah)}₂]·

2H₂O, Cs₂[CH₂{VO^V(sal-nah)}₂]·2H₂O, Cs₂[CH₂{VO^V-

(sal-inh)}₂]·2H₂O, Cs₂[CH₂{VO^V(sal-bhz)}₂]·2H₂O and

Cs₂[CH₂{VO^V(sal-fah)}₂]·2H₂O exhibited around 89% con-

version when using a substrate-to-H₂O₂molar ratio of 1:2

with all three products^[29]as reported here. But the forma-

tion of 5-bromosalicylaldehyde is slightly lower, whereas

that of 3,5-dibromosalicylaldehyde is higher than those

found here.

Oxidative Bromination of Salicylaldehyde

Vanadium(V) complexes also catalyze the oxidative brom-

ination of salicylaldehyde in the presence of H₂O₂. In the

present study, complexes 3–6 were used as catalyst

precursors with water as solvent. The catalytic oxidative

bromination of salicylaldehyde gave 5-bromosalicylalde-

hyde, 3,5-dibromosalicylaldehyde and 2,4,6-tribromophenol

(Scheme 7). These were the same products obtained when

using related V^VO₂complexes of ONO donor ligands.^[29]

After several trials, the optimized reaction conditions for

maximum conversion of salicylaldehyde were obtained.

These were salicylaldehyde (2.44 g, 20 mmol), KBr (5.95 g,

50 mmol), aqueous 30% H₂O₂(15.0 g, 120 mmol), catalyst

precursor (0.0070 g of 4, 0.0060 g of 6, 0.0060 g of 3 and

0.0050 g of 5), aqueous 70% HClO₄(4.02 g, 80 mmol) and

water (40 mL). It was observed that the addition of HClO₄

in four distinct portions during the first two hours was nec-

essary to obtain a better conversion. The conversion of sali-

cylaldehyde and the selectivity toward different products af-

ter 7 h of reaction time are presented in Table 6.

Mechanism of Oxidative Bromination

The mode of action of V-dependent bromoperoxidase en-

zymes (V-BrPOs) has received much attention.^{[1,5,6a,40b,47–51]}

The accepted mode of action of V-BrPOs involves the pres-

ence of vanadium in their active sites. This metal in the

presence of hydrogen peroxide forms a peroxido vanadium

derivative that oxidizes a bromide ion, thus forming a

Scheme 7. Products obtained upon the catalytic oxidative bromin-

ation of salicylaldehyde using complexes 3–6 as catalyst precursors

and water as solvent.

From the table it may be observed that with the catalyst bromine equivalent intermediate. Such an intermediate may

precursor 6 and with a substrate-to-H₂O₂molar ratio of then either brominate an appropriate organic substrate or

1:2, approximately 89% conversion was achieved with high- react with another molecule of Br^–to form bromine. The

est selectivity towards the formation of 5-bromosalicylalde- role of the V^Vion is to serve as a strong Lewis acid in the

hyde (81.3%), followed by the formation of 3,5-dibromosal- activation of the primary oxidant, H₂O₂.

12

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Vanadium Complexes of Binucleating Ligand Systems

The suggestion that the high efficacy of this process is

related to the formation of the intermediate, with the brom-

ination reaction occurring in two different compartments of

the enzymes – that is, the first step in a hydrophilic region

of the protein and the second in a hydrophobic region – has

led to model the reaction on the development of two-phase

systems:^[5](i) the vanadium precursor, H₂O₂and KBr are

dissolved in water, in which the formation of a peroxido V^V

derivative and the oxidation of Br^–take place to form an

intermediate; (ii) this intermediate is then transferred to the

organic phase, a chlorinated solvent (i.e., CHCl₃or

CH₂Cl₂), in which the bromination of the substrate takes

place. The processes that occur in the aqueous phase re-

quire acidic conditions, probably to promote the proton-

ation of the peroxido moiety.

From the mechanistic point of view, there have been sev-

eral attempts to elucidate the reaction pathways that involve

the oxybromination reactions by combining reactivity

analysis with, for example, spectroscopic techniques, mainly

⁵¹V NMR spectroscopy, and theoretical calculations.^[5,49–51]

A mechanistic proposal^[5,6a,51]included two intermediates:

a vanadium-bound hypobromite ion, which was responsible

for the formation of the bromohydrin, and the second one,

bromine, which was responsible for the formation of the

dibromo products. Both pathways started from a hypob-

romite-like vanadium intermediate, formed in the reaction

between the monoperoxido vanadium complex and Br^–.

