Mercury binding by ferrocenoyl peptides with sulfur-containing side chains: Electrochemical, spectroscopic and structural studies

Article abstract of DOI:10.1016/j.jorganchem.2008.06.005

Ferrocenoyl peptides incorporating amino acids derived from either l-methionine, l-cysteine or dl-homocysteine have been synthesised and investigated as agents for heavy metal binding and detection. Heavy metal-peptide interactions have been characterised using cyclic voltammetry to follow changes in the potential of the Fe(II)/Fe(III) redox couple, revealing that these systems interact with mercury(II) ions more strongly than with other thiophilic heavy metals such as cadmium(II), silver(I) and lead(II). Proton NMR experiments have demonstrated 1:1 peptide:mercury binding and enabled quantitative characterisation of this binding interaction. Crystal structures for two of these ferrocenoyl peptide derivatives have been elucidated, revealing that these compounds adopt a P-1,3′ open solid state conformation in the absence of mercury; this arrangement precludes intramolecular hydrogen bonding between chains, while extensive intermolecular hydrogen bonding is evident. The particular affinity of these systems for mercury(II) opens the possibility of incorporating them in new, biologically inspired sensors for detecting this toxic pollutant.

Full text of DOI:10.1016/j.jorganchem.2008.06.005

Journal of Organometallic Chemistry 693 (2008) 2869–2876
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Mercury binding by ferrocenoyl peptides with sulfur-containing side chains:
Electrochemical, spectroscopic and structural studies
Conor C.G. Scully a,b, Paul Jensen a, Peter J. Rutledge a,
*
a School of Chemistry F11, University of Sydney, NSW 2006, Australia
b Centre for Synthesis and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
Ferrocenoyl peptides incorporating amino acids derived from either L-methionine, L-cysteine or DL-homo-
Received 7 December 2007
Received in revised form 28 May 2008
Accepted 2 June 2008
cysteine have been synthesised and investigated as agents for heavy metal binding and detection. Heavy
metal–peptide interactions have been characterised using cyclic voltammetry to follow changes in the
potential of the Fe(II)/Fe(III) redox couple, revealing that these systems interact with mercury(II) ions
more strongly than with other thiophilic heavy metals such as cadmium(II), silver(I) and lead(II). Proton
NMR experiments have demonstrated 1:1 peptide:mercury binding and enabled quantitative character-
isation of this binding interaction. Crystal structures for two of these ferrocenoyl peptide derivatives have
been elucidated, revealing that these compounds adopt a P-1,30 open solid state conformation in the
absence of mercury; this arrangement precludes intramolecular hydrogen bonding between chains, while
extensive intermolecular hydrogen bonding is evident. The particular affinity of these systems for mer-
cury(II) opens the possibility of incorporating them in new, biologically inspired sensors for detecting this
toxic pollutant.
Available online 7 June 2008
Keywords:
Bioorganometallic chemistry
Ferrocene compounds
Mercury
Toxic metal ions
Amino acids
Peptides
Ó 2008 Elsevier B.V. All rights reserved.
1. Introduction
Because of the high toxicity of mercury and its derivatives, con-
siderable effort has been invested in the development of efficient
The heavy metals of Group 12 constitute some of the most toxic
materials known in Nature [1,2]. Both mercury and cadmium are
capable of attacking their respective target organs in humans at
very low concentrations, with the kidneys most affected by both
elements [1,2]. Without a defense mechanism against them, ani-
mal and plant life in locales prone to high levels of cadmium and
mercury pollution would be at substantial risk of poisoning by
these toxins [3].
Central to biological defense strategies against heavy metal poi-
soning are sulfur-rich metal-sequestering proteins, metallothione-
ins (MTs) and phytochelatins (PCs) [4,5]. Sulfur donor atoms are
found at the metal-binding sites of many metalloenzymes and pro-
teins, and bind tightly to various soft metal ions [6]. However MTs
represent a special subset of sulfur-containing proteins, possessing
very high percentages of cysteine residues (up to 30% of the pri-
mary structure) [5], much higher than most metal-binding pro-
teins. It is this characteristic that makes MTs effective agents for
the sequestration of both mercury(II) and cadmium(II) ions: the
numerous sulfur atoms bind these metals tightly, locking them
away either permanently or until they can be excreted from the
organism.
strategies for their detection [7–9]. Redox-active systems demon-
strating excellent sensitivity and high selectivity for mercury over
other metals have been reported previously [10–12]. Most of these
involve fluorescent or colorimetric techniques, but some electro-
chemical systems are also known [13].
Ferrocene derivatives have been extensively utilised to study
the interactions of chemical hosts with metal ions and other sub-
strates, exploiting the electrochemical properties of the Fe(II)/
Fe(III) redox couple [14–18]. The highly reproducible redox behav-
iour of the ferrocene/ferrocenium redox system enables a range of
electrochemical methods, with cyclic voltammetry (CV) most com-
monly employed [14,16].
In parallel, the bio-organometallic chemistry of ferrocene has
attracted considerable attention in recent years, and the literature
concerning the preparation and properties of ferrocenoyl peptide
derivatives is expanding rapidly [19–22]. However the use of ferr-
ocenoyl peptides in cation sensing applications has received com-
paratively little attention to date. Kraatz et al. recently utilised
ferrocene-containing bioconjugates for the selective detection of
various cations including Li(I), K(I), Cs(I), Mg(II) and La(III)
[23,17], and in a related study Cheng et al. have prepared a family
of ferrocene-linked cyclopseudopeptides and examined their bind-
ing properties to alkaline earth metals [24].
Our strategy uses sulfur-containing amino acids and peptides
based on the metal-binding motif of MTs in conjunction with the
* Corresponding author. Tel.: +61 2 9351 5020; fax: +61 2 9351 3329.
