Redox-Tagged Carbon Monoxide-Releasing Molecules (CORMs): Ferrocene-Containing [Mn(C^N)(CO)4] Complexes as a Promising New CORM Class

Article abstract of DOI:10.1021/acs.inorgchem.7b00509

This study describes the synthesis and characterization of a new class of ferrocene-containing carbon monoxide-releasing molecules (CORMs, 1-3). The ferrocenyl group is both a recognized therapeutically viable coligand and a handle for informative infrared spectroelectrochemistry. Deoxymyoglobin CO-release assays and in situ infrared spectroscopy confirm compounds 2 and 3 as photoCORMs and 1 as a thermal CORM, attributed to the increased sensitivity of the Mn-ferrocenyl bond to protonation in 1. Electrochemical and infrared spectroelectrochemical experiments confirm a single reversible redox couple associated with the ferrocenyl moiety with the Mn tetracarbonyl center showing no redox activity up to +590 mV vs Fc/Fc⁺, though no concomitant CO release was observed in association with the redox activity. The effects of linker length on communication between the Fe and Mn centers suggest that the incorporation of redox-active ligands into CORMs focuses on the first coordination sphere of the CORM. Redox-tagged CORMs could prove to be a useful mechanistic probe; our findings could be developed to use redox changes to trigger CO release.

Full text of DOI:10.1021/acs.inorgchem.7b00509

Article
pubs.acs.org/IC
Redox-Tagged Carbon Monoxide-Releasing Molecules (CORMs):
Ferrocene-Containing [Mn(C^N)(CO)4] Complexes as a Promising
New CORM Class
Benjamin J. Aucott, Jonathan S. Ward, Samuel G. Andrew, Jessica Milani, Adrian C. Whitwood,
Jason M. Lynam,* Alison Parkin,* and Ian J. S. Fairlamb*
Department of Chemistry, University of York, York, YO10 5DD, United Kingdom
S
* Supporting Information
ABSTRACT: This study describes the synthesis and charac-
terization of a new class of ferrocene-containing carbon
monoxide-releasing molecules (CORMs, 1−3). The ferrocenyl
group is both a recognized therapeutically viable coligand and a
handle for informative infrared spectroelectrochemistry.
Deoxymyoglobin CO-release assays and in situ infrared
spectroscopy confirm compounds 2 and 3 as photoCORMs
and 1 as a thermal CORM, attributed to the increased
sensitivity of the Mn−ferrocenyl bond to protonation in 1.
Electrochemical and infrared spectroelectrochemical experi-
ments confirm a single reversible redox couple associated with
the ferrocenyl moiety with the Mn tetracarbonyl center
showing no redox activity up to +590 mV vs Fc/Fc+, though no concomitant CO release was observed in association with
the redox activity. The effects of linker length on communication between the Fe and Mn centers suggest that the incorporation
of redox-active ligands into CORMs focuses on the first coordination sphere of the CORM. Redox-tagged CORMs could prove
to be a useful mechanistic probe; our findings could be developed to use redox changes to trigger CO release.
groups could also provide an additional mechanistic handle for
the CO-release mechanism, which is often difficult to pin down.
Various methods have been used to promote CO release,
including thermal, enzymatic, and photochemical triggers. Early
work by Motterlini and co-workers involved simple structures
such as the DMSO-soluble complexes [RuCl2(CO)3]2, Fe-
(CO)5, and Mn2(CO)10, of which the latter two complexes
require photolysis to deliver CO to myoglobin.13 Crucially, this
work demonstrated that the vasodilatory and antihypertensive
effects of HO1 could also be conferred by CO delivery from
CORMs. The first water-soluble CORM, fac-[Ru(CO)3Cl-
(glycinate)] (CORM-3),14 has since become widely used to
study the effects of CO release on biological systems.