However, direct evidence of the formation of either the hy-

droperoxido or the hypobromite-type vanadium intermedi-

ates has not yet been obtained, although the involvement

of a V^V-containing brominating species has been confirmed

in the two-phase reaction with adamantylideneadamantane,

in which a salt that contains the bromiranium cation, to-

gether with the vanadate anion, was isolated and charac-

terized.^[52]

The catalytic oxidation of styrene described in this study

also follows the approach of using a two-phase system. In

our systems we believe we have been able to identify the

monoperoxido complexes CV and CVI (Scheme 3), which

probably act as the oxidant of the Br^–ion as well as the

oxidant of salicylaldehyde.

Thus, during oxidation, the vanadium in complexes 3–6

may coordinate with H₂O₂to form V^V–oxidomonoperoxido

species [e.g., CV (and CVI)] (Scheme 3). Under acidic con-

ditions, oxidohydroxido complexes such as CIV might

form, and in the presence of H₂O₂CVI might also form.

By adding KBr to these solutions, a new ⁵¹V NMR spectro-

Figure 12. ⁵¹V NMR spectra for solutions (ca. 4 mm) of

Cs₂[CH₂{V^VO₂(sal-sbdt)}₂]·2H₂O (4): (a) in DMSO, (b) with

4.0 equiv. of H₂O₂(added as an aqueous solution of 30% H₂O₂)

and (c) with 5 equiv. KBr (total) added to the solution of (b). (d)

Solution of (c) after leaving the tube open for 24 h.

Br^–is prone to interact with the other peroxidic oxygen has

been proposed,^[49]with weak interactions between Br^–and

V^Vbeing also plausible prior to the oxo-transfer step.^[49]In

the VHPO of the fungus Curvularia inaequalis, for example,

a lysine side chain (from Lys353) also helps in the polariza-

tion of the V-bound peroxido moiety and tunes its reactiv-

ity.^[49]It is possible that in CV and/or CVI a similar type of

effect may operate, but the data available does not allow us

to discuss this further.

Antiamoebic Activity

The prepared V^VO₂complexes along with ligands I and

scopic resonance appears at δ = –586 ppm (Figure 12). We II were screened for antiamoebic activity in vitro against

suggest that this resonance might correspond to species the most common HM1:IMSS (from a human in Mexico,

CVII (with a vanadium-bound hypobromite ion) or to a obtained from the Instituto Mexicano del Seguro Social),

similar species that includes donor atoms of the ligand also an axenic and highly virulent strain of E. histolytica. The

bound to V^V. This species CVII might be responsible for IC₅₀values are in the micromolar range and are shown in

the formation of the bromohydrin. Accordingly, the hypob- Table 7. The results were estimated by plotting a graph of

romite-like species formed would be directly involved in the logarithm of concentration versus percentage growth inhibi-

“Br⁺” transfer process or, at least, it is one of the active tion as compared with the untreated controls wells. The

species in the bromination process.^[5,48]

IC₅₀values were obtained by interpolation in the corre-

The occurrence during the catalytic cycle of a species in sponding dose response curves at 50% inhibition concen-

which the equatorial peroxido oxygen is protonated and the tration. Among the sbdt series the ligand CH₂(sal-sbdt)₂

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FULL PAPER

(IC₅₀= 0.56 μm) and its V^Vcomplexes K₂[CH₂{V^VO₂(sal- complexes might be potent inhibitors for the development

sbdt)}₂]·2H₂O (3) (IC₅₀

= 0.353 μm) and Cs₂[CH₂- of E. histolytica in vitro and that they are more active than

{V^VO₂(sal-sbdt)}₂]·2H₂O (4) (IC₅₀= 0.092 μm) were found the standard drug metronidazole.

to be most active (IC₅₀lower than for metronidazole),

whereas all the compounds of the smdt series were found to

be much less active, except for K₂[CH₂{V^VO₂(sal-smdt)}₂]·

2H₂O (5) (IC₅₀= 0.85 μm), which might be considered to

be moderately active. Within the active sbdt series an in-

crease in the activity was demonstrated with the incorpora-

tion of metal. The presence of a larger group (benzyl in

sbdt) with higher hydrophobic character rather than the

smaller group (methyl in smdt) is therefore important for

the antiamoebic activity in the present set of compounds

tested. Among all the complexes it was also observed that

V^IVO compounds are less active than V^VO₂compounds.