E-mail address: p.rutledge@chem.usyd.edu.au (P.J. Rutledge).
0022-328X/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2008.06.005

2870
C.C.G. Scully et al. / Journal of Organometallic Chemistry 693 (2008) 2869–2876
SR
SR
Ph
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
H
N
H
N
H
N
H
O
O
S
S
O
O
O
O
Fe
Fe
Fe
Fe
H
N
H
N
H
N
H
N
O
O
O
SR
Ph
SR
7
Me
1
6
R =
2
3
4
5
R = Me
8
R = CPh3
R = CH2Ph
R = CHPh2
R = CPh3
Fig. 1. Ferrocenoyl amino acid derivatives 1–8.
iron(II)/iron(III) redox couple of ferrocene as an electrochemical re-
porter, to realise new systems for heavy metal recognition and
detection. As part of this approach to utilise amino acid and pep-
tide derivatives for sensing heavy metals in a biomimetic context,
we report herein the synthesis and metal-binding properties of
2. Results and discussion
2.1. Synthesis of ferrocenoyl peptides
Ferrocenoyl peptides 1–7 were synthesised from ferrocene-1,10-
dicarboxylic acid 9 and 2 equiv. of the corresponding amino acid
methyl ester, coupled using standard peptide coupling methods
(Fig. 2) [25]. The cyclic peptide 8 was prepared by coupling ferro-
ferrocenoyl peptides derived from
DL-homocysteine (Fig. 1): the methionine analogue Fe(C5H4–CO–
Met–OMe)2 (1), four thioether derivatives of -cysteine Fe(C5H4–
L-methionine, L-cysteine or
L
cene-1,10-dicarboxylic acid and
L-cystine dimethyl ester at high
CO–Cys(Me)–OMe)2 (2), Fe(C5H4–CO–Cys(Bn)–OMe)2 (3), Fe(C5H4–
CO–Cys(Bzh)–OMe)2 (4), Fe(C5H4–CO–Cys(Trt)–OMe)2 (5), and the
S-tritylhomocysteine compound Fe(C5H4–CO–hCys(Trt)–OMe)2
dilution (0.001 mol Lꢀ1) and over an extended reaction time
(72 h). All compounds were fully characterised. The methionine
derivative 1 and the S-benzylcysteine compound 3 have previously
been reported as part of investigations into the hydrogen bonding
properties and helical chirality of ferrocenoyl peptides [26,27],
while the phenylalanine analogue 7 [28,29] and cystine derivative
8 [24] have also been synthesised previously.
(6); we have also tested the
CO–Phe–OMe)2 7 as a negative control (since this compound lacks
the key sulfur atoms) and the cyclic -cystine derivative 8.
L-phenylalanine analogue Fe(C5H4–
L
The results presented here examine the effect of the ‘R’ group
attached to sulfur on the metal-binding affinity of ferrocenoyl pep-
tides 1–6. Four different thioether groups are present in these com-
pounds, with differing steric and electronic properties: methyl,
benzyl (CH2Ph), benzhydryl (CHPh2) and trityl (CPh3). The corre-
sponding free thiol derivatives were also investigated (c.f. com-
pounds 1 and 2 above, with R = H), as it is the SH group that is
responsible for heavy metal binding in vivo. However under the
conditions used for these binding studies, molecules containing
the free thiols bind indiscriminately to transition metal ions and
immediately form insoluble precipitates.
Modulating the steric and electronic properties of the sulfur
atom using a sulfide in place of the cysteine thiol aids solubility
and brings selectivity to interactions of these ferrocenoyl peptides
with metal ions: mercury binds to the sulfide derivatives while
cadmium, zinc, silver and lead interact weakly or not at all. These
interactions have been characterised electrochemically and by
NMR. The solid state structures of two representative compounds
2.2. Electrochemistry
To probe the metal-binding properties of the ferrocenoyl pep-
tides 1–8, cyclic voltammetry was carried out on these compounds
in the presence and absence of the metal ions Hg(II), Cd(II), Zn(II),
Pb(II) and Ag(I) in acetonitrile solution. In the ‘free’ state – i.e. with-
out an additional metal salt present – all of these ferrocene deriv-
atives demonstrate the expected fully reversible one-electron
oxidation of Fe(II) to Fe(III) (Table 1). The forward sweep half wave
peaks (EF), reverse sweep half wave peaks (ER), peak separations
(DEP) and half wave potentials (E1/2) are summarised in Table 1.
The half wave potentials measured for these compounds are in
good agreement with those presented elsewhere for such systems
[30,31]. Covalently bound amino acids exert an electron withdraw-
ing effect on ferrocene due to the amide bond, which effectively
lowers the electron density on the cyclopentadienyl ring making
the iron(II) centre more difficult to oxidise; thus the redox poten-
(the
L-methionine and S-methyl-L-cysteine compounds 1 and 2)
have also been elucidated.
O
O
R
O
O
OH
OH
N
H
R
HBTU, Et3N, DCM/DMF
24 h, 51-85%
O
O
O
+
2
Fe
Fe
H2N
H
N
O
O
O
R
9
1-7
Fig. 2. Synthesis of 1,10-substituted ferrocenoyl peptides 1–7. Yields: 1 R = CH2CH2SMe 51%; 2 R = CH2SMe 85%; 3 R = CH2SCH2Ph 65%; 4 R = CH2SCHPh2 77%; 5 R = CH2SCPh3
72%; 6 R = CH2CH2SCPh3 73%; 7 R = CH2Ph 58%. (For the cyclic peptide 8, starting materials were ferrocene-1,10-dicarboxylic acid and
L-cystine dimethyl ester, reaction time
72 h, yield 29%.)

