Diversity and design of metal-based carbon monoxide-releasing molecules (CO-RMs) in aqueous systems: Revealing the essential trends

Article abstract of DOI:10.1039/b822157j

The CO-releasing ability of a diverse library of primary metal carbonyl complexes has been assessed using a deoxymyoglobin-carbonmonoxymyglobin assay. A wide spectrum of rates for the CO-release process was observed in aqueous systems. For octahedral d

Full text of DOI:10.1039/b822157j

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Diversity and design of metal-based carbon monoxide-releasing molecules
CO-RMs) in aqueous systems: revealing the essential trends†
(
Wei-Qiang Zhang, Anthony J. Atkin, Robert J. Thatcher, Adrian C. Whitwood, Ian J. S. Fairlamb and
Jason M. Lynam*
Received 10th December 2008, Accepted 17th February 2009
First published as an Advance Article on the web 14th March 2009
DOI: 10.1039/b822157j
The CO-releasing ability of a diverse library of primary metal carbonyl complexes has been assessed
using a deoxymyoglobin-carbonmonoxymyglobin assay. A wide spectrum of rates for the CO-release
6
process was observed in aqueous systems. For octahedral d complexes, the rate was found to decrease
in the sequence FeI
controlled by the metal–carbon bond strengths. Within the series, [NEt
2
(CO)
4
> [NEt
4
][V(CO)
6
] > MnBr(CO)
5
> Cr(CO)
6
implying that CO-release is not
][MX(CO)
4
5
] (M = Cr, Mo, W;
X = Cl, Br, I), the rate of CO-release was found to decrease down the group (Cr > Mo > W), whilst
4
within the chromium series a similar trend was observed for the halide (Cl > Br > I). The d complexes
6
[
NEt
4
][MI
3
(CO)
4
] (M = Mo, W) exhibit faster release than their d congeners. A mechanistic
-
investigation into the [NEt
4
][MX(CO)
5
] series revealed the intermediacy of [{M(CO)
5
}
2
(m-X)] in the
CO-release process and that the hydrolysis of the M–X bond, rather than the intrinsic strength of
M–CO bonds, controls the rate of CO-release in aqueous systems.
Introduction
these species was demonstrated to be due to their ability to release
CO.
Carbon monoxide has recently been identified as a target for
therapeutic intervention as it possesses critical signalling func-
tions, including inflammation, cellular proliferation, apoptotic cell
We have developed a series of CO-RMs using the biologically-
9
compatible 2-pyrone ligand as a motif. Coordination of the
4
2
F9),
-pyrone ligand to iron(0), in an h -binding mode (CO-RM-F1-
1
death, and neural transmission. The majority of endogenously-
10,11
or to iron(II) (CO-RM-F6 and F7) and molybdenum(II)
produced CO is as a result of oxidation of heme, catalysed by
the heme oxygenase (HO) series of enzymes. Three isoforms of
HO are known, HO-1 is inducible and is up-regulated during
stress, HO-2 is constitutive and its function may be related to
neurotransmission. Far less is known about HO-3, although,
unlike HO-1 and HO-2, it is a poor catalyst for heme degradation.
The potential therapeutic effects of CO are widely recognized in
vasodilation, inflammation, hypertension, organ transplantation
and cerebral malaria. There is a pharmacological requirement
to deliver precise amounts of CO to specific locations under phys-
iological conditions and thus the development of CO-releasing
molecules (CO-RMs) as benign CO reservoirs is highly desirable.
Homoleptic and heteroleptic transition metal carbonyls (Fig. 1),
12,13
1
(
CO-RM-F4 and F10),
in an h (O)-bonding mode, results in
a series of complexes, which generally exhibit low toxicity and the
CO-release behaviour is modulated by the nature of the metal and
the substituents on the 2-pyrone ligand.
2
3
More recently, a number of water soluble complexes based on
5
14
the “[Fe(h -C
5
H
4
R)(CO) ]” unit have been reported. Here, the
2
introduction of an ester group into the cyclopentadienyl ligand
enhances water solubility. An example of photoinduced CO-
4
,5
release from a manganese tricarbonyl complex [Mn(CO) (tmp)]
3
15
[
tmp = tris(pyrazolylmethane)] has also been reported. This
study demonstrated that the complex was only an effective
cytotoxic agent against human colon cancer cells under irradi-
ation. The tmp ligand within these complexes was subsequently
1
such as Fe(CO)
CO-RMs, in addition Mn
CO photochemically. Mann and Motterlini have developed a
series of water soluble CO-releasing molecules: the first in this
5
, and [RuCl
2
(CO)
3
]
2
(CO-RM-2) are prototypical
developed to include peptide groups without inhibiting the CO-
16
2
(CO)10 has been shown to release
release behaviour. In addition, Na
[H
BCO ] has also been
2
3
2
6
shown to be an effective, transition metal-free, water-soluble
17
CO-RM.