The reason why the V^Vcomplexes are more active than the

ligands is not clear. However, it is possible that complex-

ation might favour permeation of the drugs through the

lipid layer of the cell membrane.^[53]Whatever the actual spe-

cies responsible for the biological effect measured, a signifi-

cant increase in the antiamoebic activity was previously

found upon coordination of several related binucleating li-

gands to V^V.^[29]This clearly indicates that the vanadium

Cytotoxicity of Compounds

The excellent antiamoebic activity of ligand I and com-

plexes 3, 4 and 5 encouraged us to test their cytotoxicity.

Therefore the cells were treated with various concentrations

of ligand (I), compounds 3, 4 and 5 or vehicle (DMSO)

alone for 48 h (as indicated in Figure 13).

Cell survival was determined by an MTT assay. Cell via-

bility was calculated as described in the Experimental Sec-

tion as the mean from three independent experiments in

which each treatment was done in triplicate. To assess the

survival effects of the compounds, human breast cancer

(MCF7) cells were used; 10000 cells per well in 200 μL of

complete Dulbecco’s modied Eagle’s medium (DMEM)

were plated. Different concentrations of the different com-

pounds were added to the wells as indicated in Figure 13.

An unusual trend in cytotoxicity was observed with the cell

viability, especially for compounds 3, 4 and 5. Initially the

viability increased with increasing compound concentration

in the range 2.5–100 μm, then it decreased significantly. We

do not know how to explain this behaviour but it may be

related to the presence of foetal bovine serum in the me-

dium. Its major component is bovine serum albumin and it

is known that binding of metal complexes (e.g., vanadium

compounds) to albumins may affect their activity; this

would depend on the complex/albumin ratio.^[54]

Table 7. Vanadium complexes 1–6 and their antiamoebic activity

against the HM1:IMSS strain of E. histolytica.

IC₅₀[μm]^[a]

s.d.^[b]

I

0.56

7.18

0.353

0.092

5.4

6.31

0.85

8.55

1.68

0.01

0.005

0.01

0.02

0.004

1

3

4

The cell survival assay was also carried out in the pres-

ence of metronidazole and overall the IC₅₀value for all the

compounds was found to be higher than 100 μm. Whatever

the actual trend in cytotoxicity observed, these results show

that all compounds evaluated are not particularly toxic, al-

though they are more toxic than the standard drug metroni-

dazole.

II

2

5

6

Metronidazole

[a] The values were obtained from at least three separate assays

done in duplicate. [b] Standard deviation.

Figure 13. Percentage of viable cells after 48 h on human breast cancer (MCF7) cells upon incubation with various concentrations of

ligand I, compounds 3, 4, 5, and MNZ or vehicle control (DMSO). Cell survival was determined by the MTT [MTT=3-(4,5-dimethylthi-

azol-2-yl)-2,5-diphenyltetrazolium] bromide assay.

14

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Vanadium Complexes of Binucleating Ligand Systems

Among antiamoebic studies reported earlier, the bi- HM1:IMSS strains of Entamoeba histolytica, are not par-

nuclear V^VO₂complexes, K₂[CH₂{V^VO₂(sal-nah)}₂]·2H₂O, ticularly toxic, although they are more toxic than the stan-

Cs₂[CH₂{V^VO₂(sal-inh)}₂]·2H₂O,

Cs₂[CH₂{V^VO₂(sal- dard drug metronidazole.

bhz)}₂]·2H₂O and Cs₂[CH₂{V^VO₂(sal-fah)}₂]·2H₂O are also

active against the HM1:1MSS strains of Entamoeba histoly-

tica (IC₅₀= 0.32–0.54 μm)^[29]but they are also relatively

more toxic than the standard drug metronidazole.

