Mononuclear iron(III) complexes supported by tripodal N3O ligands: Synthesis, structure and reactivity towards DNA cleavage

Article abstract of DOI:10.1016/j.ica.2009.12.039

A new synthetic route to the known tripodal tetradentate N₃O ligand L¹ (HL¹ = [N-(3,5-di-tert-butyl-2-hydroxybenzyl)-N,N-di-(2-pyridylmethyl)]amine) is reported. The related compounds HLⁿ (n = 2, 3) were prepared by a similar procedure. Treatment of HLⁿ (n = 1-3) with FeCl₃·6H₂O in hot methanol led to the mononuclear iron(III) complexes [Fe(Lⁿ)Cl₂] (1: n = 1, 2: n = 2, 3: n = 3). The solid-state structures of complexes 1 and 2 were determined by X-ray crystallography. [Fe(L¹)Cl₂] (1) showed effective nuclease activity in the presence of hydrogen peroxide, converting supercoiled plasmid DNA to its linear form.

Full text of DOI:10.1016/j.ica.2009.12.039

Inorganica Chimica Acta 363 (2010) 1246–1253
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Inorganica Chimica Acta
journal homepage: www.elsevier.com/locate/ica
Mononuclear iron(III) complexes supported by tripodal N3O ligands: Synthesis,
structure and reactivity towards DNA cleavage
Yee-Lok Wong a, Chun-Yin Mak a,b, Hoi Shan Kwan b, Hung Kay Lee a,
*
a Department of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, People’s Republic of China
b Department of Biology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
A new synthetic route to the known tripodal tetradentate N3O ligand L1 (HL1 = [N-(3,5-di-tert-butyl-2-
hydroxybenzyl)-N,N-di-(2-pyridylmethyl)]amine) is reported. The related compounds HLn (n = 2, 3) were
prepared by a similar procedure. Treatment of HLn (n = 1–3) with FeCl3ꢀ6H2O in hot methanol led to the
mononuclear iron(III) complexes [Fe(Ln)Cl2] (1: n = 1, 2: n = 2, 3: n = 3). The solid-state structures of com-
plexes 1 and 2 were determined by X-ray crystallography. [Fe(L1)Cl2] (1) showed effective nuclease activ-
ity in the presence of hydrogen peroxide, converting supercoiled plasmid DNA to its linear form.
Ó 2009 Elsevier B.V. All rights reserved.
Article history:
Received 29 May 2009
Received in revised form 10 December 2009
Accepted 19 December 2009
Available online 29 December 2009
A manuscript submitted to Inorganica
Chimica Acta for a Special Issue dedicated to
Professor Jonathan R. Dilworth.
Keywords:
Iron complexes
N-capped tripodal tetradentate N3O ligands
Synthesis
X-ray structures
Electrochemistry
Oxidative DNA cleavage activity
1. Introduction
(HL1) have been reported as synthetic models for bioinorganic and
organometallic studies [14,15]. Recently, we have reported on the
Over the past decades, tremendous efforts have been devoted to
the development of various types of supporting ligands in order to
generate the desired metal complexes for structural and reactivity
studies [1–5]. A wide variety of supporting ligands with different
denticity and donor type have been reported. Besides, the steric
and electronic properties of the ligands are also known to play vital
roles in determining the structure and reactivity of the correspond-
ing metal complexes. The coordination chemistry of N-capped
tripodal N3O ligands (Fig. 1) has received considerable attention
[5–16]. Among these N3O donor ligands, di(pyridylmethyl)amine-
phenolate ligands (III) have been studied in detail and used for sta-
bilising reactive complexes in bioinorganic model studies [8–16].
One interesting feature of the di(pyridylmethyl)amine-phenolate
ligands is their slightly flexible ligand scaffold. The latter property
of these ligands leads to metal complexes with the two pyridyl
groups coordinating to the metal centre either in a cis or trans fash-
ion [15].
synthesis and oxygenation chemistry of the binuclear Cu(I) com-
plex [(HL1)Cu( -I)]2 [16]. The HL1 ligand binds to the Cu(I) centre
l
in a N,N-chelating fashion via its pyridyl nitrogen atoms. Interest-
ingly, the phenoxyl proton on HL1 was not deprotonated, even in
the presence of base (Et3N) during the preparation of [(HL1)Cu
(l-I)]2. Continuing our work on tripodal N3O ligands, we extended
our studies on the coordination chemistry of HL1 to other metals.
Herein, we report on the synthesis and structures of a series of
Fe(III) complexes supported by the Ln (n = 1–3) ligands
(Scheme 1). A new synthetic route to the proligands HLn (n = 1–
3) was developed in this work. The reactivity of [Fe(L1)Cl2] (1) to-
wards oxidative cleavage of DNA is also presented.
2. Experimental
2.1. General procedures
Metal complexes supported by the conjugated base of [N-(3,5-
di-tert-butyl-2-hydroxybenzyl)-N,N-di-(2-pyridylmethyl)]amine
All reactions were carried out under an atmosphere of dinitro-
gen using standard Schlenk-line techniques; workups were per-
formed in air. Dichloromethane and acetonitrile were pre-dried
over 4 Å molecular sieves and distilled from calcium hydride.
Tetrahydrofuran (THF) was distilled over sodium/benzophenone.
* Corresponding author. Tel.: +852 26096331; fax: +852 26035057.
E-mail address: hklee@cuhk.edu.hk (H.K. Lee).
0020-1693/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.ica.2009.12.039

Y.-L. Wong et al. / Inorganica Chimica Acta 363 (2010) 1246–1253
1247
R
OH
C
N
OH
NEt2
N
O
n
N
R
N
NEt2
R = Me, But
n = 1, 2
(I)
(II)
R1
But
R3
Me
OH
OH
N
N
N
N
R2
But
N
R3
N
MeN
R1, R2, R3 = H
R1, R2 = But; R3 = H, Me
R1 = H; R2 = NO2; R3 = H
(IV)
(III)
Fig. 1. Examples of N-capped tripodal N3O ligands.