C.C.G. Scully et al. / Journal of Organometallic Chemistry 693 (2008) 2869–2876
2871
Table 1
[14,16]. Upon addition of Hg(II) (as a solution of Hg(NO3)2 in ace-
tonitrile), the redox potentials of ferrocenoyl peptides 1, 2, 3, 5
and 6 shift to higher potential, with the extent of the shift depen-
dent on the concentration of mercury in the system (Fig. 3 and 4,
Table 2). The highest shift in redox potential is shown by
Fe(C5H4–Cys(Me)–OMe)2 (2) which, in the presence of 2 equiv. of
Hg(II) changes by 69 mV from the redox potential of the free pep-
tide; the other four compounds exhibit potential changes of be-
tween 31 and 47 mV in response to Hg(II). These changes are
modest, but are comparable to shifts exhibited by other cation-
binding ferrocenoyl peptide systems [17,23]. Each mercury re-
sponse curve shows a similar plateau effect, with potential changes
halting abruptly once between one and 2 equiv. of Hg(II) have been
added (reflecting the limited binding capacity of each molecule).
Maximum responses for each molecule are summarised in Table 2.
The most striking outcome of this electrochemical analysis is the
preference of these compounds for Hg(II) over other metal cations
(Fig. 3 and Supplementary material). In contrast to the changes ob-
served in response to Hg(II), compounds 1, 2, 3, 5 and 6 show little
or no response to other thiophilic metals such as Cd(II), Zn(II), Pb(II)
and Ag(I). Each of these compounds also exhibits some affinity for
other metals, but always significantly less than their affinity for
Hg(II). For example Fe(C5H4–CO–Cys(Trt)–OMe)2 (5) shows a small
response to Cd(II) and Zn(II), to a total shift of only 5 mV over the
same concentration range at which Hg(II) induces a 60 mV shift.
Fe(C5H4–CO–Cys(Me)–OMe)2 (2) undergoes a positive shift of
8 mV in response to Ag(I), and Fe(C5H4–CO–hCys(Trt)–OMe)2 (6)
undergoes a similar shift in response to Cd(II). All other compounds
experience only slight perturbations in the presence of other cat-
ions tested, none higher than the accepted experimental error of
5 mV. This observation correlates with results reported by Lippolis,
who observed that the incorporation of sulfur atoms into a macro-
cyclic system imparted a similar selectivity for Hg(II) over Cd(II),
Pb(II) and Zn(II) [34], and raises interesting possibilities for the
development of new, mercury-selective sensor systems based on
ferrocenoyl peptides.
Basic electrochemical properties of 1,10-substituted ferrocenoyl compounds
Compound
EF (mV)
ER (mV)
D
EP (mV)
T (mV)
½
1
2
3
4
5
6
7
8
856
868
861
868
883
870
821
842
795
794
794
800
807
799
758
778
61
74
67
68
76
71
63
64
826
831
828
834
846
835
790
810
tial is raised relative to ferrocene itself (E1/2 = 448 mV versus Ag/
Ag+) [23]. In addition to the electron withdrawing effect of the
amide, the amino acid side chain also influences the redox poten-
tial of the ferrocene core, as borne out by the observation that com-
pounds 1–6 with sulfur-containing residues appended to the
cyclopentadiene ring exhibit higher potentials than the phenylala-
nine derivative 7 which incorporates a non-polar side chain. The
through-bond distance between the sulfur and the redox core also
effects the redox potential: compare the redox potentials of
Fe(C5H4–CO–Met–OMe)2 (1) (826 mV) vs. Fe(C5H4–CO–Cys(Me)–
OMe)2 (2) (831 mV), or Fe(C5H4–CO–hCys(Trt)–OMe)2 (6)
(835 mV) vs. Fe(C5H4–CO–Cys(Trt)–OMe)2 (5) (846 mV).
The reversibility of the redox event is indicated by the peak sep-
arations: the theoretical peak separation for a diffusion-limited re-
dox event involving the transfer of one electron is 59 mV [32]. In
practice, uncompensated resistance exists in the solvent between
the reference electrode and the working electrode, so actual values
for the peak separation can deviate such that a difference of 10–
20 mV above the theoretical value is not uncommon [33]. Of the
compounds tested, Fe(C5H4–CO–Met–OMe)2 (1) has the smallest
peak separation at 61 mV and Fe(C5H4–CO–Cys(Trt)–OMe)2 (5)
has the highest at 76 mV; the majority of the values measured
deviate by less than 10 mV from the theoretical value.
Complexation of such systems with a cation usually causes a
positive shift in the Fe(II)/Fe(III) redox potential, because the posi-
tive charge on the adjacent ion inhibits oxidation of the iron centre
In addition to selectivity, a second important factor to consider
when discussing the response of these systems to Hg(II) is
Fig. 3. Titration curves for ferrocenoyl peptide 2 Fe(C5H4–CO–Cys(Me)–OMe)2 in response to metal ions Hg(II), Cd(II), Zn(II), Pb(II) and Ag(I), as demonstrated by changes in
the potential of the Fe(II)/Fe(III) redox couple in CH3CN solution. Data points are characterised by y-axis standard error bars calculated from the standard error equation in
Microsoft EXCELÒ and are connected by a trendline based on the points.

2872
C.C.G. Scully et al. / Journal of Organometallic Chemistry 693 (2008) 2869–2876
Fig. 4. Activity of S-containing ferrocenoyl peptides 1–6 in response to mercury, demonstrated by changes in the potential of the Fe(II)/Fe(III) redox couple (all in CH3CN
solution).
sensitivity. This is inherent in how quickly the redox potential
changes with respect to increasing mercury concentration, so can
be calculated from the slope of the mercury response line. The S-
methylcysteine analogue Fe(C5H4–CO–Cys(Me)–OMe)2 (2) is the
most sensitive (1.73 mV ppmꢀ1) of these compounds, but the sen-
sitivity we have observed does not come close to the best mercury
sensors reported previously [7,8,35,36].
since both the S-benzylcysteine 3 and S-tritylcysteine 5 analogues
respond to mercury, and the S-benzhydryl group would be ex-
pected to display properties intermediate between these two
(CH2Ph vs. CHPh2 vs. CPh3).