Experimental Section

Materials: Acetylacetone (Hacac, E. Merck, India), styrene (Acros,

USA), 30% aqueous H₂O₂, KBr (E. Merck, India), salicylaldehyde,

hydrazine hydrate, CsOH·H₂O, benzyl chloride (S.D. fine chemi-

cals, India), methyl iodide (Himedia, India) and 70% HClO₄(Qua-

ligens, India) were used as obtained. Other chemicals and solvents

were of analytical reagent grade. S-Benzyldithiocarbazate,^[55]S-

methyldithiocarbazate^[56]and 5,5Ј-methylbis(salicylaldehyde),^[57]

K[V^VO₂(sal-sbdt)(H₂O)] (7)^[28b]and Na[V^VO₂(sal-smdt)(H₂O)₂] (8)

Conclusion

The hydrazones CH₂(H₂sal-sbdt)₂(I) and CH₂(H₂sal-

smdt)₂(II) derived from 5,5Ј-methylenebis(salicylaldehyde)

[CH₂(Hsal)₂] and S-benzyldithiocarbazate CH₂(Hsal-sbdt)₂

(for I) or S-methyldithiocarbazate CH₂(Hsal-smdt)₂(for II)

and their V^IVO and V^VO₂complexes were synthesized and

characterized. The complexes are dinuclear in the solid state

and in solution, but no significant interactions were de-

tected between the vanadium centres.

[10g]

were prepared as reported in the literature.

Instrumentation and Characterization Procedures: Elemental analy-

ses of the compounds were carried out with an Elementar model

Vario-El-III. IR spectra were recorded as KBr pellets with a Nico-

let NEXUS Aligent 1100 series FTIR spectrometer. Electronic

spectra were measured in methanol with a UV-1601 PC UV/Vis

Solutions of the V^IVO complexes [CH₂{V^IVO(L)}₂]·2H₂O

[CH₂(HL)₂= I (1) and II (2)] were studied by UV/Vis, EPR

and ⁵¹V NMR spectroscopy, and also by adding H₂O₂or

acid (HCl). The speciation of solutions of the V^Vcomplexes

in MeOH and DMSO was also studied by the same spectro-

scopic techniques. The formation of several species was es-

tablished, with some of them probably intermediates in the

catalytic processes studied, namely, [CH₂{V^VO(O₂)(L)}₂]^2–

and [CH₂{V^VO(OH)(L)}₂]. Upon addition of acid (HCl),

the V^Vspecies present were partly reduced/hydrolyzed,

thereby yielding several species, namely, the oxidohydroxido

complex.

1

spectrophotometer. H NMR spectra were obtained with a Bruker

200, ¹³C and ⁵¹V NMR spectra with a Bruker Avance III 400 MHz

spectrometer with the common parameter settings. NMR spectra

were usually recorded in [D₆]DMSO, and δ (⁵¹V) values are refer-

enced relative to neat V^VOCl₃as external standard. Thermogravi-

metric analyses of the complexes were carried out under an oxygen

atmosphere with a TG Stanton Redcroft STA 780 instrument. The

magnetic susceptibilities were measured with a vibrating sample

magnetometer model 155 supplied by Princeton Applied Research

and by using nickel as standard. Diamagnetic corrections were car-

ried out by using Pascal’s constants.^[58]EPR spectra were recorded

with a Bruker ESP 300E X-band spectrometer. The spin-Hamilto-

nian parameters were obtained by simulation of the spectra with

the computer program by Rockenbauer and Korecz.^[38]A Thermax

Nicolet gas chromatograph fitted with a HP–1 capillary column

(30 mϫ0.25 mmϫ0.25 μm) and a flame ionization detector (FID)

was used to analyze the reaction products and their quantifications

were made on the basis of the relative peak area of the respective

product. Oxidation and oxidative bromination of styrene have also

been normalized from the set of calibration curve for styrene to get

response factors, and the obtained results are nearly same within

experimental error. The identity of the products was confirmed

with a Clarus 500 GC–MS from Perkin–Elmer and by comparing

the fragments of each product with the library available.

The V^VO₂complexes 3–6 were shown to be functional

models of vanadium-dependent haloperoxidases and satis-

factorily catalyzed the oxidative bromination of salicylalde-

hyde and styrene. Complexes 4 and 6 are also catalyst pre-

cursors for the oxidation of styrene. Under optimized reac-

tion conditions, the selectivity of the products formed by

using Cs₂[CH₂{V^VO₂(sal-sbdt)}₂]·2H₂O (4) as catalyst fol-

lowed the order 1-phenylethane-1,2-diol Ͼ benzoic acid Ͼ

phenylacetaldehyde Ͼ benzaldehyde Ͼ styrene oxide. In the

case of Cs₂[CH₂{V^VO₂(sal-smdt)}₂]·2H₂O (6), however, the

order was benzoic acid Ͼ 1-phenylethane-1,2-diol Ͼ benz-

aldehyde Ͼ styrene oxide Ͼ phenylacetaldehyde. Formation

of styrene oxide in very poor yield suggested the conversion

of styrene oxide into other products.