R4
R4
R4
OH
OH
OH
SnCl4, NBu3, (HCHO)n
toluene, 100°C
NaBH4
MeOH
R5
R5
CHO
R5
CH2OH
R4, R5 = H or But
R4
R4
OH
N
N
H
N
N
N
OH
PBr3
N
R5
CHCl3
NEt3, THF, reflux
R5
CH2Br
R4 = R5 = But
HL1:
HL2: R4 = But, R5 = H
HL3:
(85%)
(82%)
R4 = H, R5 = But
(73%)
Scheme 1.
N,N-Dimethylformamide (DMF) was dried over and distilled from
barium oxide under reduced pressure. All other reagents and sol-
vents were of reagent grade and used as received. Plasmids
pUC18, pGEM-3Zf(+) and pBK-CMV were purchased from Gene-
Script, Promega and Stratagene, respectively. QLAEX II Agarose
GelExtraction Kit was obtained from QLAGEN. All 1H and 13C{1H}
NMR spectra were recorded on a Bruker DPX300 spectrometer
(1H at 300 MHz and 13C at 75.4 MHz). Chemical shifts were refer-
enced to internal SiMe4 (d = 0). Liquid secondary ion (LSI) mass
spectra were measured on a Bruker APEX 47e Fourier-transform
ion cyclotron resonance (FT-ICR) mass spectrometer with 3-nitro-
benzyl alcohol as matrix. Electrospray (ESI) mass spectra were col-
lected on a Finnigan MAT 95XL mass spectrometer. UV–Vis
absorption spectra were recorded on a Varian Cary 5G UV–Vis-
NIR spectrophotometer. Cyclic voltammetry was performed using
a Princeton Applied Research Electrochemical Workstation Model
263A. The electrochemical cell used in our studies consisted of a
platinum ball working electrode, a silver wire reference electrode,
and a platinum foil auxiliary electrode. All sample solutions were
prepared in acetonitrile with tetrabutylammonium hexafluoro-
phosphate (0.15 M) as the supporting electrolyte. All potentials
were internally referenced to the FeCp2þ/FeCp2 redox couple. Ele-

1248
Y.-L. Wong et al. / Inorganica Chimica Acta 363 (2010) 1246–1253
mental analyses were performed by MEDAC Ltd., Brunel Univer-
sity, UK. The gel photographs were taken by a Gel Doc 1000UV
with Fluorescent Gel Doc PC System (BIO RAD).
during the addition and stirring was continued for 1 h at room
temperature. All the volatiles were then removed using a rotary
evaporator and the resulting residue was quenched with water
(50 ml). The resulting aqueous mixture was neutralised with gla-
cial acetic acid and then extracted with CH2Cl2 (3 ꢁ 150 ml). The
combined organic extract was dried over anhydrous MgSO4 and
then concentrated to give a white crystalline solid. Yield: 3.44 g
(97%). 1H NMR (CDCl3): d 7.53 (bs, 1H, ArOH), 7.28 (s, 1H, ArH),
6.90 (s, 1H, ArH), 4.85 (s, 2H, ArCH2), 1.43 (s, 9H, But), 1.28 (s,
9H, But).
2.2. Synthesis
2.2.1. N,N-Bis(2-pyridylmethyl)amine
To a solution of 2-aminomethylpyridine (5.41 g, 50.0 mmol) in
MeOH (100 ml) was added 2-pyridinecarboxaldehyde (5.35 g,
50.0 mmol). A dark brown mixture developed immediately. After
stirring at room temperature for 10 h, sodium borohydride
(3.78 g, 100 mmol) was added slowly. The brown mixture turned
to a pale yellow solution during the addition and stirring was con-
tinued for another 2 h. All the volatiles were then removed under
reduced pressure. Water (100 ml) was added and the resulting
aqueous solution was neutralised with 32% hydrochloric acid, fol-
lowed by extraction with CH2Cl2 (3 ꢁ 200 ml). The combined or-
ganic extract was dried over anhydrous MgSO4 and rotary
evaporated to give a yellow liquid which was used directly for
the following reactions without purification. Yield: 1.62 g (99%).
1H NMR (CDCl3): d 8.50 (d, J = 4.8 Hz, 2H, PyH), 7.58 (t, J = 7.7 Hz,
2H, PyH), 7.30 (d, J = 7.5 Hz, 2H, PyH), 7.10 (t, J = 7.7 Hz, 2H, PyH),
3.93 (s, 4H, PyCH2), 3.21 (bs, 1H, NH). 13C{1H} NMR: d 159.2,
149.1, 136.3, 122.2, 121.9, 54.5.
2.2.6. 3-tert-Butyl-2-hydroxybenzyl alcohol
This compound was synthesised from 3-tert-butyl-2-hydroxy-
benzaldehyde (4.34 g, 24.4 mmol) and NaBH4 (1.84 g, 48.8 mmol)
in MeOH (50 ml) using a procedure similar to that of 3,5-di-tert-
butyl-2-hydroxybenzyl alcohol. The compound was isolated as a
pale yellow liquid. Yield: 4.22 g (96%). 1H NMR (CDCl3): d 7.74 (s,
1H, ArOH), 7.26 (dd, J = 1.2 and 7.8 Hz, 1H, ArH), 6.90 (d,
J = 6.9 Hz, 1H, ArH), 6.80 (t, J = 7.5 Hz, 1H, ArH), 4.86 (s, 2H, ArCH2),
1.44 (s, 9H, But).