-
series [RuCl(glycinate)(CO)
3
] (CO-RM-3) has been extensively
Despite the proven beneficial therapeutic effects of CO-RMs,
the precise factors controlling the CO-release process are not fully
understood. It is clear that water-solubility, electron density and
oxidation state of a transition metal centre are potentially key
factors in controlling the ability of a given CO-RM to liberate
CO. In order to aid the design of future generations of CO-RMs it
is evident that an understanding of the interplay between these
factors and the mechanism of CO-release under physiological
conditions is required. The kinetics of substitution of CO in metal
carbonyls has been extensively investigated in organic solvents, but
there are fewer examples of comprehensive mechanistic studies in
studied and shown to effectively mimic the biological role of
6,7
CO gas. CO-RM-2 and CO-RM-3 (along with MnBr(CO)
5
and
[
NEt ][MoBr(CO) ], which are part of this study) have be shown
4
5
8
to be effective antimicrobial agents. Again, the mode of action of
Department of Chemistry, University of York, Heslington, York, UK YO10
5
DD. E-mail: jml12@york.ac.uk; Tel: +44 01904 432 534
†
Electronic supplementary information (ESI) available: CO-release pro-
files and details of kinetic and mechanistic studies. CCDC reference
numbers 710806, 710807 and 720399. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/b822157j
This journal is © The Royal Society of Chemistry 2009
Dalton Trans., 2009, 4351–4358 | 4351

Table 1 CO-release data for complexes reported in this work
b
t
1/2/s
-1a
Entry
Complex
n(CO)/cm
60 mM
40 mM
20 mM
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
Cr(CO)
[NEt ][V(CO)
MnBr(CO)
FeI (CO)
6
1981 s
1854 s
2138 w, 2051 s, 212 m
2138 m, 2092 s, 2074 sh
2102 m, 2055 s
2099 w, 2054 s
2057 s, 2008 s
—
685
c1049
—
965
d1434
—
1546
d1200
4
6
]
5
2
4
d
mer-FeI
2
(CO)
(CO)
3
(P{OCH
3
}
3
)
465
340
300
235
133
180
239
718
932
1306
2999
2138
3488
200
192
502
369
416
mer-FeI
2
3
(P{CH
2
OH}
3
)
509
764
419
140
183
all cis-FeI
cis,cis,trans-FeI
2
(CO)
2
(P{OCH
3
}
3
)
2
2
(CO)
2
(P{OCH
3
}
3
)
2
2051 s, 2004 s
320
[NEt
[NEt
[NEt
[NEt
[NEt
[NEt
[NEt
[NEt
[NEt
[NEt
[NEt
[NEt
[NEt
4
4
4
4
4
4
4
4
4
4
4
4
4
][CrCl(CO)
][CrBr(CO)
][CrI(CO)
][MoCl(CO)
][MoBr(CO)
][MoI(CO)
][WCl(CO)
5
]
2061 w, 1923 s, 1857 m
2059 w, 1922 s, 1857 m
2054 w, 1922 s, 1865 m
2066 w, 1926 s, 1852 m
2069 w, 1928 s, 1855 m
2067 w, 1929 s, 1859 m
2066 w, 1916 s, 1846 m
2065 w, 1918 s, 1850 m
2064 w, 1917 s, 1856 m
2062 w, 1944 s, 1932 s, 1869 m
2062 w, 1943 s, 1929 s, 1866 m
2062 w, 1943 s, 1929 s, 1866 m
2062 w, 1943 s, 1929 s, 1866 m
2063 m, 1940 s
99
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
5
]
136
279
5
]
269
5
]
]
1196
1611
1114
2376
3486
1801
226
181
917e
2440
1517e
1758e
2440e
3237
163
5
5
]
]
]
f
g
5
f
g
][WBr(CO)
][WI(CO)
5
f
g
5
]
][{Cr(CO)
][{Cr(CO)
][{Cr(CO)
][{Cr(CO)
5
5
5
5
}
}
}
}
2
2
2
2
(m-Cl)]
(m-Br)]
(m-Br)]
(m-Br)]
227h
h
h
194i
223i
193
i
243
215
585
278
231
591
252
Cr(=C{OCH
}CH
)(CO)
)(CO)
)(CO)
208
397e
3966
3
3
5
Mo(=C{OCH
}CH
}CH
(CO)
(CO)
(CO)
2071 m, 1946 s
2071 m, 1940 s
2072 m, 2015 s, 1949 m
2071 m, 2003 s, 1938 m
2027 m, 1923 s
3
3
5
f
g
W(=C{OCH
7924 (2927 )
333
4111
356
93
3
3
5
d
[NEt
[NEt
W(k -acac)
4
][MoI
][WI
3
4
]
90
j
4
2
3
4
]
3
205
j
2
74
78
a
b
IR spectra were recorded in dichloromethane solution; CO-release rates were determined by measuring the conversion of a standardised deoxy-Mb
◦
c
d
solution (ca. 60 mM) to Mb-CO [PBS pH = 7.4, 37.8 C]; Deoxy-Mb assay was saturated by CO instantaneously; After the addition of CO-RM, over
e
f
2
0% of deoxy-Mb was converted into Mb-CO within 1 min (t1/2 < 20 s); Time required to form 5 mM Mb-CO; Time required to form 15 mM Mb-CO;
g
h
i
Time required to form 10 mM Mb-CO; CO-RM incubated in DMSO for 6 min before being administered to the assay; CO-RM incubated in DMSO
j
for 30 min before being administered to the assay; Half life < 1 min.
1
8
aqueous solution. Although it is tempting to draw correlations
between both the electron density and oxidation state of a metal
centre with the CO-release profile, it is not clear if, in aqueous
systems, such an approach is valid as the precise mechanism(s) of
CO-release are not fully understood.
Mb-CO with concentration of 15 mM, 10 mM and 5 mM (from
60 mM, 40 mM and 20 mM respectively) were employed. The
results from this study are presented in Table 1 and a sample
reaction profile for deoxy-Mb–Mb-CO conversion by the CO
being released from [Et
4
N][CrI(CO) ] is shown in Fig. 1. Within
5
In order to provide insight into how the properties of an
individual metal complex may affect the CO-release profile, we
have undertaken a survey of a diverse library of metal carbonyl
complexes with various co-ligands, formal charges and oxidation
states.
the series of compounds reported, the spectra obtained for the
conversion of deoxy-Mb to Mb-CO all exhibit isobestic points at
510, 550, 570 and 585.
Results and discussion
Examination of CO-releasing properties of metal
carbonyl complexes
The CO-releasing ability of a series of metal carbonyl com-
plexes was assessed using a deoxymyoglobin (deoxy-Mb)–
◦
19
carbonmonoxymyoglobin (Mb-CO) assay at 37.8 C. Here, the
liberated CO from a metal complex is captured by the deoxy-
Mb to afford Mb-CO and the resulting changes in a 60 mM
solution of a given CO-RM to produce an Mb-CO concentration
of 30 mM was calculated (t1/2). Corresponding data for 40 mM
and 20 mM solutions of CO-RM to generate 20 and 10 mM of
Mb-CO, respectively, were also determined. In cases where CO-
release was very slow the time taken to generate solutions of
Fig. 1 Previous transition metal complexes studied as potential CO-RMs.