In recent years, there has been considerable interest in
photochemical CO release from so-called photoCORMs
(Figure 1). A diverse array of metals and coligands has been
employed, as comprehensively discussed in several recent
reviews.15−18
Many photoCORMs employ Mn(I) chemistry due to the
thermal stability associated with this oxidation state, the relative
ease of synthesis and handling, and the typically low toxicity of
these compounds.19,20 This has allowed for further function-
alization to improve selectivity and alter the CO release
INTRODUCTION
■
Carbon monoxide (CO) is produced endogenously by
mammals. The largest source of CO generation is the heme
oxygenase (HO) family of enzymes, involved in the catabolism
of heme.1 Two heme oxygenase isoforms are known to catalyze
this reaction: the inducible HO1 and the constitutive HO2.1 A
third, HO3, has been characterized to a lesser extent.2 Studies
of the ubiquitous HO1 show that this enzyme is upregulated
during stress and plays a vital role in the biochemical response
to many forms of stress.3,4
The status of CO as a biochemical signaling molecule and
the beneficial effects of exogenous CO are becoming
established,5,6 including antimicrobial,7,8 antimalarial,9 and
vasodilatory10 effects. Thus, the use of therapeutic CO
represents an intriguing area of study in drug discovery. The
administration of CO gas presents challenges in terms of
localization and selectivity, in addition to engineering
difficulties. An alternative approach is to employ carbon
monoxide-releasing molecules (CORMs).11 These compounds,
predominantly metal carbonyl complexes, are designed to
achieve controlled CO delivery, to specific tissue and cellular
targets, for therapeutic prodrug applications.12 The incorpo-
ration of redox-active ligands into CORMs could provide an
alternative trigger for CO release. In addition to providing a
conceivable way of modulating CO-release rates, redox-active
Received: February 28, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.inorgchem.7b00509
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Inorganic Chemistry
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Figure 2. Ferrocenyl CORMs synthesized in this work. Note: complex
3 is racemic (planar chirality).
Figure 1. Selected Mn-containing photoCORMS.
centers is varied and the electrochemical, photochemical, and
CO-release properties are assessed. The reporter properties of
both the metal carbonyl center and the ferrocenyl tag enable
the effect of linker length on communication between the Fe
and Mn centers to be studied. The ferrocenyl moiety can also
be considered as a therapeutically active coligand comple-
mentary to CO; derivatives of ferrocene are validated as
therapeutics, including anticancer32 and antimalarial33 agents.
properties. Schatzschneider and co-workers synthesized a
versatile photoCORM based on a [Mn(CO)3(tpm)]+ scaffold
[where tpm = tris(pyrazolyl)methane]. The tpm backbone
allowed installation of an alkynyl group for further function-
alization with peptides.21 Zobi and co-workers took a
comparable approach in their synthesis of CORM conjugates
with cobalamin.22 Mascharak and co-workers have combined
theoretical and experimental approaches to better understand
the photochemical properties of some Mn(I) tricarbonyl
photoCORMs, leading to the development of one class of
visible-light-triggered photoCORMs.23 Soluble, water-stable,
and nontoxic Mn(I) tricarbonyl complexes of amino acids19,24
and recently dinuclear complexes with cysteamine20 have also
been developed as photoCORMs with desirable properties.
Fairlamb and co-workers additionally reported Mn(I) tetra-
carbonyl species bearing a readily functionalizable cyclo-
manganated 2-phenylpyridine ligand, which can be function-
alized to improve water solubility25 and enable further
conjugation via Suzuki couplings.26
Complementary to the advances in photoCORMs is the
drive to develop other mechanisms for triggering CO release.
One such possibility is redox-triggered CO release. Many
changes of state of both healthy and diseased cells are
accompanied by a change in cellular redox balance.27 It is
therefore desirable to produce CORMs sensitive to a redox
environment. Depending on the target, both oxidative and
reductive mechanisms may be desirable. For example, reductive
activation of other classes of anticancer compounds is already
established,28 while some ferricenium salts have been shown to
have increased antitumor activity compared to ferrocene.29
Taking forward structures related to those tested by Lynam
and co-workers,30 Pryce and co-workers demonstrated that a
Cr(CO)5(aminocarbene) complex slowly releases 1 equiv of
CO upon electrochemical oxidation.31 Further examples and
mechanistic investigation are required to inform the design of
future redox-triggered CORMs.
EXPERIMENTAL SECTION
■
Reagents and Solvents. Reactions in O2-free or anhydrous
conditions were performed with dry, deoxygenated solvents under an
inert atmosphere, using either standard Schlenk techniques (under
N2) or a balloon (of argon), as specified in the procedures.
Commercial chemicals were purchased from either Acros Organics,
Alfa Aesar, Fluorochem, or Sigma-Aldrich and were used without
further purification unless otherwise stated. Dry Et2O, THF, toluene,
dichloromethane, and hexane were dispensed from a Pure Solv MD-7
solvent machine and stored in oven-dried ampules under N2. Dry THF
and Et2O were then deoxygenated by bubbling with N2 and sonication.
Water, EtOH, and tBuOH were deoxygenated by vigorous bubbling of
N2 through the solution for at least 1 h. “Petrol” refers to petroleum
ether (bp 40−60 °C).