Preparation of CH₂(H₂sal-sbdt)₂(I) and CH₂(H₂sal-smdt)₂(II):

Compounds I and II were prepared by adapting methods reported

in the literature.^[59]The preparation of representative ligand I is

described here.

A solution of 5,5Ј-methylbis(salicylaldehyde)

Plausible intermediates involved in these catalytic pro-

cesses were established by UV/Vis, EPR and ⁵¹V NMR

spectroscopic studies, namely, monoperoxido–V^Vcom-

plexes. A ⁵¹V NMR spectroscopic peak detected at δ =

–586 ppm was probably due to a V^Vcomplex that contained

coordinated hypobromite ion. The vanadium complexes

along with ligands I and II were also screened against

HM1:IMSS strains of Entamoeba histolytica. The results

showed that the IC₅₀values of compounds 3, 4 and 5 are

significantly lower than that of metronidazole, thereby sug-

gesting that they might be promising drugs for the treat-

ment of amoebiasis. Cytotoxicity studies show that the V^V

(2.65 g, 10 mmol) was prepared in hot methanol (40 mL) and a

solution of S-benzyldithiocarbazide (3.966 g, 20 mmol) in meth-

anol (20 mL) was added to the above. The reaction mixture was

heated at reflux for 3 h on a water bath and was put in a refrigera-

tor for 12 h. The deposited yellow solid was filtered, washed with

methanol and dried in a desiccator. Finally, it was recrystallized

from methanol to give a fine needle-like solid.

Data for CH₂(H₂sal-sbdt)₂(I): Yield 6.45 g (67.7%). C₃₁H₂₈N₄O₂S₄

(616.83): calcd. C 60.36, H 4.58, N 9.08; found C 60.1, H 4.6, N

8.9.

Data for CH₂(H₂sal-smdt)₂(II): Yield 4.38 g (73.5%).

C₁₉H₂₀N₄O₂S₄(464.63): calcd. C 49.12, H 4.34, N 12.06; found C

complexes 3, 4 and 5, although very active against the 49.2, H 4.4, N 12.1.

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Preparation of [CH₂{V^IVO(sal-sbdt)(H₂O)}₂] (1): A filtered solution

of [V^IVO(acac)₂] (2.56 g, 10 mmol) in dry methanol (30 mL) was

added to a filtered solution of I (3.08 g, 5 mmol) prepared in dry

hot methanol (150 mL) while shaking the reaction flask. The reac-

tion mixture was heated at reflux on a water bath for 4 h. After

reducing the volume of the solvent to approximately 30 mL and

keeping it at room temperature for 10 h, the separated brown solid

was filtered, washed with methanol and dried in a desiccator with

C 30.9, H 2.7, N 7.5. ⁵¹V NMR (400 MHz, [D₆]DMSO, 25 °C): δ

= –462 ppm.

Preparation of Cs₂[CH₂{V^VO₂(sal-smdt)₂}]·2H₂O (6): This complex

was prepared by the procedure outlined as method A and B for

Cs₂[CH₂{VO₂(sal-sbdt)₂}]·2H₂O(4). Yield from method A: 0.591 g

(63.7%); from method B: 0.735 g (79.2%). C₁₉H₂₀Cs₂N₄O₈S₄V₂

(928.29): calcd. C 24.6, H 2.2, N 6.0; found C 24.5, H 2.1, N 6.2.

⁵¹V NMR (400 MHz, [D₆]DMSO, 25 °C): δ = –463 ppm.

silica gel; yield 3.16 g (80.5%). μ_eff(293 K)

=

1.73 μ_B.

Oxidation of Styrene: In a typical procedure, styrene (1.04 g,

10 mmol) and 30% (w/v) aqueous H₂O₂(1.13 g, 10 mmol) were

dissolved in methanol (7 mL) and the flask was maintained at

80 °C with an electrically heated oil bath. The catalyst to be tested,

C₃₁H₂₈N₄O₆S₄V₂(782.68): calcd. C 47.57, H 3.61, N 7.16; found

C 47.7, H 3.5, N 7.2.