This journal is © The Royal Society of Chemistry 2009
4
352 | Dalton Trans., 2009, 4351–4358

6
◦
Primary metal carbonyls. The octahedral d first row transition
Table 2 Selected bond lengths ( A˚ ) and angles ( ) for mer-FeI (CO) -
2
3
(
P{OMe}
3
) and cis,cis,trans-FeI
2
(CO)
3
(P{OMe}
3 2
)
metal carbonyls exhibit a wide range of release profiles, for
example, Cr(CO)
of an EtOH solution of FeI
of the assay. Quantitatively, the assay indicated that the rate of
release of CO increased in the series FeI (CO) > [NEt ][V(CO)
MnBr(CO) > Cr(CO) . It is somewhat counter-intuitive that
Et N][V(CO) ] is a better CO-releasing molecule than Cr(CO)
6
did not show any CO-release, whereas addition
cis,cis,trans-FeI
(P{OMe}
2 3
(CO) -
2
(CO) resulted in the rapid saturation
4
mer-FeI
2
(CO)
3
(P{OMe}
3
)
3 2
)
2
4
4
6
]
Fe–I(1)
Fe–I(2)
Fe–C(1)
Fe–C(2)
Fe–C(3)
Fe–P(1)
Fe–P(2)
I(1)–Fe–I(2)
I(1)–Fe–C(1)
I(1)–Fe–C(2)
I(1)–Fe–C(3)
P(1)–Fe–P(2)
C(1)–Fe–C(2)
C(1)–Fe–C(3)
C(2)–Fe–I(2)
2.6447(6)
2.6406(6)
1.833(3)
1.794(4)
1.829(4)
2.1907(10)
2.6499(3)
2.6593(3)
1.773(2)
1.777(2)
>
5
6
[
4
6
6
.
As reflected in the carbonyl stretching frequencies, the lower
formal oxidation state of the metal carbonyl anion is expected to
result in stronger M–C bonds which would be expected to inhibit
release. In aqueous solution however, it is clear that M–C bond
strength is not the sole factor controlling spontaneous CO-release.
—
2.2343(6)
2.2383(6)
—
93.086(17)
87.68(11)
84.91(11)
84.11(12)
95.344(10)
179.79(7)
85.34(7)
—
178.94(2)
94.81(9)
—
The decomposition of [NEt
4
][V(CO) ] in water was monitored
6
—
by real time IR spectroscopic analysis. No intermediates were
observed and the intensity of the carbonyl band in the IR spectra
for this complex decreased in intensity, exhibiting first order
kinetics.
These data prompted us to examine an alternative d metal
N][CrI(CO) ]. In this case a fast and
controllable CO release profile was observed. The UV-vis spectra
92.12(15)
168.45(16)
177.94(11)
178.28(7)
6
The same trend (Cr > Mo > W) in rate of release is observed
20
carbonyl anion: [Et
4
5
within the carbene complexes M(=C{OCH
}CH
)(CO)
(M = Cr,
3
3
5
II
Mo, W). In addition, CO-release from the M carbonyl anions
showing the conversion of deoxy-Mb to Mb-CO by the CO being
[
NEt
4
][WI
3
(CO)
4
] and [NEt
4
][MoI
3
(CO)
4
] was investigated, as was
-
released from [CrI(CO)
deoxy-Mb by [Et
00 s (t1/2 = 272 s).
5
] is displayed in Fig. 2. Saturation of
21
the related compound W(acac)
2
(CO) .
3
4
N][CrI(CO)
5
] was observed over a period of ca.
4
The CO-release from these d -metal anions is more rapid than
7
6
in the corresponding d species [NEt
4
][MI(CO)
5
] (M = Mo, W),
4
but, in contrast, the t1/2 values for release by the d tungsten and
molybdenum complexes were similar. It should, however, be noted
that [NEt
4
][Mo(CO)
4
3
I ] undergoes a rapid reaction in DMSO
solution (the delivery medium for the assay) to form a species
which appears to release CO at a slow rate.
Iron complexes
The rapid CO-release exhibited by FeI
by the incorporation of phosphite ligands into the coordina-
tion sphere of the metal. Compounds mer-FeI (CO) ),
(P{OMe}
mer-FeI (CO) OH}), all cis-FeI (CO) (P{OMe} and
(P{CH
cis,cis,trans-FeI (CO) were prepared by the ad-
(P{OMe}
dition of the appropriate phosphorus-containing ligand to
2
(CO)
4
could be modulated
2
3
3
2
3
2
2
3
)
3 2
2
3
)
3 2
2
2
FeI
2
(CO)
4
.
The stereochemistry of mer-FeI
2
(CO)
3
(P{OMe}
3
)
and cis,cis,trans-FeI
viously been reported by Bancroft, was elucidated from single-
crystal X-ray diffraction experiments (Fig. 3, Table 2). In addition,
2
(CO) , both of which had pre-
3
(P{OMe}
3 2
)
2
2
4 5
Fig. 2 CO-release profile for [Et N][CrI(CO) ]. The conversion of de-
oxy-Mb to Mb-CO monitored against time using the Q-bands of the heme
group.