2.2.7. 5-tert-Butyl-2-hydroxybenzyl alcohol
This compound was synthesised from 5-tert-butyl-2-hydroxy-
benzaldehyde (3.77 g, 21.2 mmol) and NaBH4 (1.60 g, 42.4 mmol)
in MeOH (50 ml) using a procedure similar to that of 3,5-di-tert-
butyl-2-hydroxybenzyl alcohol. The compound was isolated as a
colourless liquid. Yield: 3.74 g (98%). 1H NMR (CDCl3): d 7.23 (dd,
J = 2.1 and 8.3 Hz, 1H, ArH), 7.10 (bs, 1H, ArOH), 7.05 (d,
J = 2.4 Hz, 1H, ArH), 6.82 (d, J = 8.1 Hz, 1H, ArH), 4.85 (s, 2H, ArCH2),
1.28 (s, 9H, But).
2.2.2. 3,5-Di-tert-butyl-2-hydroxybenzaldehyde
To a solution of 3,5-di-tert-butylphenol (20.6 g, 100 mmol) and
tributylamine (9.6 ml, 40.0 mmol) in toluene (15 ml) was added
SnCl4 (1.2 ml, 10.0 mmol) dropwise under nitrogen. A white fume
appeared immediately during the addition and the reaction mix-
ture was stirred at room temperature for 15 min. Paraformalde-
hyde (6.60 g, 220 mmol) was added in a single portion and the
resulting mixture was heated at 100 °C for 10 h. After cooling to
room temperature, water (20 ml) was added and the resulting
aqueous solution was extracted with diethyl ether (6 ꢁ 100 ml).
The combined organic extract was dried over anhydrous MgSO4,
concentrated and chromatographed using CHCl3/hexanes (1:1) as
eluent. The first band was collected and rotary evaporated to give
a pale yellow solid. Yield: 19.2 g (82%). 1H NMR (CDCl3): d 9.87 (s,
1H, CHO), 7.60 (d, J = 2.4 Hz, 1H, ArH), 7.35 (d, J = 2.4 Hz, 1H, ArH),
1.43 (s, 9H, But), 1.33 (s, 9H, But).
2.2.8. 3,5-Di-tert-butyl-2-hydroxybenzyl bromide
To
a solution of 3,5-di-tert-butyl-2-hydroxybenzyl alcohol
(3.44 g, 14.6 mmol) in CHCl3 (50 ml) was added PBr3 (0.7 ml, 7.3
mmol). A white fume appeared immediately during the addition
and the mixture was stirred at room temperature for 1 h. The reac-
tion mixture was then treated with cold water (30 ml) with vigor-
ous stirring for 2 min. The organic layer was separated and the
aqueous residue was extracted with CHCl3 (2 ꢁ 50 ml). The com-
bined organic extracts were dried over anhydrous MgSO4, concen-
trated and dried in vacuo to give the desired product as a pale
yellow liquid. The compound was used in the following reactions
without further purification. Yield: 4.23 g (97%).
2.2.3. 3-tert-Butyl-2-hydroxybenzaldehyde
This compound was synthesised from 3-tert-butylphenol
(15.0 g, 100 mmol), tributylamine (9.6 ml, 40.0 mmol), paraformal-
dehyde (6.60 g, 220 mmol), and SnCl4 (1.2 ml, 10.0 mmol) in tolu-
ene (15 ml) using a procedure similar to that of 3,5-di-tert-butyl-2-
hydroxybenzaldehyde. The compound was isolated as a pale yel-
low liquid. Yield: 13.4 g (75%). 1H NMR (CDCl3): d 9.87 (s, 1H,
CHO), 7.53 (dd, J = 1.7 and 7.7 Hz, 1H, ArH), 7.39 (dd, J = 1.7 and
7.7 Hz, 1H, ArH), 6.94 (t, J = 7.7 Hz, 1H, ArH), 1.42 (s, 9H, But).
2.2.9. 3-tert-Butyl-2-hydroxybenzyl bromide
This compound was synthesised from 3-tert-butyl-2-hydroxy-
benzyl alcohol (4.22 g, 23.4 mmol) and PBr3 (1.1 ml, 11.7 mmol)
in CHCl3 (50 ml) using a similar procedure as described for 3,5-
di-tert-butyl-2-hydroxybenzyl bromide. The product was isolated
as a pale yellow liquid. Yield: 5.57 g (98%).
2.2.10. 5-tert-Butyl-2-hydroxybenzyl bromide
2.2.4. 5-tert-Butyl-2-hydroxybenzaldehyde
This compound was synthesised from 3-tert-butyl-2-hydroxy-
benzyl alcohol (3.74 g, 20.8 mmol) and PBr3 (1.0 ml, 10.4 mmol)
in CHCl3 (50 ml) using a similar procedure as described as for
3,5-di-tert-butyl-2-hydroxybenzyl bromide. The product was iso-
lated as a pale yellow liquid. Yield: 4.95 g (98%).
This compound was synthesised from 5-tert-butylphenol
(15.0 g, 100 mmol), tributylamine (9.6 ml, 40.0 mmol), paraformal-
dehyde (6.60 g, 220 mmol), and SnCl4 (1.2 ml, 10.0 mmol) in
toluene (15 ml) using a procedure similar to that of 3,5-di-tert-
butyl-2-hydroxybenzaldehyde. The compound was isolated as a
pale brown liquid. Yield: 13.0 g (73%). 1H NMR (CDCl3): d 9.89 (s,
1H, CHO), 7.59 (dd, J = 2.4 and 8.7 Hz, 1H, ArH), 7.52 (d,
J = 2.4 Hz, 1H, ArH), 6.94 (d, J = 8.7 Hz, 1H, ArH), 1.33 (s, 9H, But).
2.2.11. General procedure for the preparation of the proligands HLn
(n = 1–3)
A
solution of 3,5-substituted-2-hydroxybenzyl bromide
(1 equiv.) in THF (50 ml) was added dropwise to a solution of
N,N-bis(2-pyridylmethyl)amine in THF (50 ml) under nitrogen.