Preparation of [CH₂{V^IVO(sal-smdt)(H₂O)}₂] (2): Complex 2 was

prepared from [V^IVO(acac)₂] (0.530 g, 2 mmol) and II (0.464 g,

1 mmol) by the method outlined for 1; yield 0.431 g (68.4%). μ_eff

(293 K) = 1.71 μ_B. C₁₉H₂₀N₄O₆S₄V₂(630.48): calcd. C 36.19, H

3.20, N 8.89; found C 36.4, H 3.0, N 8.9.

either

Cs₂[CH₂{V^VO₂(sal-smdt)₂}]·2H₂O

(6)

(0.0010 g,

0.0012 mmol) or Cs₂[CH₂{V^VO₂(sal-sbdt)₂}]·2H₂O (4) (0.0030 g,

0.0028 mmol), was added and the reaction mixture was stirred for

8 h. The products were extracted in n-heptane and analyzed quanti-

Preparation of K₂[CH₂{V^VO₂(sal-sbdt)}₂]·2H₂O (3): Method A: A tatively by GC with a Thermo trace gas chromatograph that had

filtered solution of [V^IVO(acac)₂] (0.530 g, 2 mmol) in methanol

(15 mL) was added to a solution of I (0.616 g, 1 mmol) in methanol

(450 mL) while stirring and was heated at reflux for 4 h. After add-

ing KOH (0.224 g, 4.0 mmol) to the above, the reaction mixture

was further heated at reflux for 2 h. The obtained light brown solu-

tion was allowed to oxidize aerially along with slow evaporation at

room temperature. After 2 d the solution became yellow, its volume

was reduced to approximately 10 mL and the solution was kept for

12 h at room temperature. A yellow solid of 3 separated out. This

was filtered off, washed with methanol and dried in a desiccator

with silica gel; yield 0.786 g (72.8%). C₃₁H₂₈K₂N₄O₈S₄V₂(892.90):

calcd. C 41.70, H 3.16, N 6.27; found C 41.8, H 3.1, N 6.3. ⁵¹V

NMR (400 MHz, [D₆]DMSO, 25 °C): δ = –462 ppm. Method B: A

mixture of [CH₂{V^IVO(sal-sbdt)(H₂O)}₂] (0.391 g, 0.5 mmol) and

KOH (0.068 g, 1.2 mmol) in methanol (25 mL) was heated at reflux

for 2 h and then left for aerial oxidation as well as slow evaporation

of the solvent at room temperature. A yellow solid of 3 slowly pre-

cipitated out over approximately 3 d. This was filtered off, washed

with cold methanol and dried in a desiccator with silica gel; yield

0.358 g (84.7%).

an HP–1 column (30 mϫ0.25 mmϫ0.25 μm) and an FID detec-

tor. The products were identified by GC–MS with a Perkin–Elmer

Clarus

500

equipped

with

an

Elite-5

column

(30 mϫ0.25 mmϫ0.25 μm). Complexes 7 and 8 were also studied

under similar conditions.

Oxidative Bromination of Salicylaldehyde: Complexes 3–8 were

used as catalyst precursors to carry out oxidative brominations. In

a typical reaction, salicylaldehyde (2.44 g, 20 mmol) was added to

an aqueous solution (40 mL) of KBr (5.95 g, 50 mmol), followed

by addition of aqueous 30% H₂O₂(15 g, 120 mmol) in a 100 mL

reaction flask. The catalyst (e.g., 0.0070 g) and 70% HClO₄(4.02 g,

20 mmol) were added and the reaction mixture was stirred at room

temperature. Three additional 20 mmol portions of 70% HClO₄

were further added to the reaction mixture at t = 30, 60 and 90 min

of reaction, in three equal portions, under continuous stirring. In

all batches, the experimental conditions (e.g., stirring speed, the

size of the magnetic bar and reaction flask) were kept as similar as

possible. After 7 h, the white solid product that had separated was

filtered off, washed with water and dried. The crude mass was dis-

solved in CH₂Cl₂; insoluble material, if any, was removed by fil-

tration, and the solvent evaporated. A CH₂Cl₂solution of this ma-

terial was subjected to gas chromatography, and the identity of the

Cs₂[CH₂{V^VO₂(sal-sbdt)}₂]·2H₂O (4): Method A: A filtered solu-

tion of [V^IVO(acac)₂] (0.530 g, 2.0 mmol) in methanol (15 mL) was

added to a solution of I (0.616 g, 1.0 mmol) in methanol (450 mL) products was confirmed by GC–MS.