The effect of the metal period and halide ligand within this
series has been systematically studied. The results from complexes
[
Et
4
N][MX(CO)
5
] (M = Cr, Mo, W; X = Cl, Br, I) are presented in
Table 1. The CO-release tests using [NEt
4
][MX(CO)
5
] (M = Mo,
W; X = Br, I) show that Mo carbonyls release CO at a faster rate
than W carbonyls but slower than Cr. The chromium-containing
CO-RMs exhibited controlled and rapid release of CO. Evidence
for the release of multiple CO ligands was obtained for this series of
compounds. For example, treatment of the deoxy-Mb assay with
20 mM solutions of [Et
4
N][CrCl(CO)
5
] and [Et
4
N][CrBr(CO) ]
5
resulted in the formation of Mb-CO solutions with concentrations
of 42.7 mM and 44.6 mM, respectively, indicating the release of at
least two molecules of CO per CO-RM.
Fig.
3
ORTEP representations of mer-FeI
2
(CO)
3
(P{OMe
3
}) and
cis,cis,trans-FeI (CO) (P{OMe }) Thermal ellipsoids shown at the 50%
2
3
3
2.
probability level; hydrogen atoms are omitted for clarity.
This journal is © The Royal Society of Chemistry 2009
Dalton Trans., 2009, 4351–4358 | 4353

we also obtained all cis-FeI
between FeI (CO) and P(OMe)
previously. The all cis geometry was demonstrated by the appear-
2
(CO)
3
(P{OMe}
3
) from the reaction
, which has not been reported
2
2
4
3
3
1
1
ance of two doublet resonances in the P{ H} NMR spectrum at
2
d 173.4 and 142.9 ppm ( JPP = 129.6 Hz) and this complex was
found to convert to the cis,cis,trans isomer even on storage in the
solid state.
In a similar manner to FeI
2
(CO)
4
, addition of mer-FeI
2
(CO) -
3
(
P{OMe}
3
) results in the immediate formation of a significant
quantity of Mb-CO, however subsequent release is slow. The
introduction of a water-solublising phosphine into the complex
mer-FeI
tion of Mb-CO with time. This release profile is mirrored by the
isomeric complexes cis,cis,trans-FeI (CO) and all cis-
(P{OMe}
FeI (CO) . CO-release from the cis,cis,trans isomer
2
(CO)
3
(P{CH
2
OH}
3
) results in a more controlled forma-
2
2
)
3 2
2
2
(P{OMe}
3 2
)
is more rapid than from the all cis isomer at all concentrations
studied.
Mechanistic study into the CO-release behaviour by metal
carbonyl anions
The library of compounds [NEt
4
][MX(CO) ] represent a poten-
5
tially important class of CO-releasing compounds as they exhibit
good water solubility and the rate of CO-release may be modulated
by the nature of both the metal and halide. However, a previous
kinetic study has demonstrated that the rate of dissociation of CO
-
from complexes [MX(CO)
5
] increased in the order Mo > Cr > W,
this is in contrast to the results obtained from the myoglobin-based
Fig. 4 (a) IR spectra for the decomposition of [Et
CH Cl with added H O. (b) [Et N][CrBr(CO) ] in CH
after addition of H O (black), isolated [Et
N][{Cr(CO)
4
N][CrBr(CO)
Cl immediately
(m-Br)] (blue).
5
] in
assay in which the rate of release increased in the series Cr >
2
2
2
4
5
2
2
23,24
Mo > W.
This suggested that the mechanism of CO-release
2
4
5 2
}
from these species in aqueous media was more complex than
simple dissociation of CO.
The rate (and extent) of formation of Cr(CO) from [CrX(CO)
]-
6
5
In CH
2
Cl
2
solution, [CrBr(CO)
5
]- exhibited no obvious degra-
did not show any significant variation if the reaction was per-
formed in either deoxygenated or oxygenated solvents, suggesting
that one-electron oxidation to form species of the type [CrX(CO)
dation over a period of 3 h and significant decomposition was
only observed after 16 h. In contrast, the addition of an excess of
5
]
water to the CH
as the only metal carbonyl containing product within 1 h. The
reaction between [NEt ][CrBr(CO) ] and one equivalent of H
in CH Cl solution resulted in the formation of an intermediate
species, characterised by a carbonyl band at 1944 cm . Over
the course of several minutes this band decreased in intensity
with a concomitant increase in the intensity of the band for
2
Cl
2
solution resulted in the formation of Cr(CO)
6
is not a dominant process under these conditions. In addition,
-
-
5
reaction of [CrI(CO)
5
] or [CrBr(CO)
5
] with [Fe(h -C
5
H
5
)
2
]PF re-
6
-
1
4
5
2
O
sulted in the formation of new bands in the IR spectra at 2023 cm
-
1
2
2
and 2032 cm , respectively, consistent with the formation of the
-
1
25
17-electron compounds [CrX(CO)
5
]. No bands attributable to
these species were observed when the reaction was performed in
the absence of the ferrocenium salt. These experiments support a
mechanism of CO-release which is not initiated by oxidation, but
Cr(CO)
species and the formation of Cr(CO)
with similar rate constants. A similar band was observed in the
6
(Fig. 4a). Both the loss of the band, due to this new
23
6
, exhibited first-order kinetics
occurs via a simple substitution reaction.
These results indicate that CO-release from [CrX(CO)
]- is
5
-
-
hydrolysis of [CrCl(CO)
5
] and [CrI(CO)
5
] and the extent to which
triggered by water. Insight into the nature of the intermediate
species was gained by treatment of a toluene suspension of
this intermediate was formed mirrored the rate of CO-release
-
as demonstrated by the deoxy-Mb assay across the [CrX(CO)
5
]
[NEt
4
][CrCl(CO) ] with an excess of water. This resulted in the
5
series (i.e. Cl > Br > I). Further experiments in MeOH
confirmed the effects conferred by trace amounts of water—
formation of a red precipitate at the interface between the two
solvents, which was isolated by filtration. Recrystallisation from
in all cases Cr(CO)
observed.