The resulting pale yellow mixture was stirred at room temperature
for 5 min. Triethylamine (1.5 molar equiv.) was added and the
reaction mixture was heated under reflux overnight. A pale brown
2.2.5. 3,5-Di-tert-butyl-2-hydroxybenzyl alcohol
NaBH4 (1.13 g, 30.0 mmol) was slowly added to a solution of
3,5-di-tert-butyl-2-hydroxybenzaldehyde (3.52 g, 15.0 mmol) in
MeOH (50 ml). The mixture turned from pale yellow to colourless

Y.-L. Wong et al. / Inorganica Chimica Acta 363 (2010) 1246–1253
1249
Table 1
solid formed, which was filtered off and discarded. The remaining
Crystallographic data for [Fe(L1)Cl2] (1) and [Fe(L2)Cl2] (2).
[Fe(L1)Cl2] (1)
yellowish brown filtrate was concentrated using a rotary evapora-
tor and the residue was chromatographed on a silica gel column
using CHCl3 followed by ethyl acetate as eluents. The second band
was collected and concentrated to give a pale yellow liquid.
[Fe(L2)Cl2] (2)
Molecular formula
Molecular weight
Colour
Crystal size (mm)
Crystal system
Space group
a (Å)
C27H34Cl2FeN3O
543.32
dark blue plate
0.42 ꢁ 0.35 ꢁ 0.10
orthorhombic
Pna21
26.996(5)
11.895(2)
9.1667(18)
90
C23H26Cl2FeN3O
487.22
dark blue plate
0.50 ꢁ 0.40 ꢁ 0.30
2.2.12. [N-(3,5-Di-tert-butyl-2-hydroxybenzyl)-N,N-di-(2-
triclinic
pyridylmethyl)]amine (HL1)
ꢀ
P1
According to the general procedure, 3,5-di-tert-butyl-2-
hydroxybenzyl bromide (4.23 g, 14.1 mmol) was stirred with
N,N-bis(2-pyridylmethyl)amine (2.81 g, 14.1 mmol) in THF
(100 ml) under nitrogen for 5 min. Triethylamine (2.9 ml,
21.2 mmol) was added and the resulting mixture was heated under
reflux overnight to give HL1 (5.00 g, 85%). 1H NMR (CDCl3): d 8.55
(d, J = 7.8 Hz, 2H, PyH), 7.61 (dt, J = 1.8, 7.8 Hz, 2H, PyH), 7.37 (d,
J = 7.8 Hz, 2H, PyH), 7.22 (d, J = 2.4 Hz, 1H, ArH), 7.11–7.15 (m,
2H, PyH), 6.89 (d, J = 2.4 Hz, 1H, ArH), 3.88 (s, 4H, PyCH2), 3.81 (s,
2H, ArCH2), 1.47 (s, 9H, But), 1.27 (s, 9H, But). 13C{1H} NMR: d
158.0, 153.7, 148.9, 140.2, 136.5, 135.4, 124.4, 123.5, 123.0,
122.1, 121.6, 59.4, 58.1, 34.9, 34.0, 31.6, 29.5. HRMS (LSI): m/z calc.
for C27H35N3O [M+H]+ 418.2853, found 418.2847.
7.9114(16)
8.1645(16)
20.033(4)
86.29(3)
81.79(3)
64.29(3)
1153.9(4)
2
1.402
0.904
2474
2474 (Rint = 0)
2175
b (Å)
c (Å)
a
(°)
b (°)
90
c
(°)
90
V (Å3)
2943.6(10)
4
1.226
Z
Density (g cmꢂ3
)
l
(mmꢂ1
)
0.716
Reflections collected
6004
Unique data measured
Observed data with I P 2
Number of parameters
2007 (Rint = 0.1622)
1910
308
R1 = 0.0783
wR2 = 0.1866
R1 = 0.0822
wR2 = 0.1902
r
(I)
272
Final R indices [I P 2
r
(I)]a
R1 = 0.0775
wR2 = 0.2307
R1 = 0.0842
wR2 = 0.2393
R indices (all data)a
2.2.13. [N-(3-tert-Butyl-2-hydroxybenzyl)-N,N-di-(2-
pyridylmethyl)]amine (HL2)
P
P
P
P
a
R1
=
||Fo| ꢂ |Fc||/ |Fo|; wR2 = { [w(F2o ꢂ Fc2)2]/ [w(Fo2)2]}1/2
.
According to the general procedure, 3-tert-butyl-2-hydroxyben-
zyl bromide (5.57 g, 22.9 mmol) was stirred with N,N-bis(2-pyri-
dylmethyl)amine (4.56 g, 22.9 mmol) in THF (100 ml) under
nitrogen for 5 min. Triethylamine (4.8 ml, 34.4 mmol) was added
the resulting mixture was heated under reflux overnight to give
HL2 (6.78 g, 82%). 1H NMR (CDCl3): d 8.56 (d, J = 6.6 Hz, 2H, PyH),
7.63 (dt, J = 1.2 and 7.7 Hz, 2H, PyH), 7.36 (d, J = 7.4 Hz, 2H, PyH),
7.14–7.21 (m, 3H, PyH and ArH), 6.92 (dd, J = 0.7 and 7.3 Hz, 1H,
ArH), 6.71 (t, J = 7.5 Hz, 1H, ArH), 3.87 (s, 4H, PyCH2), 3.82 (s, 2H,
ArCH2), 1.46 (s, 9H, But). 13C{1H} NMR: d 157.9, 156.4, 148.8,
136.7, 136.6, 128.0, 126.2, 123.5, 122.6, 122.2, 118.2, 59.2, 57.7,
34.7, 29.5. HRMS (LSI): m/z calc. for C23H28N3O [M+H]+ 362.2227,
found 362.2221.
2.7 mmol) in MeOH (10 ml) to give complex 1 (1.06 g, 72%) as a
dark blue solid. Recrystallisation of the crude product from CHCl3
afforded the title compound as dark blue crystals. HRMS (LSI): m/z
calc. for C27H35Cl2FeN3O [M+H]+ 542.1424, found 542.1406. Anal.