while stirring and heated at reflux for 4 h. After adding CsOH·H₂O

Oxidative Bromination of Styrene: Complexes 3–8 were also used

(0.403 g, 2.4 mmol), the reaction mixture was further heated at re-

flux for 2 h. The obtained light green solution was allowed to oxid-

ize aerially while slowly evaporating at room temperature. After 2 d

the green solution turned yellow, the volume was reduced to around

10 mL and the mixture was kept overnight at room temperature. A

yellow solid of 4 separated out. This was filtered off, washed with

methanol and dried in a desiccator with silica gel; yield 0.786 g

(72.8%). C₃₁H₂₈Cs₂N₄O₈S₄V₂(1080.49): calcd. C 34.46, H 2.61, N

5.19; found C 34.3, H 2.5, N 5.3. ⁵¹V NMR (400 MHz, [D₆]DMSO,

25 °C): δ = –463 ppm. Method B: A mixture of [CH₂{V^IVO(sal-

sbdt)(H₂O)}₂](1) (0.782 g, 1.0 mmol) and CsOH·H₂O (0.404 g,

2.4 mmol) in methanol (25 mL) was heated at reflux for 2 h and

then left for aerial oxidation at room temperature over a period of

approximately 3 d. A yellow solid of 4 precipitated out. This was

filtered off, washed with methanol and dried in a desiccator with

silica gel; yield 0.965 g (89.3%).

as catalyst precursors to carry out the oxidative bromination of

styrene. In a typical reaction, styrene (1.04 g, 10 mmol) was added

to an aqueous solution (20 mL) of KBr (3.57 g, 30 mmol), followed

by the addition of CH₂Cl₂(20 mL) and 30% aqueous H₂O₂(3.40 g,

30 mmol) in a 100 mL reaction flask. The catalyst (0.0010 g) and

70% HClO₄(1.43 g, 10 mmol) were added, and the reaction mix-

ture was stirred at room temperature. Three additional 10 mmol

portions of 70% HClO₄were further added after every 10 min with

continuous stirring. In all batches, the experimental conditions

(e.g., stirring speed, the size of the magnetic bar and reaction flask)

were kept as similar as possible. After 1 h, the orange organic layer

was separated with a separatory funnel, washed with water and

dried. The crude mass was redissolved in CH₂Cl₂; insoluble mate-

rial, if any, was removed by filtration, and the solvent evaporated.

The reaction products were separated by using a silica gel column.

Elution of the column with 1% CH₂Cl₂in n-hexane first separated

a mixture of bromo derivatives followed by 1-phenylethane-1,2-

diol. The two bromo derivatives were finally separated from each

other with the silica gel column again by eluting with pure n-hex-

ane. The identity of all products was confirmed by GC–MS and

¹H NMR spectroscopy.

Preparation of K₂[CH₂{V^VO₂(sal-smdt)₂}]·2H₂O (5): This complex

was prepared by the procedures outlined for K₂[CH₂{VO₂(sal-

sbdt)₂}]·2H₂O (3) by using both methods A and B. Yield from

method A: 0.513 g (73.9%); from method B: 0.602 g (86.7%).

C₁₉H₂₀K₂N₄O₈S₄V₂(740.71): calcd. C 30.81, H 2.72, N 7.56; found

16

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Vanadium Complexes of Binucleating Ligand Systems

1

1,2-Dibromo-1-phenylethane: H NMR (CDCl₃): δ = 7.29–7.39 (m, (10000 per well) were incubated in triplicate in a 96-well plate in

5 H, aromatic), 5.11–5.13 (q, 1 H, CH), 3.97–4.06 (septet, 2 H,

CH₂) ppm.

1-Phenylethane-1,2-diol: ¹H NMR (CDCl₃): δ = 7.29–7.39 (m, 5 H,

aromatic), 4.9 (q, 1 H, CH), 3.5 (q, 1 H of CH₂), 3.6 (q, 1 H of

CH₂), 2.7 (br., 1 H, OH) ppm.

2-Bromo-1-phenylethane-1-ol: ¹H NMR (CDCl₃): δ = 7.29–7.39 (m,

5 H, aromatic), 5.1 (q, 1 H, CH), 3.9 (septate, 2 H, CH₂) ppm.

the presence of various concentrations of ligand I, compounds 3,

4 and 5 as well as metronidazole or vehicle (DMSO) alone in a

final volume of 200 μL at 37 °C in a humidified chamber for 48 h.