The decomposition of complexes [NEt
6
was the only carbonyl-containing product
CH
for study by X-ray diffraction and the resulting structure de-
termination demonstrated that [NEt (m-Cl)] (Fig. 5)
][{Cr(CO)
had been formed. This species was originally prepared by Ruff
from the photochemical reaction between [NEt ][CrCl(CO) ] and
Cr(CO) . The structure of [NEt (m-Cl)] consists of
2
Cl
2
–toluene resulted in the formation of crystals suitable
4
][CrX(CO)
5
] (X = Cl, Br,
4
5 2
}
26
I) in water was monitored by real time IR spectroscopic analysis. A
-
1
similar series of bands were observed in each case [2058 cm (w),
4
5
939 cm- (s), and 1885 cm (m)] suggesting that related species
were formed. It is proposed that these species are identical to those
formed in the above experiment in CH Cl , in which a band was
1
-1
][{Cr(CO)
}
1
6
4
5 2
discrete cations and anions and the ethyl groups of the cation
are disordered over two positions. The anion consists of two
2
2
-
1
observed at 1944 cm .
chloride-bridged Cr(CO)
5
units, the two chromium atoms
4
354 | Dalton Trans., 2009, 4351–4358
This journal is © The Royal Society of Chemistry 2009

resulting profiles (Table 1, entries 20 and 21, Fig. 6) demonstrated
that this was indeed the case: incubation for 30 min resulting in a
slower rate of release at all concentrations studied. Treatment of
CH
2
Cl
2
solutions of [NEt
4
][CrBr(CO)
5
] with DMSO also resulted
(DMSO),
in the formation of the bands assigned to Cr(CO)
5
although at a slower rate. We therefore propose that the interaction
of these species with DMSO is a deactivation pathway and is more
rapid in the case of the dimeric complexes.
Fig. 5 ORTEP representation of [NEt
ellipsoids shown at the 50% probability level, hydrogen atoms omit-
4
][{Cr(CO)
5
}
2
(m-Cl)], thermal
ted for clarity and only one of the two orientations of the dis-
◦
ordered cation shown. Selected bond lengths ( A˚ ) and angles ( ):
Cr(1)–Cl(1) 2.4900(4), Cr(2)–Cl(1) 2.4721(4), Cr(1)–C(1) 1.9154(17),
Cr(1)–C(2) 1.8301(15), Cr(1)–C(3) 1.8973(16), Cr(1)–C(4) 1.9019(16),
Cr(1)–C(5) 1.9118(16), C(1)–O(1) 1.139(2), C(2)–O(2) 1.1645(18),
C(3)–O(3) 1.1440(19), C(4)–O(4) 1.142(2), C(5)–O(5) 1.136(2), Cr(2)–C(6)
1
1
1
1
.9076(15), Cr(2)–C(7) 1.9008(15), Cr(2)–C(8) 1.9023(14), Cr(2)–C(9)
.9176(14), Cr(2)–C(10) 1.8343(16), C(6)–O(6) 1.1397(19), C(7)–O(7)
.1414(18), C(8)–O(8) 1.1434(17), C(9)–O(9) 1.1389(17), C(10)–O(10)
.1578(19); Cr(2)–Cl(1)–Cr(1) 129.990(16), C(2)–Cr(1)–Cl(1) 173.44(5),
C(10)–Cr(2)–Cl(1) 177.93(5).
are asymmetrically coordinated to the halide (Cr(1)–Cl(1)
˚
˚
2
.4900(4) A, Cr(2)–Cl(1) 2.4721(4) A). The two carbonyl ligands
Fig. 6 CO-release profile for [NEt
various incubation periods in DMSO.
4
][{Cr(CO)
5
}
2
(m-Br)] (40 mmol) after
which are in positions trans to the halide ligand are more
tightly bound to the metal (Cr(2)–C(10) 1.8343(16) A, Cr(1)–C(2)
˚
˚
1
.8301(15) A) than those in positions cis to the chloride (mean
˚
Cr–C bond length 1.9046 (0.0120) A). The two Cr(CO) groups
5
We propose the following mechanism for CO-release by the
are staggered when viewed down the Cr–Cr axis (angle between
-
complexes [MX(CO)
CO-release process from complexes [MX(CO)
the M–X bond to afford a putative [M(CO)
5
]
(Scheme 1). The initial step in the
◦
planes Cr1–C1–C4–Cr2 and Cr1–C6–C8–Cr2 = 43.51(5) ).
-
5
] is hydrolysis of
A similar hydrolysis reaction with [NEt
4
][CrBr(CO) ] resulted in
5
5
] fragment, which
the formation of [NEt
to prepare [NEt
][{Cr(CO)
unsuccessful. IR spectra of [NEt
Br) prepared by hydrolysis were in good agreement this those
4
][{Cr(CO)
(m-I)] by this method have been
][{Cr(CO) (m-X)] (X = Cl,
5
}
2
(m-Br)], although our attempts
-
in CH
2
Cl
2
solution, reacts rapidly with [MX(CO)
5
]
to form
4
5
}
2
[
{M(CO)
}
(m-X)]
-
This dimeric species then releases CO, which
5
2
.
4
5
}
2
may be captured by [MX(CO)
] or [{M(CO)
-
}
(m-X)] to give
-
5
5
2
-
M(CO)
6
: in the latter case [MX(CO)
5
] would be regenerated.
26
reported previously by Ruff and matched those observed for the
intermediate formed on addition of water to [NEt ][CrX(CO)
X = Cl, Br) (Fig. 4b). In addition, CH Cl solutions of the isolated
NEt (m-Cl)] smoothly converted to Cr(CO)
Consistent with this proposal, independent carbonylation of
4
5
]
[
CrBr(CO)
] using CO gas afforded M(CO)
-
. In the case where
5
6
(
2
2
the reaction is performed in the presence of myoglobin then the
[
4
][{Cr(CO)
5
}
2
6
both in
liberated CO is captured by the protein. The precise mechanism
the presence and absence of added water.