1
Nuclear Magnetic Resonance Spectroscopy. Solution H and
13C NMR analysis was carried out at 298 K on JEOL ESC400/ESX400
and Bruker AV500/AV700 spectrometers. The spectra were processed
by MNova software. All coupling constants are quoted to the nearest
0.5 Hz. All chemical shifts are reported in ppm and are referenced to
the residual NMR solvent (1H: CDCl3, 7.26 ppm; DMSO-d6, 2.50
ppm; MeOH-d4, 3.31 ppm; CD2Cl2, 5.32 ppm. 13C: CDCl3, 77.36
ppm; DMSO-d6, 39.52 ppm; MeOH-d4, 49.00 ppm; CD2Cl2, 53.49
ppm). The 13C NMR spectra of some tetracarbonyl manganese(I)
complexes did not show the metal carbonyl resonances due to the long
relaxation times of metal carbonyls. In such cases, infrared
spectroscopic analysis confirmed the presence of these metal
carbonyls.
Infrared Spectroscopy. Spectra were recorded on a Bruker Alpha
IR spectrometer, usually at a resolution of 4 cm−1. Details of the
method (ATR, transmission cell, solvent etc.) are given next to the
data. Peak intensities are grouped qualitatively as very strong (vs),
strong (s), medium (m), and weak (w), according to common
convention.
Mass Spectrometry. Mass spectrometry was carried out using a
Bruker microTOF spectrometer in positive ion mode using electro-
spray ionization (ESI) or liquid injection field desorption ionization
(LIFDI) as the ionization methods. High-resolution ESI data are
within 5 ppm error of the theoretical value unless otherwise stated. All
LIFDI data are within 120 ppm error.
Elemental Analysis. Elemental analyses were performed on an
Exeter Analytical CE-440 elemental analyzer. The quoted percentage
compositions of C, H, and N are the average of two experiments.
In designing a CORM, there is inherently a compromise
between the inclusion of multiple equivalents of CO and the
tendency of CO ligands to stabilize low oxidation states,
shifting the redox potential. Controllable redox activity at the
metal carbonyl center at a biologically relevant redox potential
is challenging as a result of this.
In this work, three ferrocenyl-substituted CORMs, 1−3,
based on the parent structure of the air- and water-stable
photoCORM Mn(CO)4(2-phenylpyridine), are synthesized
(Figure 2). The linker length connecting the Fe and Mn
B
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UV−Visible Spectroscopy. All UV−visible spectra were recorded
with a JASCO V-560 spectrometer using standard methods. Extinction
coefficients (ε) were calculated by fitting measured absorbance to the
Beer−Lambert law using at least five different concentrations.
Melting Point Determination. Melting points were measured on
a Stuart SMP30 apparatus (ramp rates of 2 or 3 °C min−1) or using
differential scanning calorimetry (DSC) on a PerkinElmer DSC7
machine calibrated with an indium standard. The DSC experiments
were run at a ramp rate of 10 °C min−1, and the melting point was
taken as the onset of the observed endothermic peak.
Chromatography. Thin-layer chromatography (TLC) was carried
out using aluminum-backed TLC plates (5554, Merck). Visualization
was by quenching of fluorescence using a lamp with λmax = 254 nm.
Flash column chromatography was performed using silica gel 60
(Fluorochem, particle size 40−63 μm).
X-ray Crystallography. Single crystals were grown in ambient
conditions using dichloromethane/pentane layering or slow evapo-
ration. A suitable crystal was selected and mounted on an Oxford
Diffraction SuperNova (Cu at zero, the orientation of the Cu source
relative to the goniometer axes in the dual-source SuperNova X-ray
diffractometer; the molybdenum source is offset relative to the
goniometer axes), with an Eos diffractometer. The crystal was kept at
110 K during data collection. Using Olex2,34 the structures were
solved with the ShelXS35 structure solution program using the
Patterson method or Superflip using charge flipping. The structures
were refined with the ShelXL36 refinement package using least squares
minimization.
removed in vacuo to give the crude product, which was purified by
flash column chromatography on silica, eluting with petrol and then
petrol/Et2O 4:1 v/v. The solvent was removed in vacuo to give the
1
title compound as a yellow oil (1.25 g, 85% yield). H NMR (400
MHz, CDCl3): δ (ppm) = 8.69 (ddd, 5.0, 2.0, 1.0 Hz, 1H, Ar−H),
7.99 (d, 8.5 Hz, 2H, Ar−H), 7.77−7.71 (m, 2H, Ar−H), 7.47 (d, 8.0
Hz, 2H, Ar−H), 7.22 (ddd, 5.5, 5.0, 2.5 Hz, 1H, Ar−H), 4.70 (s, 2H,
CH2), 4.23 (s, 2H, CH2), 1.09 (m, 21 H, CH and CH3 from TIPS).