Calc. for C27H34Cl2FeN3O: C, 59.7; H, 6.3; N, 7.7. Found: C, 59.7;
H, 6.3; N, 7.7%.
2.2.17. [Fe(L2)Cl2] (2)
According to the general procedure, FeCl3ꢀ6H2O (0.27 g,
1.0 mmol) in MeOH (10 ml) was treated with HL2 (0.36 g,
1.0 mmol) in MeOH (10 ml) to give complex 2 (0.43 g, 88%) as a
dark purple solid. Recrystallisation of the crude product from
DMF afforded the title compound as dark blue crystals. HRMS
(ESI): m/z calc. for C23H26Cl2FeN3O [M+K]+ 525.0434, found
525.0435. Anal. Calc. for C23H26Cl2FeN3O: C, 56.7; H, 5.4; N, 8.6.
Found: C, 56.7; H, 5.4; N, 8.6%.
2.2.14. [N-(5-tert-Butyl-2-hydroxybenzyl)-N,N-di-(2-
pyridylmethyl)]amine (HL3)
According to the general procedure, 5-tert-butyl-2-hydroxyben-
zyl bromide (4.95 g, 20.4 mmol) was stirred with N,N-bis(2-pyri-
dylmethyl)amine (4.05 g, 20.4 mmol) in THF (100 ml) under
nitrogen for 5 min. Triethylamine (4.2 ml, 30.6 mmol) was added
and the resulting mixture was heated under reflux overnight to
give HL3 (5.38 g, 73%). 1H NMR (CDCl3): d 8.57 (d, J = 7.5 Hz, 2H,
PyH), 7.63 (dt, J = 1.8 and 7.7 Hz, 2H, PyH), 7.37 (d, J = 7.8 Hz, 2H,
PyH), 7.14-7.21 (m, 3H, PyH and ArH), 7.04 (d, J = 2.4 Hz, 1H,
PyH), 6.84 (d, J = 8.4 Hz, 1H, ArH), 3.90 (s, 4H, PyCH2), 3.79 (s, 2H,
ArCH2), 1.27 (s, 9H, But). 13C{1H} NMR: d 158.2, 155.0, 148.8,
141.4, 136.8, 126.9, 125.7, 123.2, 122.2, 121.8, 115.8, 59.1, 57.4,
33.8, 31.5. HRMS (LSI): m/z calc. for C23H28N3O [M+H]+ 362.2227,
found 362.2244.
2.2.18. [Fe(L3)Cl2] (3)
According to the general procedure, FeCl3ꢀ6H2O (0.35 g,
1.3 mmol) in MeOH (10 ml) was treated with HL3 (0.47 g,
1.3 mmol) in MeOH (10 ml) to give complex 3 (0.35 g, 56%) as a
dark blue solid. Recrystallisation of the crude product from DMF
afforded the title compound as dark blue crystals. HRMS (ESI): m/
z calc. for C23H26Cl2FeN3O [M+K]+ 525.0434, found 525.0450. Anal.
Calc. for C23H26Cl2FeN3O: C, 56.7; H, 5.4; N, 8.6. Found: C, 56.7; H,
5.4; N, 8.6%.
2.2.15. General procedure for the preparation of [Fe(Ln)Cl2] (n = 1–3)
To a pale brown methanolic solution of FeCl3ꢀ6H2O was added
an equimolar amount of HLn (n = 1–3) in methanol. Upon mixing,
a deep violet-blue suspension formed immediately. The resulting
mixture was gently heated at 50 °C and stirring was continued
for 15 min to ensure a complete reaction. The resulting dark blue
solid was collected by filtration, washed with small amount of eth-
anol, diethyl ether and hexanes, and dried in vacuo.
2.3. X-Ray crystallographic analysis
Single crystals of [Fe(L1)Cl2] (1) suitable for X-ray diffraction
analysis were grown from slow evaporation of a CHCl3 solution
in air, whereas suitable crystals of [Fe(L2)Cl2] (2) were obtained
by vapour diffusion of hexanes into a DMF solution.1 X-Ray data
were collected on a Rigaku RAXIS-IIC diffractometer at 293 K using
graphite-monochromatised Mo K
a radiation (k = 0.71073 Å) by
2.2.16. [Fe(L1)Cl2] (1)
1
According to the general procedure, FeCl3ꢀ6H2O (0.73 g,
Only thin plate crystals of complexes 1 and 2 could be obtained in our studies.
2.7 mmol) in MeOH (10 ml) was treated with HL1 (1.13 g,
This accounts for the unsatisfactory crystal data of the two complexes.

1250
Y.-L. Wong et al. / Inorganica Chimica Acta 363 (2010) 1246–1253
taking oscillation photos. Computations were performed using the
SHELX-97 PC programme package on a PC computer. The structures
were solved by direct phase determination and refined by full-ma-
trix least squares with anisotropic thermal parameters for the non-
hydrogen atoms [17]. Hydrogen atoms were introduced in their
idealised positions and included in structure factors calculations
with assigned isotropic temperature factors [18]. Selected crystal-
lographic data for 1 and 2 are shown in Table 1.
3. Results and discussion
3.1. Synthesis of ligands and Fe(III) complexes
Previous reports on the synthesis of the proligand [N-(3,5-di-
tert-butyl-2-hydroxybenzyl)-N,N-di-(2-pyridylmethyl)]amine
(HL1) involved the reaction of 3,5-(di-tert-butyl)-2-hydroxybenzal-
dehyde with bis(2-pyridylmethyl)amine [12,14a,15]. The latter
compound was prepared by reductive amination of 2-pyridinecar-
boxaldehyde with 2-(aminomethyl)pyridine. An alternative syn-
thetic route to HL1 was developed in our studies. As outlined in
Scheme 1, treatment of N,N-bis(2-pyridylmethyl)amine with 3,5-
di-tert-butyl-2-hydroxybenzyl bromide in the presence of triethyl-
amine in refluxing THF afforded HL1 in good yield. The related 3- or
5-tert-butyl-substituted derivatives HLn (n = 2, 3) were prepared in
a similar manner using the appropriate benzyl bromide. All the
compounds HLn (n = 1–3) were characterised by 1H and 13C NMR
spectroscopy and high-resolution mass spectrometry.