2.3. NMR binding studies
Control experiments were carried out using ferrocene itself and
the phenylalanine derivative Fe(C5H4–CO–Phe–OMe)2 (7), neither
of which includes a metal-binding sulfide, to test for interactions
between ‘non-sulfur’ regions of the ferrocenoyl peptide and metal
ions. Monitoring the redox potentials of these derivatives upon
stepwise addition of mercury(II) nitrate showed both to be unaf-
fected by the heavy metal ions (data not shown), confirming that
sulfur–mercury interactions are central to the metal binding
observed.
NMR analysis provides further evidence of the interaction be-
tween Hg(II) and the sulfur centres in these ferrocenoyl peptides
in solution (Fig. 5; NMR binding experiments were carried out in
DMSO-d6 as the mercury–peptide complexes are not sufficiently
soluble in CD3CN at the concentrations required for this analysis).
In the absence of mercury, the SCH3 protons in Fe(C5H4–CO–Met–
OMe)2 (1) resonate at 2.12 ppm (Fig. 5a), while on addition of mer-
cury(II) nitrate, these protons shift downfield, moving to 2.28 ppm
with 0.5 equiv. and 2.44 ppm with 1 equiv.,
a total shift of
In a less expected result, the cyclic system 8 also demonstrated
no discernible redox change upon addition of mercury. This mole-
cule has previously been used to recognise alkaline-earth metals
via a binding mode that involves encapsulating the cation via the
amide groups [24]. A different mode of interaction was anticipated
in the context of heavy metal sensing. It is known that metal ions
such as Hg(II) can reduce disulfide bridges in cystinyl peptides
[37], and it was anticipated that this could allow the peptide 8 to
bind strongly to mercury and respond electrochemically. However
it is apparent that this does not occur at the concentrations exam-
ined here (0–60 ppm). More surprising again, the S-benzhydryl
compound Fe(C5H4–CO–Cys(Bzh)–OMe)2 4 also failed to respond
to the presence of Hg(II). The reasons behind this are not clear,
0.32 ppm. The methylene protons CH2SCH3 exhibit a correspond-
ing perturbation, experiencing a total downfield shift of 0.40 ppm
upon complexation. The signals of protons further from sulfur
are also affected by metal addition, shifted downfield to a lesser
extent as would be expected; for example the amide protons in
1, four bonds distant from the metal-binding sulfur atoms, move
only by 0.10 ppm. In sharp contrast to the changes seen in the
presence of Hg(II), the NMR spectrum of 1 does not change discern-
ibly in the presence of Cd(II) or Zn(II), confirming that there is little
or no interaction between these metal ions and the peptide. A sim-
ilar set of NMR results is seen with the S-methylcysteine com-
pound 2 (data not shown).
A series of NMR titrations were carried out with compounds 1
and 2, and changes in the NMR shifts utilised to calculate the asso-
ciation constants of each peptide with Hg(II). Job plots reveal a 1:1
binding stoichiometry in each case (Supplementary material), so
the results were analysed as a binary mixture according to the pro-
cedure of Hunter et al. [38]. The association constants were calcu-
Table 2
Hg(II) binding properties of 1,10-substituted compounds
Compound
Maximum potential
shift (mV)
Hg(II) saturation
point (ppm)
Sensitivity
(mV ppmꢀ1
lated to be 21 L molꢀ1 for the
25 L molꢀ1 for the S-methyl-
-cysteine derivative 2. These values
L-methionine complex 1 and
)
L
1
2
3
5
6
47
69
40
31
33
53
40
51
58
36
0.89
1.73
0.78
0.53
0.92
indicate weak binding (<104 L molꢀ1) [36], which is presumably
due primarily to the solvent environment (DMSO-d6): much stron-
ger interactions (ꢁ106 L molꢀ1) between methionine/S-methylcys-
teine and Hg(II) would be expected under aqueous conditions
[39,40]. The similar values obtained for the two complexes reflect
the similar binding environments in the two peptides.
Compounds 4, 7 and 8 are not shown because no response to mercury was observed
for these compounds.

C.C.G. Scully et al. / Journal of Organometallic Chemistry 693 (2008) 2869–2876
2873
Table 3
Crystallographic data for 1 and 2
Fe(C5H4–CO–Met–OMe)2
(1)
Fe(C5H4–CO–Cys(Me)–OMe)2
(2)
Formula of the
refinement
model
Model molecular
weight
C
24H32FeN2O6S2
C22H28FeN2O6S2
536.43
564.49
Crystal system
Space group
a (Å)
Triclinic
P1 (#1)
Orthorhombic
P212121 (#19)
12.2256(4)
19.8102(7)
40.4300(14)
9791.8(6)
1.456
10.003(1)
10.547(1)
12.536(2)
1308.1(3)
1.433
b (Å)
c (Å)
V (Å3)
Dcalc (g cmꢀ3
)
Z
2
16
Crystal colour
Crystal habit
Orange
Plate
Orange
Plate
Crystal size (mm)
Temperature (K)
0.44 ꢂ 0.27 ꢂ 0.14
0.29 ꢂ 0.27 ꢂ 0.08
150(2)
150(2)
k(Mo K
a
a
) (Å)
0.7107
0.777
0.7107
0.827
l
(Mo K
) (mmꢀ1
)
T(Gaussian)min,max
2hmax (°)
hkl range
N
0.747, 0.905
56.62
0.794, 0.936
60
ꢀ12 13, ꢀ13 13, ꢀ16 16
ꢀ17 17, ꢀ27 27, ꢀ56 55
12488
70809
Nind
10760 (Rmerge 0.0357)
28136 (Rmerge 0.0205)
Nobs
10083 (I > 2
r
(I))
25677 (I > 2r(I))
Nvar
639
0.0312, 0.0798
1205
0.0328, 0.0777
Residualsa R1(F),
wR2(F2)
GoF (all)
Residual
1.002
ꢀ0.245, 0.485
1.04
ꢀ0.306, 0.650
Fig. 5. Change in the 1H NMR spectrum of Fe(C5H4–CO–Met–OMe)2 (1) induced by
the addition of mercury; (a) changes in the position of the SCH3 proton shift – a
move downfield of 0.40 ppm is seen when 1 equiv. of Hg(II) is added; (b) the
corresponding change in the amide proton signal, which moves only 0.1 ppm with
1 equiv. of Hg(II).