13C NMR (101 MHz, CDCl3): δ (ppm) = 157.7, 150.2, 139.4, 138.8,
137.2, 129.0, 127.4, 122.5, 120.9 (Ar); 103.4 (CC−Si); 88.4 (C
C−Si); 70.7 (benzylic CH2); 57.8 (propargylic CH2), 18.4 (TIPS
CH3); 11.0 (TIPS CH). HRMS (ESI+): m/z = 380.2391 [MH]+
(C24H34NOSi requires 380.2410). IR (CH2Cl2, cm−1): 2170 (w), 1703
(w), 1603 (w), 1589 (w), 1580 (w), 1565 (w), 1468 (s), 1436 (m),
1384 (w), 1351 (m), 1210 (w), 1153 (w), 1079 (s), 1029 (w), 1017
(w), 998 (m), 991 (m).
Tetracarbonyl (2-(4′-[(3″-Triisopropylsilyl-prop-2-ynyloxy)-
methyl]phenyl)-κ,C2-pyridine-κ,N) Manganese(I) (5). Using general
procedure 1, BnMn(CO)5 (1 equiv, 2.93 mmol, 840 mg) and 2-(4-[(3-
triisopropylsilyl-prop-2-ynyl-oxy)methyl]phenyl)pyridine (0.96 equiv,
2.82 mmol, 1.07 g) were reacted in hexane (40 mL). The title
compound was isolated as a yellow solid (1.35 g, 88% yield) with no
1
additional purification required. Mp: 82 °C (DSC). H NMR (400
MHz, CDCl3): δ (ppm) = 8.72 (d, 5.5 Hz, 1H, Ar−H), 7.92 (s, 1H,
Ar−H), 7.87 (d, 8.0 Hz, 1H, Ar−H), 7.82−7.75 (m, 2H, Ar−H), 7.20
(dd, 8.0, 1.5 Hz, 1H, Ar−H), 7.11 (ddd, 7.5, 5.0, 1.5 Hz, 1H, Ar−H),
4.70 (s, 2H, CH2), 4.30 (s, 2H, CH2), 1.11 (m, 21H, CH and CH3
from TIPS). 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 220.0,
214.5, 213.4 (Mn−CO); 172.5, 164.7, 154.4, 145.9, 140.9, 139.1,
139.0, 124.5, 124.0, 123.7, 120.0 (Ar); 104.3 (CC−Si); 86.8 (C
C−Si); 70.5 (benzylic CH2); 57.3 (propargylic CH2); 18.4 (TIPS
CH3); 10.6 (TIPS CH). HRMS (ESI+): m/z = 568.1327 [MNa]+
(C28H32MnNNaO5Si requires 568.1328). Elemental analysis (CHN):
C 61.48%, H 5.91%, N 2.51% (C28H33NO5SiMn requires C 61.64%, H
5.91%, N 2.57%). IR (CH2Cl2, cm−1): 3685 (w), 3157 (w), 2961 (m),
2946 (m), 2927 (m), 2893 (m), 2866 (m), 2076 (s), 1991 (vs), 1976
(vs), 1933 (vs), 1605 (m), 1587 (m), 1567 (m), 1479 (m), 1467 (m),
1351 (s).
Myoglobin CO-Release Assay. Experiments and data analysis
were performed according to the procedures described previously.37
Electrochemistry. Cyclic voltammograms were recorded in a
three-electrode cell comprising a Pt disk working electrode, a Pt wire
counter electrode, and an Ag wire pseudo-reference electrode. Each
+
analyte was calibrated to the FeCp2/FeCp2 redox couple by the
addition of ferrocene or acetylferrocene {Fe(η-C5H4COMe)Cp/
[Fe(η-C5H4COMe)Cp]+} measured to be +276 mV vs FeCp2/
+
+
FeCp2 to enable potentials to be quoted against FeCp2/FeCp2 . All
voltammograms were performed in the presence of NBu4PF6, at a
concentration of 1 M, with a scan rate of 100 mV s−1.
Synthetic Procedures and Characterization (General Proce-
Tetracarbonyl (2-(4′-[(Prop-2″-ynyloxy)methyl]phenyl)-κ,C2-pyri-
dine-κ,N) Manganese(I) (6). To a solution of tetracarbonyl (2-(4′-
[(3″-triisopropylsilyl-prop-2′-ynyloxy)methyl]phenyl)-κ,C2-pyridine-
κ,N) manganese(I) (1 equiv, 1.10 mmol, 599 mg) in CH2Cl2 (2 mL)
was added a solution of TBAF·3H2O (1.2 equiv, 1.32 mmol, 417 mg)
in CH3CN (10 mL). The brown solution was stirred under air for 25
min, at which time the reaction was judged complete (TLC analysis).