2.4. General procedure for catalytic DNA cleavage experiments
2.4.1. Isolation of supercoiled DNA
Three commercially available plasmids, namely pGEM-3Zf(+),
pUC18 and pBK-CMV, were used for the DNA cleavage experi-
ments. Supercoiled DNA was separated by electrophoresis tech-
nique on an agarose gel and further purified by the QLAEX II
Agarose GelExtraction Kit (QLAGEN)™. All centrifugation steps
were carried out at 13 000 rpm in a conventional bench-top
microcentrifuge. Ten microliters of the plasmid was loaded on a
0.8% agarose gel and electrophoresed at 70 V for 1 h. The gel was
then stained with ethidium (3,8-diamino-5-ethyl-6-phenylphe-
nanthridium) bromide. The supercoiled DNA fragment was excised
from the agarose gel using a clean and sharp scalpel. The gel slice
was weighed in a 1.5-ml microcentrifuge tube. Three volumes of
Buffer QX1 were added to one equivalent of gel slice. The QLAEX
Treatment of FeCl3ꢀ6H2O with one molar equivalent of HLn
(n = 1–3) in hot methanol led to the corresponding Fe(III) com-
plexes [Fe(Ln)Cl2] (1: n = 1, 2: n = 2, 3: n = 3) in good to satisfactory
yields (Scheme 2). Complexes 1 and 3 were isolated as dark blue
crystals, whereas 2 was obtained as dark purple crystals. Results
of elemental analysis were consistent with the empirical formula
of 1–3 as shown in Scheme 2. Complex 1 showed good solubility
in common organic solvents, whilst complexes 2 and 3 were found
to be less soluble. It is believed that the presence of two But sub-
stituents on the phenolate pendant arm of L1 enhances the solubil-
ity of 1 in organic solvents.
II was re-suspended by vortexing for 30 s. An aliquot of 10
ll of
QLAEX II was added to the sample, followed by incubation at
50 °C for 10 min. The QLAEX II was kept in suspension by vor-
texing every 2 min. The sample was centrifuged for 30 s and the
supernatant was removed using a pipette. The resulting pellet
was washed with Buffer QX1 (500 ll) to remove residual agarose
contaminants. The sample was centrifuged for another 30 s and
3.2. Structural studies
The molecular structures of [Fe(L1)Cl2] (1) and [Fe(L2)Cl2] (2)
were established by X-ray diffraction. The perspective views of
their structures are shown in Figs. 2 and 3, respectively. Selected
bond distances and angles for these complexes are summarised
in Table 2. Both complexes 1 and 2 are mononuclear and exhibit
a similar distorted octahedral geometry around the Fe atom. Com-
plex 1 crystallises in the orthorhombic space group Pna21 whereas
the supernatant was removed and discarded. The pellet was
washed with Buffer PE (2 ꢁ 500
ll) to remove residual salt con-
taminants. The sample was centrifuged for 30 s and all the super-
natant was removed. The pellet was air-dried for 10–15 min.
Water (20 ll) was added to re-suspend the pellet and the sample
was incubated at room temperature for 5 min. The DNA was
eluted by centrifugation for 30 s. The eluted DNA was stored at
ꢂ20 °C for further applications.
ꢀ
complex 2 crystallises in the triclinic space group P1: The Fe atom
in both complexes is bound by two pyridyl nitrogen atoms (N(1)
and N(2)), one amine nitrogen (N(3)), one phenolate oxygen, and
two terminal chloride ligands. The two pyridyl nitrogen atoms
N(1) and N(2) occupy cis coordination positions. The structural fea-
tures of 1 and 2 are close to those of the related [FeLCl2] complexes,
where L is [N-(2-hydroxybenzyl)-N,N-di-(2-pyridylmethyl)]amine
or [N-(5-nitro-2-hydroxybenzyl)-N,N-di-(2-pyridylmethyl)]amine
[11,13]. The Fe–O bond distances of 1.861(6) Å (in 1) and
1.885(5) Å (in 2) are similar to those of 1.884(5)–1.928(3) Å re-
2.4.2. DNA cleavage experiments
The DNA cleavage experiments were performed using various
combinations of plasmid DNA (4
l), hydrogen peroxide (10 mM, 4
0.1 M, 3 l) solutions. The reaction mixtures were incubated at
l
l), Fe complex (0.025 mM,
4
l
ll) in Tris buffer (pH 7.4,
l
25 °C for 1 h. The DNA products were electrophoresed on a 0.8%
agarose gel stained with ethidium bromide at 70 V for 1 h and vis-
ualised under ultra-violet illumination.
R4
Cl
R4
OH
N
Cl
O
Fe
N
MeOH
50°C
.
N
+
N
FeCl3 6H2O
R5
R5
N
N
R4 = R5 = But
2: R4 = But, R5 = H
(72%)
(88%)
1:
R4 = H, R5 = But (56%)
3:
Scheme 2.

Y.-L. Wong et al. / Inorganica Chimica Acta 363 (2010) 1246–1253
1251
The two chloride ligands are located at slightly different distances
from the Fe atom: 2.296(3) and 2.348(3) Å in 1, and 2.289(3) and
2.347(2) Å in 2. This is ascribed to the different ligands located
trans to each chloride anion. The Fe–Cl distances in 1 and 2 are
close to those of 2.271(2)–2.334(3) Å reported for the [FeLCl2] com-
plexes. A few dichloro-iron(II) and -iron(III) complexes, supported
by tripodal tetradentate ligands, which contained asymmetric Fe–
Cl bond distances have also been reported [19,13].