extrema (e Åꢀ3
)
a
R1
=
R
||Fo| ꢀ |Fc||/
R
|Fo| for Fo > 2
r
(Fo); wR2 = (
R
w(F2o ꢀ F2c)2/
R
(wF2c)2)1/2 all
reflections w = 1/[
r
2(Fo2) + (0.0379P)2 + 2.4892P] where P = (Fo2+2F2c)/3.
2.4. X-ray crystallography
bonding leads to extended hydrogen-bonded networks in the solid
state, in which the amide NH and carbonyl oxygens of adjacent
molecules are linked in a head-on fashion.
X-ray crystal structures were solved for both Fe(C5H4–CO–Met–
OMe)2 (1) and Fe(C5H4–CO–Cys(Me)–OMe)2 (2) (Table 3 and
Fig. 6). Red-orange crystals were obtained by slow diffusion of hex-
ane into a chloroform solution of each ferrocenoyl peptide. Both
peptides crystallise in chiral space groups [41]: Fe(C5H4–CO–
Met–OMe)2 (1) crystallises in the P1 chiral space group and its
asymmetric unit cell contains two independent molecules (only
one is shown in Fig. 6 for clarity), while Fe(C5H4–CO–Cys(Me)–
OMe)2 (2) crystallises in the P212121 space group and its asymmet-
ric unit cell contains four independent molecules (Fig. 6 shows
only one for clarity).
The CAC bonds are identical between the two Cp rings of each
compound, while the dihedral angles between the ring and the car-
bonyl double bond show that the amides are co-planer with the
ring. The Cp CAC, amide C@O and amide CAN bond distances are
all comparable to other ferrocenoyl peptide systems [42]. Both
compounds adopt a P-1,30 open conformation [22] in the solid
state, minimising interactions between the two peptide chains on
one ferrocene hub. In the P-1,30 conformation (or ‘Xu Conforma-
tion’), first reported by Kraatz et al. [43] the substituents on the
two Cp rings of one ferrocene moiety are oriented out opposite
sides of the sandwich: the angle h between the peptide chains is
137.5° for 2 and 158.6° for 1. Such an arrangement precludes intra-
molecular hydrogen bonding between the chains, however exten-
sive intermolecular hydrogen bonding is evident within the unit
cell of both crystals. Hydrogen bonding in molecules of this type
has been well studied [42,44,45], and the non-bonding distances
between the carbonyl oxygen and amide NH of an adjacent mole-
cule seen in the crystal structures of 1 and 2 (2.86–2.95 Å) are opti-
mal hydrogen bonding distances. This intermolecular hydrogen
2.5. Conclusions
In conclusion, we have used a strategy that builds from the me-
tal-binding motif of the MT proteins to design and synthesise a ser-
ies of simple ferrocenoyl peptide systems which bind mercury
more strongly than other metals. The presence of a thioether group
at the sulfur atom in the side chain lends these systems a greater
affinity for mercury than for other Group 12 metals, silver and lead.
Although the sensitivity observed in this study does not rival that
seen with the best mercury sensors reported previously
[7,8,35,36], the preference of these systems for Hg(II) over other
metals opens the possibility of incorporating an S-methyl, S-benzyl
or S-trityl binding motif in more responsive contexts to create mol-
ecules with high selectivity and sensitivity in detecting this toxic
pollutant.
3. Experimental
3.1. Synthesis of ferrocenoyl peptides
Ferrocene-1,10-dicarboxylic acid was synthesised following
the literature procedure [46], as were S-methyl-
-cysteine using sodium metal and methyl iodide in absolute
ethanol [47], S-benzyl- -cysteine (from -cysteine and benzyl
bromide) [48], S-benzhydryl- -cysteine (from -cysteine and
diphenylmethanol in trifluoroacetic acid (TFA)) [49], S-trityl- -cys-
teine and S-trityl-DL-homocysteine (from the free amino acid and
L-cysteine (from
L
L
L
L
L
L

2874
C.C.G. Scully et al. / Journal of Organometallic Chemistry 693 (2008) 2869–2876
Fig. 6. X-ray crystal structures for the ferrocenoyl peptide derivatives (a) Fe(C5H4–CO–Met–OMe)2 (1); and (b) Fe(C5H4–CO–Cys(Me)–OMe)2 (2). Thermal ellipsoids are drawn
on the 50% probability level. Hydrogen atoms have been omitted for clarity.
triphenylmethanol in TFA) [50]. S-Protected amino acids were con-
verted to their methyl esters in quantitative yield by reaction with
thionyl chloride and methanol [51].