Water (10 mL) was added and the mixture extracted with CH2Cl2 (3
× 15 mL). The combined organic layers were dried (MgSO4) and
filtered. The solvent was removed in vacuo to yield the crude product,
which was purified by flash column chromatography on silica gel,
starting with petrol/EtOAc 10:1 v/v and increasing the gradient
slightly to 10:1.5 v/v to afford the product. The solvent was removed
in vacuo to give the title compound as a light brown solid (0.253 g,
dure 1). This general procedure for cyclomanganation with
BnMn(CO)5 is referred to elsewhere as “general procedure 1”.38
A
typical reaction was conducted on a 0.5 mmol scale. To an oven-dried
Schlenk tube containing a stirrer bar, BnMn(CO)5 (1 equiv), and
“CH^N” ligand (1 equiv) was added dry, deoxygenated hexane (16
mL/mmol of BnMn(CO)5) via syringe. The solution was heated to
reflux for between 6 and 24 h (covered in aluminum foil to exclude
ambient light). Reaction progress was monitored by IR spectroscopic
analysis by taking aliquots directly from the reaction mixture. On
reaction completion, the mixture was allowed to cool to room
temperature and then filtered through a pipet packed with cotton
wool. Any solid product that precipitated out of solution was dissolved
in a small amount of CH2Cl2. The solvent was removed in vacuo to
afford the product. Where required, further purification was performed
using flash column chromatography.
2-(4′-[(3″-Triisopropylsilyl-prop-2-ynyl-oxy)methyl]phenyl)-
pyridine (4). To an oven-dried Schlenk tube containing a solution of
2-(4-[(prop-2-ynyloxy)methyl]phenyl)pyridine (1.0 equiv, 3.87 mmol,
0.865 g) in dry, deoxygenated THF (40 mL) at −78 °C was added a
solution of LDA (1.0 equiv, 3.87 mmol, 9.6 mL) in THF via syringe
over 5 min. The LDA was freshly prepared by lithiation of freshly
distilled diisopropylamine with n-BuLi (titrated against n-benzylben-
zamide before use).39 After the addition of LDA was complete, the
Schlenk tube was placed in an ice/water bath at 0 °C for 10 min before
being cooled back to −78 °C for the addition of TIPS-Cl (1.0 equiv,
3.87 mmol, 0.84 mL). The reaction mixture was then allowed to warm
(to rt) and left for 19 h, at which point TLC analysis indicated reaction
completion. The reaction was quenched using saturated ammonium
chloride (30 mL) and extracted with Et2O (3 × 50 mL). The
combined organic layers were washed with water (30 mL) and brine
(30 mL), before being dried (MgSO4) and filtered. The solvent was
1
59% yield). Mp: 107 °C (dec). H NMR (400 MHz, DMSO-d6): δ
(ppm) = 8.76 (d, 5.5 Hz, 1H, Ar−H), 8.24 (d, 8.0 Hz, 1H, Ar−H),
8.07−8.00 (m, 2H, Ar−H), 7.78 (s, 1H, Ar−H), 7.37 (m, 1H, Ar−H),
7.12 (dd, 1.0, 8.0 Hz, 1H, Ar−H), 4.57 (s, 2H, CH2), 4.25 (t, 2.5 Hz,
2H CH2), 3.52 (d, 2.5 Hz, 1H, CC−H). 13C NMR (101 MHz,
CDCl3): δ (ppm) = 175.4, 166.4, 154.2, 146.1, 141.4, 139.3, 138.2,
124.3, 124.3, 122.7, 119.7 (Ar); 80.1, 75.0, 72.3, 57.8 (propargylic
CH2). IR (CH2Cl2, cm−1): 3664 (w), 3302 (w), 2964 (m), 2945 (m),
2929 (w), 2893 (m), 2866 (m), 2075 (s), 1991 (vs), 1976 (vs), 1932
(vs), 1605 (m), 1588 (m), 1566 (w), 1478 (m), 1468 (m). HRMS
(ESI+): m/z = 411.9992 [MNa]+ (C19H12MnNNaO5 requires
411.9994). Elemental analysis (CHN): C 58.58%, H 3.23%, N
3.48% (C19H13NO5Mn requires C 58.62%, H 3.11%, N 3.60%).