-
of CO-release from [{M(CO)
5
}
2
(m-X)] may simply involve CO-
-
These data indicate that complexes [{Cr(CO)
5
}
2
(m-X)] are
dissociation from the metal or alternatively, the formation of the
-
formed from hydrolysis of the mononuclear species [CrX(CO)
5
] .
dimer may be reversible and “[M(CO)
5
]” may be the active agent.
The rate of CO-release, as quantified by the myoglobin assay of
-
complexes [{Cr(CO)
5
}
2
(m-X)] , is in general slightly slower than
that of the mononuclear precursors. Although this appears to
-
preclude the intermediacy of complexes [{Cr(CO)
5
}
2
(m-X)] in
the CO-release process, further studies demonstrated that this
was not necessarily the case. Treatment of CH Cl solutions of
NEt (m-Br)] with DMSO (the delivery medium in the
][{Cr(CO)
CO-release assay) resulted in rapid changes in the IR spectrum—
2
2
[
4
5 2
}
-
1
-1
-1
notably bands at 2080 cm (w), 2004 cm and 1953 cm (s)
were observed to grow in intensity. The species responsible for
this band was tentatively assigned to Cr(CO) (DMSO) which
5
did not appear to rapidly release CO. In order to confirm that
reaction with DMSO was inhibiting CO-release tests, solutions
-
-
of [NEt
4
][{Cr(CO)
5
}
2
(m-Br)] were incubated for 6 and 30 min in
Scheme
(iv) +[MX(CO)
1
(i) +H O, -X ; (ii) +[MX(CO) ]- (iii) -[MX(CO) ] ;
2
5
5
-
DMSO before being administered to the myoglobin assay. The
5
] or [NEt
4
][{M(CO)
5
}
2
(m-X)]; (v) +deoxy-Mb.
This journal is © The Royal Society of Chemistry 2009
Dalton Trans., 2009, 4351–4358 | 4355

Conclusions
mer-FeI
2
(CO)
3
(P{CH
2
OH}
3
)
Within this series of primary metal carbonyls, a wide spectrum of
rates of CO-release, covering two orders of magnitude, has been
observed. It is clear from these data that a priori predication of CO-
releasing properties is extremely difficult and an understanding of
the precise mechanism of CO-release in an aqueous medium is
required.
FeI (CO)
2
4
(421 mg, 1 mmol) and P(CH
2
OH) (124 mg, 1 mmol)
3
was dissolved in THF (15 mL). The reaction mixture was stirred
◦
at 0 C for 2 h and the resulting reaction monitored by IR
spectroscopy. mer-FeI
oil after silica gel column using hexane–acetone (6 : 5) as eluent.
2
(CO)
3
(P{CH
2
OH}
3
) was isolated as a red
-
1
1
Yield 100 mg (21%). IR (CH
(CDCl ): d 4.93 (br s, 1H, OH), 4.60 (br s, 2H, CH
NMR (CDCl ): d 60.3 (s). HR-MS for C FeI
·NH
535.7905, expected 535.7914.
2
Cl , cm ): 2099 w, 2054 s H NMR
2
For example, within the series of complexes [MX(CO)
5
]- the
3
2
); P{ H}
found
31
1
rate of CO-release is not controlled by the M–C bond strengths
but crucially by the rate of hydrolysis of the halide ligand. The
3
6
H
9
2
O
6
P
2
4
data obtained for the carbene complexes M(=C{OMe}CH
also implies that the strength of the metal–carbonyl bond is not
)(CO)
3
5
All cis-FeI (CO) (P{OMe} ) and cis,cis,trans-
2
2
3 2
27
controlling the rate of CO-release. Casey has demonstrated that
FeI (CO) (P{OMe} )
2
2
3 2
1
3
the rate of CO exchange with complexes M(=C{OMe}Ph)(CO)
5
FeI
2
(CO)
4
(421 mg, 1 mmol) was dissolved in THF (15 mL)
decreases in the series Mo > Cr > W—this pattern is consistent
with the previous kinetic studies on [MX(CO)
◦
-
and cooled to 0 C. P(OMe)
3
(230 mL, 219 mg, 2 mmol)
5
] , but again
was added and the reaction mixture stirred for 3 h. After this
time, the solvent was removed under vacuum. Separation by
column chromatography afforded three products, mer-FeI
inconsistent with the CO-release data. Therefore, CO-release in
both these systems is not a simple loss of CO from the coordination
sphere of the metal and it is the nature of the interaction between
the CO-RM and water which appears to control CO-release.
In the case of the carbene complexes we have not, to date,
been able to elucidate the precise mechanism of this interaction
and this remains an important future goal for this research
2
(CO)
21 mg
89 mg (16%). All
3
-
(
(
P{OCH
4%), and cis,cis,trans-FeI
(CO)
(P{OMe}
H NMR (CD Cl ): d 3.92 (d,
1
3
}
3
) 92 mg (20%), all cis-FeI
(CO)
(P{OMe}
IR (CH Cl , cm ): 2051 s, 2004 s
2
(CO)
2
(P{OMe}
3
)
2
2
2
)
3 2
-
1
cis- FeI
2
2
3
)
2
2
2
1
3
2
2
J
PH = 10.2 Hz, 9H), 3.80
3
31
28
(d,
J
PH = 10.5 Hz, 9H); P{ H} NMR (CDCl
3
): d 174.2
programme.
2
and 143.8 ( JPP = 121.6 Hz). HR-MS for C
8
H
18FeI
2
O
8
P
2
·Na
found 636.7817, expected 636.7808. Elemental analysis expected:
Experimental
C 15.65 H 2.96%; Found: C 15.47 H 2.83%. cis,cis,trans-
-
1
1
FeI
NMR (CD
NMR(CD Cl
31.8273, expected 631.8254.