Peptide coupling reactions were carried out using the following
general procedure [25].
methyl ester hydrochloride salt (0.29 g, 1.60 mmol. Purified by
flash chromatography on silica (Et2O) to give a bright orange solid
(0.33 g, 77%); Rf 0.33 (Et2O); m.p. 132–133 °C; dH (300 MHz,
CDCl3): 2.17 (6H, s, 2 ꢂ SCH3); 2.85 (2H, dd, HA of ABX, JAB 14.0
Hz, JAX 5.0 Hz, 2 ꢂ HA of CH2S); 3.02 (2H, dd, HB of ABX, JBA
14.0 Hz, JBX 9.0 Hz, 2 ꢂ HB of CH2S); 3.84 (6H, s, 2 ꢂ OCH3); 4.38–
4.42 (2H, m, 2 of Fe(C5H4)2); 4.53–4.58 (2H, m, 2 of Fe(C5H4)2);
Ferrocene-1,10-dicarboxylic acid (2.5 mmol) was dissolved in
acetonitrile (10 mL) and triethylamine (5.0 mmol) and stirred
while O-(benzotriazol-1-yl)-N,N,N0,N0-tetramethyluronium hexa-
fluorophosphate (HBTU) (5.0 mmol) was added. Stirring was
continued for 15 min before the amino acid methyl ester hydro-
chloride salt (5.0 mmol) was added along with additional triethyl-
amine (5.0 mmol) and stirring continued for 24 h. The reaction
mixture was diluted with ethyl acetate (50 mL) to prevent the for-
mation of emulsions and the organic phase was washed with water
(50 mL), 1 M HCl (25 mL), water (50 mL), saturated aqueous NaH-
CO3 (25 mL), water (50 mL) and brine (50 mL), then dried over
MgSO4. The solvent was evaporated in vacuo to give a brown solid,
which was purified by flash chromatography.
4.70–4.74 (2H, m,
2 of Fe(C5H4)2); 4.86–4.91 (2H, m, 2 of
Fe(C5H4)2); 4.98–5.06 (2H, dd, HX of ABX, JXB 9.0 Hz, JXA 5.0 Hz,
2 ꢂ NHCH); 7.57 (2H, d, 2 ꢂ NH); dC (75.4 MHz, CDCl3): 16.2
(SCH3); 35.8 (CH2S); 52.1 (OCH3); 53.3 (NHCH); 70.6, 71.1, 71.9,
72.3 (8 ꢂ CH of Fe(C5H4)2); 76.4 (2 ꢂ Cipso of Fe(C5H4)2); 170.9,
174.1 (4 ꢂ C@O); mmax (cmꢀ1, CHCl3): 3377 (m), 2999 (m), 1732
(s), 1647 (s), 1533 (m), 1437 (m), 1194 (s); m/z (ES+): 559.2
(100%, [M+Na]+), 537.0 (30%, [MH]+); HRMS: found [M+Na]+
559.0633, C22H28FeN2NaO6S2 requires 559.0635.
3.4. Ferrocenoyl-1,10-di-S-benzyl-
-cysteine methyl ester (3)
L
3.2. Ferrocenoyl-1,10-di-
-methionine methyl ester (1)
L
Synthesised according to the general procedure using ferro-
cene-1,10-dicarboxylic acid (0.16 g, 0.58 mmol) and S-benzyl-
-cys-
teine methyl ester hydrochloride (0.30 g, 1.16 mmol). Purified by
flash chromatography on silica (EtOAc:hexane, 4:6) to yield an
orange oil (0.26 g, 65%) with data matching those previously
reported [26].
L
Synthesised according to the general procedure from ferrocene-
1,10-dicarboxylic acid (0.68 g, 2.5 mmol) and
-methionine methyl
L
ester hydrochloride salt (1.00 g, 5.0 mmol). Purified by flash chro-
matography on silica (Et2O) to give a bright orange solid (0.97 g,
69%) with data matching those previously reported [26].
3.5. Ferrocenoyl-1,10-di-S-benzhydryl-
-cysteine methyl ester (4)
L
3.3. Ferrocenoyl-1,10-di-S-methyl-
-cysteine methyl ester (2)
L
Synthesised according to the general procedure using ferro-
Synthesised according to the general procedure from ferrocene
1,10-dicarboxylic acid (0.22 g, 0.80 mmol) and S-methyl-
-cysteine
cene-1,10-dicarboxylic acid (0.10 g, 0.36 mmol) and S-benzhydryl-
L

C.C.G. Scully et al. / Journal of Organometallic Chemistry 693 (2008) 2869–2876
2875
L
-cysteine methyl ester hydrochloride (0.22 g, 0.72 mmol) to fur-
amine (0.20 mL, 1.44 mmol) was added. The mixture was diluted
with DCM (10 mL) and stirred for 30 min, then diluted with further
DCM (250 mL) to give solution A. L-Cystine dimethyl ester dihydro-
nish an orange solid (0.23 g, 77%); m.p.: 70–73 °C; dH (300 MHz,
CDCl3): 2.72 (2 H, dd, HA of ABX, JAX 5.0 Hz, JBA 14.0 Hz, 2 ꢂ HA of
CH2S), 2.80 (2H, dd, HB of ABX, JBX 9.0 Hz, JAB 14.0 Hz, 2 ꢂ HB of
CH2S), 3.65 (6 H, s, 2 ꢂ OCH3)), 4.40–4.41 (2H, m, 2 of Fe(C5H4)2),
4.56–4.57 (2H, m, 2 of Fe(C5H4)2), 4.73–4.74 (2H, m, 2 of Fe(C5H4)2),
4.90–4.91 (2H, m, 2 of Fe(C5H4)2), 4.98–5.05 (2H, dd, HX of ABX, JXA
5.0 Hz, JXB 9.0 Hz, 2 ꢂ NHCH), 5.25 (2H, s, 2 ꢂ SCH(C6H5)2), 7.20–
7.43 (20H, m, 2 ꢂ (C6H5)2); dC (75.4 MHz, CDCl3): 33.8 (2 ꢂ CH2S),
52.0 (2 ꢂ OCH3), 53.1 (2 ꢂ SCH(C6H5)2), 54.0 (2 ꢂ NHCH), 70.3,
70.7, 71.6, 72.0 (8 ꢂ CH of Fe(C5H4)2), 75.6 (2 ꢂ Cipso of Fe(C5H4)2),
127.3, 127.4, 128.2, 128.4, 128.6 (20 ꢂ CH of C6H5), 140.5 (4 ꢂ Cipso
of C6H5), 170.2, 173.6 (4 ꢂ C@O); mmax (cmꢀ1, CHCl3): 3324 (m),
3012 (w), 1731, 1650 (s), 1527 (m), 1438 (m), 1211 (s); m/z
(ES+): 863 (60%, [M+Na]+), 841 (20%, [MH]+).