Tetracarbonyl (2-[4-(([1-(Ferrocenyl)-1H-1,2,3-triazol-4-yl]-
methoxy)methyl)phenyl]-κ,C2-pyridine-κ,N) Manganese(I) (1). To a
solution of tetracarbonyl (2-(4′-[(prop-2-ynyloxy)methyl]phenyl)-
κ,C2-pyridine-κ,N) manganese(I) (1.0 equiv, 0.2 mmol, 78 mg) in
N2-saturated tBuOH (3 mL) were added azidoferrocene (1.0 equiv, 0.2
C
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Scheme 1. Synthesis of Alkynyl Building Block 6 and Ferrocenyl Complex 1
mmol, 46 mg) and water (2.7 mL). Copper(II) sulfate (0.3 equiv, 0.06
mmol, 200 μL of 300 mM aqueous solution) and sodium ascorbate
(0.6 equiv, 0.12 mmol, 120 μL of 500 mM aqueous solution) were
added, and the reaction mixture was stirred at room temperature in the
dark under an argon balloon. After 24 h, the reaction mixture was
diluted with water (20 mL). The product was extracted with EtOAc (4
× 20 mL). The combined organic layers were dried with MgSO4 and
filtered, before removal of the solvent yielded the crude product. The
crude product was purified by flash column chromatography on silica,
using petrol/EtOAc, starting with 3:2 v/v and moving to 1:1 v/v to
elute the product. The solvent was removed to give the title
compound (74 mg, 60% yield) as a yellow crystalline solid. Mp: 143
procedure 1 with BnMn(CO)5 (1.0 equiv, 0.25 mmol, 72.5 mg), [4-
(2′-pyridinyl)phenyl]ferrocene (1.0 equiv, 0.25 mmol, 84.5 mg), and
hexane (4 mL). Infrared spectroscopic analysis showed that the
reaction was complete after 6 h. The title compound was purified by
flash column chromatography on silica, using petrol and then petrol/
EtOAc 9:1 v/v. The solvent was removed in vacuo to afford a red
microcrystalline solid (79 mg, 59% yield). Mp: 138 °C (dec). 1H
NMR (700 MHz, CDCl3): δ (ppm) = 8.70 (d, 5.0 Hz, 1H, Ar−H),
8.12 (s, 1H, Ar−H), 7.84 (d, 8.0 Hz, 1H, Ar−H), 7.77 (apr. t, 1H, Ar−
H), 7.68 (d, 8.0 Hz, 1H, Ar−H), 7.28 (s, 1H, Ar−H), 7.08 (dd, 6.5, 6.0
Hz, 1H, Ar−H), 4.77 (t, 2.0 Hz, 2H, Cp-H), 4.37 (t, 2.0 Hz, 2H, Cp-
H), 4.09 (s, 5H, Cp-H). 13C NMR (176 MHz, CDCl3) δ (ppm) =
220.4, 214.2, 214.1 (Mn−CO); 174.2, 166.2, 153.8, 144.0, 141.4,
139.0, 137.7, 123.9, 122.2, 121.8, 119.0 (Ar); 85.4, 69.8, 69.2, 67.1
(Cp). MS (LIFDI+): m/z = 505.04 [M+] C29H21N4O5MnFe requires
504.9809. Elemental analysis (CHN): C 59.69%, H 3.27%, N 2.73%
(C29H21N4O5MnFe requires C 59.44%, H 3.19%, N 2.77%). IR
(CH2Cl2, cm−1): 2967 (w), 2074 (s), 1990 (s), 1975 (s), 1931 (s),
1733 (w), 1606 (m), 1583 (m), 1563 (m), 1474 (m), 1425 (w).
2-(Ferrocenyl)pyridine (9). Bromoferrocene (1.0 equiv, 1.9 mmol,
513 mg) was stirred in dry ethyl acetate (10 mL) at −78 °C. After the
dropwise addition of n-BuLi (1.1 equiv, 2.0 mmol, 800 μL) over 15
min, the solution was allowed to warm to room temperature and
stirred for a further 10 min when a bright orange precipitate had
formed. The reaction mixture was cooled back to −78 °C and
transferred via cannula onto dry ZnCl2 (2.0 equiv, 3.8 mmol, 518 mg)
at −78 °C. After the reaction mixture had been stirred at room
temperature for 1 h, it was transferred via cannula to a Schlenk tube
containing Pd(PPh3)4 (10 mol %, 0.19 mmol, 220 mg), and 2-
bromopyridine (2.5 equiv, 4.75 mmol, 450 μL) was added dropwise.