2
(CO)
2
(P{OMe}
Cl
): d 3.91 ( JPH + JPH = 10.8 Hz, 18H); P{ H}
): d 140.3. HR-MS for C found
·NH
3
)
2
IR (CH
2
Cl
2
, cm ): 2057 s, 2008 s. H
All manipulations were conveniently accomplished by us-
ing standard Schlenk line and Glove Box apparatus. Com-
3
5
31
1
2
2
2
2
8
H
18FeI
2
O
8
P
2
4
2
9,30
31
32
plexes [NEt
4
][V(CO)
], [NEt ][W(CO)
and [NEt
Cl, Br, I) were prepared according to literature procedures.
mer-FeI (CO) ), all cis-FeI (CO) (P{OCH and
(P{OCH
cis,cis,trans-FeI (CO) were prepared by a modifica-
(P{OCH
tion of the literature procedures as detailed below. Cr(CO)
6
],
MnBr(CO)
5
,
FeI
2
(CO)
4
,
[NEt
4
][Mo-
6
21
21
21
(CO)
4
I
3
4
4
I
3
], W(CO)
3
(acac)
2
,
M(=C{OCH
3
}-
3
3
20
CH )(CO)
3
5
,
4
][MX(CO)
5
]
(M = Cr, Mo, W; X =
[
NEt
4
][{Cr(CO)
5
}
2
(l-Cl)]
2
3
3
}
3
2
2
3
} )
3 2
[
NEt
][CrCl(CO)
] (132 mg, 0.4 mmol) was suspended in 5 mL
4
5
2
2
3
} )
3 2
toluene and degassed water (2 mL) was added with vigorous
stirring. The reaction was monitored by IR spectroscopy: after
2
2
6
was
purchased from Aldrich and sublimed prior to use. Myoglobin,
light mineral oil and PBS were purchased from Sigma and sodium
dithionite from Alfa Aeasar. IR spectra were acquired on a
Mattson Research Series FTIR spectrometer using CsCl solution
cells or on a Mettler-Toledo AutoChem ReactIR system. NMR
spectra were recorded on a Bruker AVANCE 300 Spectrometer
1
5 min the bands for [NEt
4
][CrCl(CO) ] were no longer present.
5
The resulting orange solid was isolated by filtration and washed
with water (1 mL) and toluene (3 ¥ 2 mL). The solid was dried
under a stream of argon for 30 min. Yield 53 mg (59%). Crystals
suitable for X-ray diffraction were obtained by the slow diffusion
of toluene into CH
-
2
Cl
2
solution of [NEt
(m-Br)] was prepared in an identical
][CrBr(CO) ]. Yield 44 mg (51%).
4
][{Cr(CO)
5
}
2
(m-Cl)] at
1
31
◦
(
operating frequencies H 300.13 MHz; P 129.49 MHz). Mass
30 C. [NEt
4
][{Cr(CO)
5 2
}
spectra were obtained on a Bruker microTOF instrument.
manner from [N(C
2
H
5
)
4
5
mer-FeI
2
(CO)
3
(P{OMe}
3
)
CO-release tests
FeI (CO)
2
4
(421 mg, 1 mmol) was dissolved in THF (10 mL) and
The release of CO from metal carbonyl compounds was studied
spectrophotometrically by measuring the conversion of deoxy-
myoglobin (deoxy-Mb) to carbonmonoxymyoglobin (Mb-CO).
The amount of Mb-CO formed was quantified by measuring the
absorbance of the heme Q-bands at 540 nm. A stock solution
of myoglobin (lyophilised horse heart) (ca. 60 mM final concen-
tration) was prepared fresh by dissolving the protein in phosphate
buffered saline (PBS) (0.01M, pH = 7.4). Sodium dithionite (0.1%)
was added to convert the myoglobin stock to deoxy-Mb. A 2 mL
quantity of this was measured to obtain a deoxy-Mb spectrum
and then bubbled with CO to get a Mb-CO spectrum. CO-RMs
◦
the solution was stirred at 0 C. P(OMe)
added causing the immediate evolution of a gas. The mixture
was stirred at 0 C for 2 h and the reaction monitored by IR
spectroscopy. The solvent was removed in vacuum and the product
isolated by silica gel column using CH
Yield 262 mg (57%). Recrystallization by slow diffusion of hexane
into a concentrated CH
crystals suitable for X-ray diffraction analysis. IR (CH
3
(115 mL, mmol) was
◦
2
2
Cl –hexanes (1 : 3) as eluent.
2
Cl
2
of mer-FeI
2
(CO)
3
(P{OMe}
3
afforded
-
1
2
Cl
2
, cm ):
1
3
2
102 m, 2055 s. H NMR (CDCl
P{ H} NMR (CDCl
3
): d 3.01 (d, 9H, JPH= 11.1 Hz,);
3
1
1
3
): d 164.0 (s).
4
356 | Dalton Trans., 2009, 4351–4358
This journal is © The Royal Society of Chemistry 2009

Table 3 Data collection and refinement details for the structures of mer-FeI
NEt (m-Cl)]
][{Cr(CO)
2
(CO)
3
(P{OMe}
3
), cis,cis,trans-FeI
2
(CO)
3
(P{OMe}
3
)
2
and
[
4
5 2
}
mer-FeI
2
(CO)
3
(P{OMe}
3
)
cis,cis,trans-FeI
2
(CO)
3
(P{OMe}
3
)
2
[NEt
4
][{Cr(CO) (m-Cl)]
5 2
}
Empirical formula
Formula weight
T/K
C
6
H
9
FeI
2
O
6
P
C
8
H
18FeI
2
O
8
P
2
18 2
C H20ClCr NO10
549.80
110(2)
0.71073
Triclinic
¯
P1
8.9467(3)
11.7102(4)
12.2157(4)
78.1820(10)
76.7670(10)
72.5950(10)
1175.91(7)
2
517.75
110(2)
0.71073
Orthorhombic
Pbca
13.0150(12)
11.8082(11)
18.5614(17)
90 .
90 .
90 .
2852.6(5)
8
2.411
5.505
1920
613.81
110(2)
0.71073
Monoclinic
P2 /c
15.8951(10)
8.7990(6)
13.4590(8)
90 .