chloride (0.12 g, 0.36 mmol) was dissolved in DMF (1 mL) and di-
luted with DCM (100 mL). This solution was added dropwise to
solution A over 1 h. Stirring was continued for 72 h. The solvent
was removed in vacuo and the residue redissolved in EtOAc
(50 mL) and washed with water (10 mL), 10% citric acid solution
(10 mL), water (10 mL), saturated aqueous NaHCO3 (10 mL), water
(10 mL) and brine (10 mL), dried (MgSO4) and concentrated in va-
cuo to afford an orange oil. This was purified by flash chromatogra-
phy on silica (EtOAc:hexane, 1:1) to yield 8 as an orange oil (0.05 g,
29%) with data matching those previously reported [24].
3.10. Cyclic voltammetry
3.6. Ferrocenoyl-1,10-di-S-trityl-
-cysteine methyl ester (5)
L
The electrochemical properties of the ferrocenoyl compounds
were analysed by cyclic voltammetry [32]. Experiments were car-
ried out at room temperature (22 2 °C) on a BAS-100 potentiostat
using a glassy carbon working electrode and a platinum wire aux-
iliary electrode. The reference electrode was Ag/AgCl (3.0 M NaCl).
Titrations were carried out in acetonitrile degassed with argon and
the background electrolyte used was 0.1 M tetrabutylammonium
perchlorate. All experiments were repeated three times to ensure
reproducibility and the working electrode was cleaned between
runs by polishing on a microcloth pad with alumina slurry fol-
lowed by washing with water then acetonitrile. The scan rate
was 100 mV sꢀ1 in all experiments and iR compensation was ap-
plied in all cases. Half wave potentials are reported relative to
the Ag/Ag+ redox potential. Redox potentials are quoted as the half
Synthesised according to the general procedure using ferrocene-
1,10-dicarboxylic acid (0.50 g, 1.82 mmol) and S-trityl-
-cysteine
L
methyl ester (1.51 g, 3.65 mmol). Purified by flash chromatography
on silica (EtOAc:hexane, 1:1) to yield an orange oil (1.20 g, 72%); dH
(400 MHz, CDCl3): 2.67 (2H, dd, HA of ABX, JAX 4.0 Hz, JAB 9.0 Hz,
2 ꢂ HA of CH2S), 2.80 (2 H, dd, HB of ABX, JBX 9.0 Hz, JAB 9.0 Hz,
2 ꢂ HB of CH2S), 3.48 (6H, s, 2 ꢂ OCH3), 4.27–4.28 (2H, m, 2 of
Fe(C5H4)2), 4.42–4.43 (2H, m, 2 of Fe(C5H4)2), 4.66–4.67 (2H, m, 2
of Fe(C5H4)2), 4.58–4.69 (2H, m, HX of ABX, 2 ꢂ NHCH), 4.76–4.77
(2H, m, 2 of Fe(C5H4)2), 7.05–7.42 (30H, m, 2 ꢂ (C6H5)3); dC
(100 MHz, CDCl3): 36.8 (2 ꢂ CH2S), 52.0 (2 ꢂ OCH3), 52.9
(2 ꢂ NHCH), 67.7 (2 ꢂ C(C6H5)3), 70.4, 71.0, 71.8, 72.1 (8 ꢂ CH of
Fe(C5H4)2), 76.0 (2 ꢂ Cipso of Fe(C5H4)2), 126.8, 128.0, 128.2, 127.9,
129.5 (30 ꢂ CH of C6H5), 144.3 (6 ꢂ Cipso of C6H5), 170.2, 173.0
(2 ꢂ C@O); mmax (cmꢀ1, CHCl3): 1730, 1683 (m), 1506 (m), 1220
(w); m/z (ES+): 1015 (100%, [M+Na]+); HRMS (ES+): found [MH]+
993.27039, C58H52FeN2O6S2 requires 993.27044.
wave potentials (E ) and are derived from the formal redox poten-
½
tial (E°0) of the Fe(II)/Fe(III) couple.