At the end of this time period, MTT solution (20 μL) [5 mg per

mL in phosphate buffer solution (PBS)] was added to each well,

and the cells were incubated at 37 °C in a humidified chamber for

4 h. After 4 h, the supernatant was removed from each well. The

coloured formazan crystals produced from MTT were dissolved in

DMSO (200 μL), and then the absorbance (A) value was measured

at 570 nm with a multiscanner autoreader. The following formula

was used for the calculation of the percentage of cell viability (CV):

CV [%] = (A of the experimental samples/A of the control)ϫ100.

In Vitro Testing Against E. histolytica: Ligands I and II and their

complexes 1 to 6 were screened in vitro for antiamoebic activity

against the HM1:IMSS strain of E. histolytica by using a micro-

plate method. E. histolytica trophozoites were cultured in TYIS-33

growth medium. DMSO (40 μL) was added to all samples (1 mg)

followed by enough fresh culture medium to obtain a concentration

of 1 mgmL^–1. The maximum concentration of DMSO in the tests

did not exceed 0.1%, at which level no inhibition of amoebal

growth occurred. Samples were dissolved or suspended by mild

sonication for a few minutes to obtain a clear solution, then further

dilution with medium to obtain a concentration of 0.1 mgmL^–1.

Twofold serial dilutions were made in the wells of a 96-well microti-

tre plate (costar) in the medium (170 μL). Each test included metro-

nidazole as the standard amoebicidal drug; control wells (culture

medium plus amoebae) were prepared from a confluent culture by

pouring off the medium, adding medium (2 mL) and chilling the

culture on ice for 8 min to detach the organisms from the side of

the flask. The number of the amoeba per millilitre was estimated

with a heamocytometer, and trypan blue exclusion was used to con-

firm viability. The cell suspension used was diluted to 10⁵organism

per millilitre by adding fresh medium, and 170 μL of this suspen-

sion was added to the test and control well in the plate with multi-

channel pipette so that the wells were completely filled (total vol-

ume, 340 μL). An inoculum of 1.7ϫ10⁴organisms per well was

chosen so that confluent, but not excessive, growth took place in

the control wells. The plate was sealed with expanded polystyrene

(0.5 mm), secured with tape, placed in a modular incubating cham-

ber (flow laboratories, High Wycombe, UK) and gassed for 10 min

with nitrogen before incubation at 37 °C for 72 h.

Supporting Information (see footnote on the first page of this arti-

cle): Electronic and ¹³C NMR spectral data, IR and ¹H NMR spec-

tra of representative ligands and complexes, speciation studies by

electronic, ⁵¹V NMR and EPR spectroscopy and catalytic data on

the oxidative bromination of styrene.

Acknowledgments

M. R. M. thanks the Department of Science and Technology

(DST), Government of India, New Delhi (SR/S1/IC-32/2010) for

financial support of the work. C. H. and A. A. K. acknowledge the

Council of Scientific and Industrial Research (CSIR), New Delhi

for a fellowship. J. C. P. and A. K. thank the Fundação para a

Ciência e Tecnologia (FEDER), project PEst-OE/QUI/UI0100/

2011, and the Portuguese NMR Network (IST-UTL Center), grant

number SFRH/BPD/34835/2007 for support.

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Eur. J. Inorg. Chem. 0000, 0–0

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Received: January 6, 2012

Published Online: ᭿

18

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Vanadium Complexes of Binucleating Ligand Systems

Vanadium Complexes

Cationic binuclear dioxovanadium(V) com-

plexes have been isolated and their charac-

terization, catalytic and antiamoebic

properties are reported

M. R. Maurya,* C. Haldar, A. A. Khan,

A. Azam, A. Salahuddin, A. Kumar,

J. Costa Pessoa* ............................. 1–19

Synthesis, Characterization, Catalytic and

Antiamoebic Activity of Vanadium Com-

plexes of Binucleating Bis(dibasic triden-

tate ONS donor) Ligand Systems

Keywords: Vanadium / Enzyme models /

Antiprotozoal agents / Hydrazones / EPR

spectroscopy / NMR spectroscopy

Eur. J. Inorg. Chem. 0000, 0–0

www.eurjic.org

19

Article Doi

Synthesis, characterization, catalytic and antiamoebic activity of vanadium complexes of binucleating bis(dibasic tridentate ONS donor) ligand systems

DOI: 10.1002/ejic.201200012

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Article abstract of DOI:10.1002/ejic.201200012

Full text of DOI:10.1002/ejic.201200012

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