The reaction mixture was stirred at room temperature for 19 h and
then quenched with sat. aq NH4Cl (15 mL). The aqueous layer was
extracted with chloroform (3 × 10 mL), and the combined organic
layers were dried with MgSO4 and filtered. Removal of the solvent in
vacuo gave an orange powder. Further purification by silica gel flash
column chromatography using petrol/EtOAc 9:1 v/v afforded an
analytically pure sample of the title compound as an orange powder
(371 mg, 74% yield). Mp: 90−92 °C. 1H NMR (700 MHz, CD2Cl2): δ
(ppm) = 8.51 (ddd, 5.0, 2.0, 1.0 Hz, 1H, Ar−H), 7.57 (ddd, 8.0, 7.5,
1.0 Hz, 1H, Ar−H), 7.41 (ddd, 8.0, 1.0, 1.0 Hz, 1H, Ar−H), 7.06 (ddd,
7.5, 5.0, 1.0 Hz 1H, Ar−H), 4.92 (dd, 2.0, 2.0 Hz, 2H, Cp-H), 4.40
(dd, 2.0, 2.0 Hz, 2H, Cp-H), 4.05 (s, 5H, Cp-H). 13C NMR (176
MHz, CD2Cl2) δ (ppm) = 159.3, 149.4, 136.0, 120.6, 120.2 (Ar); 83.7,
70.0, 69.7, 67.3 (Cp). HRMS (ESI+): m/z = 264.0473 [M − H]+
(C15H14NFe requires 264.0470). IR (CH2Cl2, cm−1): 1609 (m), 1588
1
°C (dec). H NMR (700 MHz, CDCl3): δ (ppm) = 8.72 (d, 5.5 Hz,
1H, Ar−H), 7.97 (d, 1.5 Hz, 1H, Ar−H), 7.89−7.86 (m, 1H, Ar−H),
7.84 (s, 1H, Ar−H), 7.81−7.76 (m, 2H, Ar−H), 7.21 (dd, 8.0, 1.5 Hz,
1H, Ar−H), 7.12 (ddd, 7.0, 5.5, 1.5 Hz, 1H, Ar−H), 4.83 (t, 2.0 Hz,
2H, Cp-H), 4.82 (s, 2H, CH2), 4.71 (s, 2H, CH2), 4.26 (t, 2.0 Hz, 2H,
Cp-H), 4.22 (s, 5H, Cp-H). 13C NMR (176 MHz, CDCl3) δ (ppm) =
220.3, 214.1, 214.0 (M−CO); 175.1, 166.1, 154.0, 145.9, 145.5,
140.7, 139.6, 138.0, 124.2, 123.9, 122.5, 122.3, 119.5 (Ar); 94.0 (Cp);
73.0 (CH2); 70.3 (Cp); 66.8 (Cp); 64.2 (CH2); 62.3 (Cp). HRMS
(ESI+): m/z = 617.0292 [MH]+ (C29H22N4O5MnFe requires
617.0315). IR (CH2Cl2, cm−1): 3048 (w), 2864 (w), 2076 (s), 1991
(vs), 1977 (vs), 1931 (s), 1606 (m), 1587 (m), 1567 (w), 1519 (w),
1472 (m), 1432 (w), 1312 (w), 1108 (m). Elemental analysis (CHN):
C 56.28%, H 3.48%, N 8.69% (C29H21N4O5MnFe requires C 56.52%,
H 3.44%, N 9.09%). UV−visible: λmax = 270 nm, ε(270 nm) = 28 500
dm3 mol−1 cm−1. Rf: 0.40 (petrol/EtOAc 3:2 v/v).
[4-(2′-Pyridinyl)phenyl]ferrocene (8). To an oven-dried Schlenk
tube with stirrer bar were added 2-(4-bromophenyl)pyridine (1.0
equiv, 1.0 mmol, 234 mg), ferroceneboronic acid (2.0 equiv, 2.0 mmol,
461 mg), Pd(OAc)2 (0.053 equiv, 0.053 mmol, 11.9 mg), PPh3 (0.21
equiv, 0.21 mmol, 55.5 mg), and K2CO3 (4.0 equiv, 4.0 mmol, 555
mg). Anhydrous, deoxygenated toluene (10 mL) was added in one
portion via syringe. The red reaction mixture was refluxed for 20 h, at
which point TLC analysis showed complete consumption of the
starting material and the appearance of a product spot. The reaction
mixture was allowed to cool and the toluene was removed in vacuo.