3.3. UV–Vis absorption spectra and electrochemical properties
The electronic spectra of complexes 1–3 in acetonitrile are dom-
inated by two distinct absorption bands at 361–362 and 624–
662 nm, respectively (Fig. 4 and Table 3). The lower energy absorp-
tion bands were assigned to phenolate-to-iron(III) charge-transfer
transitions [8,13,20]. The energy of these charge-transfer bands
follows the order [Fe(L1)Cl2] (1) < [Fe(L2)Cl2] (2) ꢃ [Fe(L3)Cl2] (3),
which is related to the number of tert-butyl substituents on the
phenolate pendant arm of the Ln ligands. It is believed that the
presence of two electron-donating tert-butyl substituents on L1
raises the energy of the frontier orbitals of this ligand. This results
in a decrease in the corresponding ligand-to-metal energy gap of 1
and, hence, the lowest energy for its phenolate-to-iron charge-
transfer transitions (kmax = 662 nm) as compared to those of com-
plexes 2 and 3 [20]. In contrast, the higher energy absorption bands
at 361–362 nm for 1–3 were found to be independent of the sub-
Fig. 2. Molecular structure of [Fe(L1)Cl2] (1) (30% thermal ellipsoid) with atom
labelling. Hydrogen atoms are omitted for clarity.
stitution pattern of the Ln ligands. They probably arise from
*
p
? p
transitions due to the Ln ligands or amine-to-iron(III)
charge-transfer transitions.
The electronic spectra of complexes 1–3 in MeCN/H2O (3:2, v/v)
were also recorded (Figs. S1–S3 in Supplementary material) in or-
der to study the stability of the three complexes in aqueous solu-
tion. The presence of the low-energy absorption bands at 631–
680 nm (which can be assignable to phenolate-to-iron(III)
Fig. 3. Molecular structure of [Fe(L2)Cl2] (2) (30% thermal ellipsoid) with atom
labelling. Hydrogen atoms are omitted for clarity.
Table 2
Selected bond distances (Å) and angles (°) for [Fe(L1)Cl2] (1) and [Fe(L2)Cl2] (2).
[Fe(L1)Cl2] (1)
[Fe(L2)Cl2] (2)
Fe(1)–O(1)
Fe(1)–N(1)
Fe(1)–N(2)
Fe(1)–N(3)
Fe(1)–Cl(1)
Fe(1)–Cl(2)
C(19)–O(1)
N(1)–Fe(1)–N(2)
N(1)–Fe(1)–N(3)
N(2)–Fe(1)–N(3)
O(1)–Fe(1)–N(1)
O(1)–Fe(1)–N(2)
O(1)–Fe(1)–N(3)
O(1)–Fe(1)–Cl(1)
O(1)–Fe(1)–Cl(2)
N(1)–Fe(1)–Cl(1)
N(2)–Fe(1)–Cl(1)
N(3)–Fe(1)–Cl(1)
N(1)–Fe(1)–Cl(2)
N(2)–Fe(1)–Cl(2)
N(3)–Fe(1)–Cl(2)
Cl(1)–Fe(1)–Cl(2)
C(19)–O(1)–Fe(1)
1.861(6)
2.168(8)
2.209(9)
2.213(7)
2.296(3)
2.348(3)
1.35(1)
81.1(3)
74.6(3)
77.6(3)
162.5(3)
90.9(3)
88.4(3)
99.8(2)
96.5(2)
96.0(2)
91.4(2)
166.4(2)
89.0(2)
167.6(2)
92.6(2)
97.1(1)
133.6(6)
1.885(5)
2.229(6)
2.230(6)
2.231(6)
2.289(3)
2.347(2)
1.339(8)
88.0(2)
73.2(2)
76.4(2)
162.8(3)
86.7(2)
89.6(2)
102.1(1)
96.0(1)
94.4(2)
91.5(1)
162.8(2)
86.9(1)
170.7(1)
94.6(1)
96.7(1)
133.4(4)
Fig. 4. UV–Vis absorption spectra of complexes 1–3 (1.67 ꢁ 10ꢂ4 M) in MeCN.
Table 3
UV–Vis spectral dataa of complexes 1–3.
ported for the [FeLCl2] complexes. The Fe–N(pyridyl) bond lengths
of 2.168(8) and 2.209(9) Å (in 1), and 2.229(6) and 2.230(6) Å (in 2)
are comparable to those of 2.195(3)–2.217(7) Å in [FeLCl2]. The Fe–
N(amine) bond distances in 1 and 2 are similar, viz. 2.213(7) and
2.231(6) Å, respectively. They correlate well with the correspond-
ing distances of 2.231(6)–2.250(3) in the [FeLCl2] counterparts.
Complex
kmax [nm] (e
[Mꢂ1 cmꢂ1])
[Fe(L1)Cl2] (1)
[Fe(L2)Cl2] (2)
[Fe(L3)Cl2] (3)
662 (2059), 362 (4634)
625 (2127), 362 (5019)
624 (1198), 361 (5604)
a
Concentration of iron complexes = 1.67 ꢁ 10ꢂ4 M in MeCN.

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Y.-L. Wong et al. / Inorganica Chimica Acta 363 (2010) 1246–1253
Table 4
1
2
3
4
5
6
M
Redox potentialsa of complexes 1–3 in MeCN solutions.