3.11. NMR binding studies
Association constants for the binding interactions of 1 and 2
with Hg(II) were calculated according to the method set forward
by Hunter and co-workers [38], working in DMSO-d6 solution as
the mercury–peptide complexes are not soluble in CD3CN at the
concentrations required. Thus Job plots for the compounds were
constructed (Supplementary material) [52], then two separate
5 mM samples of the peptide and Hg(II) were made up and distrib-
3.7. Ferrocenoyl-1,10-di-S-trityl-DL-homocysteine methyl ester (6)
Synthesised according to the general procedure using ferro-
cene-1,10-dicarboxylic acid (0.04 g, 0.15 mmol) and S-trityl-DL
-
homocysteine methyl ester (0.13 g, 0.30 mmol) to yield an orange
oil (0.22 g, 73%); dH (400 MHz, CDCl3): 1.16–1.26 (4 H, m,
2 ꢂ CH2CH2S), 2.16–2.31 (2H, m, 2 ꢂ CH2S), 3.68 (6H, s, 2 ꢂ OCH3),
4.34–4.54 (2H, m, 2 ꢂ NHCH), 4.56–4.59 (2H, m, 2 of Fe(C5H4)2),
4.64–4.68 (2H, m, 2 of Fe(C5H4)2), 4.77–4.81 (2H, m, 2 of Fe(C5H4)2),
4.87–4.89 (2H, m, 2 of Fe(C5H4)2), 7.10–7.42 (30H, m, 2 ꢂ (C6H5)3);
dC (75.4 MHz, CDCl3): 29.7 (CH2CH2S), 30.5 (CH2S), 53.0 (OCH3),
53.5 (NHCH), 70.7, 70.9, 71.6 (8 ꢂ CH of Fe(C5H4)2), 76.8 (2 ꢂ Cipso
of Fe(C5H4)2) 126.1, 127.1, 127.3, 128.8, 129.3 (30 ꢂ CH of C6H5),
145.9, 146.9 (6 ꢂ Cipso of C6H5), 169.8, 172.4 (4 ꢂ C@O); mmax
(cmꢀ1, CHCl3): 2981 (s), 1737 (m), 1685 (m), 1213 (w); m/z
(ES+): 1044 (100%, [M+Na]+); HRMS (ES+): found [M+Na]+
1043.28499, C60H56FeN2NaO6S2 requires 1043.28366.
uted into ten samples such that the molar ratio (
tide:Hg(II) varied incrementally from 1.0 to 0.0. The product of
the molar ratio and induced shifts ( d) with respect to the shift
v) of pep-
D
for the free ligand was then plotted against the molar ratio.
3.12. X-ray data collection
Both compounds 1 and 2 gave orange crystals in a plate habit.
For each, one crystal was attached with Exxon Paratone N to a
short length of fibre supported on a thin copper wire inserted in
a copper mounting pin, then quenched in a cold nitrogen gas
stream from an Oxford Cryosystems Cryostream.
3.8. Ferrocenoyl-1,10-di-
-phenylalanine methyl ester (7)
L
For Fe(C5H4–CO–Met–OMe)2 (1) a Bruker CCD-1000 area detec-
tor diffractometer employing graphite monochromated Mo K
a
Synthesised according to the general procedure using ferro-
cene-1,10-dicarboxylic acid (0.05 g, 0.18 mmol) and
-phenylala-
nine methyl ester (0.08 g, 0.36 mmol) to afford an orange oil
(0.06 g, 58%) which presented data matching those previously re-
ported [29].
radiation generated from a fine-focus sealed tube was used for data
collection. Cell constants were obtained from a least squares
refinement against 8713 reflections located between 4.97° and
L
56.77° 2h. Data were collected at 150(2) kelvin with
x scans to
56.62° 2h. The intensities of 184 standard reflections recollected
at the end of the experiment did not change significantly during
the data collection.
3.9. Ferrocenoyl-1,10-
-cystine dimethyl ester (8)
L
For Fe(C5H4–CO–Cys(Me)–OMe)2 (2) a Bruker-Nonius FR591
Kappa APEX II diffractometer employing graphite monochromated
Ferrocene-1,10-dicarboxylic acid (0.10 g, 0.36 mmol) and HBTU
(0.30 g, 0.79 mmol) were dissolved in DMF (1 mL) and triethyl-
Mo K
a radiation generated from a fine-focus rotating anode was

2876
C.C.G. Scully et al. / Journal of Organometallic Chemistry 693 (2008) 2869–2876
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against 9036 reflections located between 4.40° and 59.87° 2h. Data
were collected at 150(2) kelvin with
x and u scans to 60.00° 2h.
The data integration and reduction were undertaken with SAINT
and XPREP (Bruker Analytical X-ray Instruments Inc, Madison, Wis-
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out with the XP SHELXTL-Plus graphical user interface (G.M. Sheldrick,
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[53]. The Fe(C5H4–CO–Met–OMe)2 (1) structure was solved in the
space group P1 (#1), the Fe(C5H4–CO–Cys(Me)–OMe)2 (2) structure
in the space group P212121 (#19), both by direct methods with
SHELXS-97 [54]; each was extended and refined with SHELXL-97 [54].
The non-hydrogen atoms in the asymmetric unit were modeled
with anisotropic displacement parameters. A riding atom model
with group displacement parameters was used for the hydrogen
atoms. The absolute structures were established with the Flack
parameter [55,56] refining to ꢀ0.004(8) (Fe(C5H4–CO–Met–
OMe)2, 1) and 0.002(5) (Fe(C5H4–CO–Cys(Me)–OMe)2, 2).
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We wish to thank Professor Robert O’Neil (UCD) for help and
advice with electrochemistry experiments and Dr Katrina Jolliffe
(USyd) for assistance with binding considerations. This work was
funded in Ireland by University College Dublin and the Centre for
Synthesis and Chemical Biology under the Programme for Research
in Third Level Institutions (PRTLI) administered by the HEA, and in
Australia by the University of Sydney.
Appendix A. Supplementary material
CCDC 670059 and 670060 contain the supplementary crystallo-
graphic data for 1 and 2. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif. Supplementary data associ-
ated with this article (full characterisation data for compounds 1, 3,
7 and 8; sample cyclic voltammagrams; titration curves for ferr-
ocenoyl peptides 1–6 in response to all metal ions tested; Job plots
from NMR binding experiments; and additional crystallographic
data for compounds 1 and 2) can be found, in the online version,
at doi:10.1016/j.jorganchem.2008.06.005.
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