90.8410(10)
90 .
1882.2(2)
4
2.166
4.279
1168
l/A˚
Crystal system
Space group
1
a/A˚
b/A˚
c/A˚
◦
◦
◦
a/
◦
◦
b/
◦
◦
◦
g /
V/A˚
3
Z
D
-3
calcd/Mg m
m/mm
F(000)
1.553
1.089
560
-1
3
Crystal size/mm
0.29 ¥ 0.20 ¥ 0.06
2.19–28.28
0.36 ¥ 0.32 ¥ 0.13
1.28–29.99
0.13 ¥ 0.10 ¥ 0.08
◦
◦
◦
◦
q range for data collection/
Index ranges
1.73–30.01
-17 ≤ h ≤ 16, -15 ≤ k ≤ 15,
-21 ≤ h ≤ 21, -12 ≤ k ≤ 12,
-12 ≤ h ≤ 12, -16 ≤ k ≤ 15,
-
24 ≤ l ≤ 24
-18 ≤ l ≤ 18
-17 ≤ l ≤ 17
Reflections collected
Independent reflections
Completeness to theta
Absorption correction
Max. and min. transmission
Refinement method
27 698
20 672
13 473
3541 [Rint = 0.0302]
5430 [Rint = 0.0215]
6652 [Rint = 0.0159]
◦
99.9%
98.9%
96.7% (30.01 )
Semi-empirical from equivalents
0.607 and 0.436
Full-matrix least-squares on F
3541/0/148
1.211
Semi-empirical from equivalents
0.573 and 0.378
Full-matrix least-squares on F
5429/0/196
1.154
R
R
Semi-empirical from equivalents
0.917 and 0.804
Full-matrix least-squares on F
6652/0/364
1.024
2
2
2
Data/restraints/parameters
2
Goodness-of-fit on F
Final R indices [I > 2s(I)]
R
1
1
= 0.0279, wR
2
2
= 0.0550
= 0.0556
1
= 0.0217, wR
2
2
= 0.0489
= 0.0497
R
1
= 0.0280, wR
2
2
= 0.0721
= 0.0755
R indices (all data)
R
= 0.0296, wR
1
= 0.0237, wR
R
1
= 0.0335, wR
Largest diffraction peak and hole/e A˚ -
3
1.283 and -1.139
0.961 and -0.456
1.049 and -0.416
were dissolved in an appropriate solvent (DMSO or EtOH) (4, 8,
2 mM) and added to deoxy-Mb in the cuvette (to give a final
Acknowledgements
1
We are grateful to the Leverhulme Trust (F/00 2244/AA), EPSRC
EP/E005152/1), The Royal Society Fellowship to IJSF and
CO-RM concentration of 20, 40, 60 mM), mixed using a pipette
and then overlaid with 500 mL light mineral oil to prevent CO
escaping or the myoglobin being oxygenated. This is the standard
procedure; other experiments have been undertaken using different
concentrations of both myoglobin and DMSO. Details of the
methods used to calculate Mb-CO concentrations are provided
in the ESI.†
(
Astra-Zeneca (unrestricted research grant to IJSF) for funding.
Mettler-Toledo AutoChem (loan of the ReactIR system) and the
technical expertise of Dr Jon Goode and the input of Prof. R N.
Perutz are gratefully acknowledged. We thank Dr R. Motterlini
(
Northwick Park Hospital, London and HemoCORM Ltd) for
discussions concerning the design of these CO-RMs.
Details of X-ray diffraction analysis
Notes and references
Details of the collection and refinement are presented in Table 3.
Diffraction data were collected at 110 K on a Bruker Smart
1
(a) T. R. Johnson, B. E. Mann, J. E. Clark, R. Foresti, C. J. Green and
R. Motterlini, Angew. Chem., Int. Ed., 2003, 42, 3722; (b) R. Alberto
and R. Motterlini, Dalton Trans., 2007, 1651; (c) B. E. Mann and R.
Motterlini, Chem. Commun., 2007, 4197; (d) R. Motterlini, Biochem.
Soc. Trans., 2007, 35, 1142.
˚
Apex diffractometer with MoKa radiation (l = 0.71073 A)
using a SMART CCD camera. Diffractometer control, data
collection and initial unit cell determination was performed using
2
R. Foresti and R. Motterlini, Free. Rad. Res, 1999, 31, 469.
3
4
“
SMART”. Frame integration and unit-cell refinement software
3 (a) W. K. McCoubrey, T. J. Huang and M. D. Maines, Eur. J. Biochem.,
1997, 247, 725; (b) S. Hayashi, Y. Omata, H. Sakamoto, Y. Higasgimoto,
T. Hara, Y. Sagara and M. Noguchi, Gene, 2004, 336, 241.
35
was carried out with “SAINT+”. Absorption corrections were
applied by SADABS (v. 2.03, Sheldrick). Structures were solved
by direct methods using SHELXS-97 and refined by full-matrix
least squares using SHELXL-97. All non-hydrogen atoms were
refined anisotropically. Hydrogen atoms were placed using a
36
4
(a) R. Motterlini, A. Gonzales, R. Foresti, J. E. Clark, C. J. Green and
R. M. Winslow, Circ. Res., 1998, 83, 568; (b) I. A. Sammut, R. Foresti,
J. E. Clark, D. J. Exon, M. J. J. Vesely, P. Sarathchandra, C. J. Green
and R. Motterlini, Br. J. Pharmacol., 1998, 125, 1437.
A. Pamplona, A. Ferreira and J. Balla, Nat. Med., 2007, 13, 703.
R. Motterlini, J. E. Clark, R. Foresti, P. Sarathchandra, B. E. Mann
and C. J. Green, Circ. Res., 2002, 90, e17.
37
38
5
6
“
riding model” and included in the refinement at calculated
positions.
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358 | Dalton Trans., 2009, 4351–4358
This journal is © The Royal Society of Chemistry 2009