Complex
Oxidation
Reduction
[Fe(L1)Cl2]
(1)
quasi-
reversible
irreversible
Eopx = 0.69 V
Erped = 0.59 V
Eopx = 0.69 V
Erped = 0.42 V
Eopx = 0.67 V
Erped = ꢂ0.84 V
Erped = ꢂ0.76 V
Erped = ꢂ0.46 V
[Fe(L2)Cl2]
(2)
quasi-
reversible
irreversible
irreversible
linear
[Fe(L3)Cl2]
(3)
irreversible
4.0
3.0
supercoiled
a
All potentials were referenced to the ferrocenium/ferrocene redox couple. Scan
rate = 100 mV sꢂ1
2.0
1.6
.
charge-transfer transitions) suggests that the Ln ligands remain
coordinated to the iron(III) ion in aqueous MeCN solutions. Small
red-shifts of these low-energy absorption bands were observed
in comparison with the corresponding absorptions in the UV–Vis
spectra of complexes 1–3 collected in pure MeCN. The shifts in
the low-energy absorption maxima together with the spectral
changes associated with the higher energy absorption bands at
ꢄ360 nm may be ascribed to substitution of the chloride ligands
in complexes 1–3 by water molecules or OHꢂ anions [11].
pBK-CMV
Fig. 6. DNA cleavage of pBK-CMV by 1 in the presence of H2O2 in Tris buffer
solutions. The DNA degradation products were resolved on 0.8% agarose gel stained
with ethidium bromide and visualised by UV illumination. Lane 1: pBK-CMV,
10 mM H2O2; Lane 2: pBK-CMV, complex 1, 10 mM H2O2; Lane 3: pBK-CMV,
complex 1; Lane 4: pBK-CMV; Lane 5: pBK-CMV, FeCl3, 10 mM H2O2; Lane 6: pBK-
CMV, FeCl3; and Lane M: 1 kb molecular ladder.
The electrochemical properties of complexes 1–3 were studied
by cyclic voltammetry in acetonitrile solutions with tetrabutylam-
monium hexafluorophosphate as the supporting electrolyte. Table
4 summarises the redox potentials (referenced to the FeCp2þ/FeCp2
redox couple) of 1–3. All of the three complexes show similar elec-
trochemical behaviour, consisting of one quasi-reversible to irre-
versible oxidation wave at 0.42–0.69 V, and an irreversible
process at ꢂ0.46 to ꢂ0.84 V. Fig. 5 shows the cyclic voltammogram
of [Fe(L1)Cl2] (1). The quasi-reversible oxidation process at about
presence of impurities in the solution or new species generated
from the oxidation of 1.
3.4. DNA cleavage
Bleomycin is a glycopeptide antibiotic currently used in chemo-
therapy against carcinomas [21]. Bleomycin promotes DNA cleav-
age in the presence of iron and dioxygen [22,23]. Based on
results from spectroscopic studies, activated bleomycin is believed
to have an iron(III)–peroxide site [24–26] Accordingly, a number of
transition metal complexes which served as synthetic analogues
for activated bleomycin have been reported [27–29].
0.65 V (Eopx = 0.69 V, Erped = 0.59 V,
DEp = 100 mV) corresponds to
phenolate-to-phenoxyl radical oxidation, whereas the irreversible
reduction process at Erped = ꢂ0.84 V can be attributed to the reduc-
tion of Fe(III) to Fe(II). The reversibility of the phenolate oxidation
process decreases in the order 1 > 2 > 3, which is dependent on the
substitution pattern of the phenolate pendant of Ln. It is notewor-
thy that the presence of tert-butyl substituents at ortho and para
positions of the coordinated phenolate group enhances the stabil-
ity of the corresponding phenoxyl radical species. The small redox
processes at about 0 V and ꢂ0.5 V may be attributed either to the
A preliminary study on the nuclease activity of [Fe(L1)Cl2] (1) in
the presence of H2O2 under ambient conditions was carried out.2
Three commercially available plasmids, namely pBK-CMV, pUC18
and pGEM-3Zf(+), were chosen for DNA cleavage experiments.
Fig. 6 shows the reactivity of complex 1 towards oxidative DNA
cleavage of the pBK-CMV plasmid with 10 mM H2O2 in Tris buffer
solutions. The DNA cleavage activity of 1 on the pUC18 and pGEM-
3Zf(+) plasmids under identical conditions are depicted in Figs. S4
and S5 (Supporting material), respectively. Complex 1 exhibited sig-
nificant oxidative DNA cleavage activities on the three plasmids,
converting their respective supercoiled form to linear form. Nishida
and co-workers have reported the DNA cleavage activity of the re-
lated [FeLCl2] complex, where L is the unsubstituted [N-(2-hydroxy-
benzyl)-N,N-di-(2-pyridylmethyl)]amine ligand [11]. The latter
complex was reported to promote the conversion of supercoiled
DNA to both relaxed circular as well as linear forms, and an iro-
n(III)–peroxide species was proposed to be an active intermediate
in the DNA cleavage reactions.3 Apparently, addition of H2O2 to com-
plex 1 results in the formation of a similar iron(III)–peroxide inter-
mediate species, which leads to subsequent DNA cleavage.3 In
order to determine if DNA cleavage reactivity stems from intact or
2
Owing to the relatively poor solubility of complexes 2 and 3 in aqueous solution,
the corresponding DNA cleavage experiments were not conducted.
3
Addition of hydrogen peroxide to a solution of complexes 1–3 in MeCN resulted
in disappearance of the phenolate-to-iron(III) charge-transfer bands at 624–662 nm
(Figs. S1–S3, Supplementary Information). This observation suggests the disappear-
ance of the phenolate group and, conceivably, with concomitant formation of an
iron(III)–peroxide species (Ref. [11] and references cited therein).
Fig. 5. Cyclic voltammogram of [Fe(L1)Cl2] (1) in MeCN solution with (NBu4)(PF6)
(0.15 M) as the supporting electrolyte. Scan rate = 100 mV sꢂ1
.

Y.-L. Wong et al. / Inorganica Chimica Acta 363 (2010) 1246–1253
1253
degraded complexes, control studies on oxidative DNA cleavage with
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This work was supported by a Direct Grant (A/C 2060300) of
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CCDC 733621 and 733622 contain the supplementary crystallo-
graphic data for 1 and 2. These data can be obtained free of charge
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cam.ac.uk/data_request/cif.
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4
We thank the reviewers of this paper for their valuable advice on carrying out
control experiments on oxidative DNA cleavage with free iron(III) ion.