The mixture was resuspended in CHCl3 (100 mL) and washed with
water (2 × 100 mL). The combined organic extract was dried
(MgSO4) and filtered. The solvent was removed in vacuo and the
crude product was purified by flash column chromatography on silica
gel using petrol/EtOAc, starting with 9:1 v/v and increasing the
gradient to 8:2 v/v. Removal of the solvent in vacuo gave the title
compound as an orange powder (173 mg, 55% yield). Mp: 122 °C. 1H
NMR (400 MHz, CDCl3): δ (ppm) = 8.69 (d, 4.5 Hz 1H, Ar−H),
7.93 (d, 8.0 Hz, 2H, Ar−H), 7.73 (d, 4.0 Hz, 2H, Ar−H), 7.58 (d, 8.0
Hz 2H, Ar−H), 7.21 (dd, 9.0, 4.0 Hz, 1H, Ar−H), 4.71 (t, 2.0 Hz, 2H,
Cp-H), 4.36 (t, 2.0 Hz, 2H, Cp-H), 4.05 (s, 5H, Cp-H). 13C NMR
(101 MHz, CDCl3) δ (ppm) = 157.4, 149.8, 140.5, 136.9, 136.8, 127.0,
126.4, 121.0, 120.3 (Ar); 84.6, 69.8, 69.3, 66.7 (Cp). HRMS (ESI+):
m/z = 340.0770 [M − H]+ (C21H18FeN requires 340.0789).
(w), 1574 (w), 1469 (m), 1434 (m), 1277 (w). UV−visible: λmax
=
314 nm, ε(314 nm) = 22 900 dm3 mol−1 cm−1; 378 nm, ε(378 nm) =
8000 dm3 mol−1 cm−1; 460 nm, ε(460 nm) = 2040 dm3 mol−1 cm−1.
( )-Tetracarbonyl (2-Ferrocenyl-κ,C2-pyridine-κ,N) Manganese(I)
(3). This reaction was performed using general procedure 1 with
BnMn(CO)5 (1.0 equiv, 2.3 mmol, 65.2 mg), 2-(ferrocenyl)pyridine
(1.0 equiv, 0.23 mmol, 60.0 mg), and hexane (6 mL). Infrared
spectroscopic analysis showed that the reaction was complete after 6 h.
The title compound was purified by flash column chromatography on
Tetracarbonyl (2-[4-Ferrocenyl]phenyl-κ,C2-pyridine-κ,N)
Manganese(I) (2). This reaction was performed using general
D
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Scheme 2. Synthesis of Complexes 2 (A) and 3 (B)
silica using petrol/Et2O/NEt3 94:5:1 v/v to afford a dark red solid
(67.2 mg, 71% yield). Mp: 109−111 °C. 1H NMR (700 MHz,
CD2Cl2): δ (ppm) = 8.50 (d, 5.0 Hz, 1H, Ar−H), 7.65 (ddd, 8.0, 7.5,
1.0 Hz, 1H, Ar−H), 7.41 (d, 8.0 Hz, 1H, Ar−H), 7.02 (ddd, 7.5, 5.0,
1.0 Hz 1H, Ar−H), 4.93 (d, 2.0 Hz, 1H, Cp-H), 4.66 (dd, 2.0, 2.0 Hz,
1H, Cp-H), 4.56 (d, 2.0 Hz, 1H, Cp-H), 4.07 (s, 5H). 13C NMR (176
MHz, CD2Cl2): δ (ppm) = 221.1, 213.2, 212.3, 211.7 (Mn−CO);
169.0, 154.4, 137.5, 120.2, 119.5 (Ar); 103.1, 90.5, 77.4, 72.4, 69.6,
65.2 (Cp). MS (LIFDI+): m/z = 426.9565 [M+] C19H12NO4MnFe
requires 426.9543. Elemental analysis (CHN): C 53.00%, H 2.91%, N
3.20% (C19H12NO4MnFe requires C 53.18%, H 2.82%, N 3.26%). IR
(CH2Cl2, cm−1): 2077 (s), 1988 (vs), 1976 (vs), 1932 (vs), 1607 (m),
1498 (s). UV−visible: λmax = 292 nm, ε(292 nm) = 18 300 dm3 mol−1
cm−1; 486 nm, ε(486 nm) = 1230 dm3 mol−1 cm−1. Rf: 0.28 (petrol/
Et2O 9:1 v/v).
coupling of aryl bromide 7 to afford ferrocenyl ligand 8 in an
acceptable yield of 55%.
The yield represents a slight improvement on the previously
reported Grignard-based synthesis of this molecule, where the
reported yield was 38%.41 Late-stage Suzuki coupling of the
cyclomanganated derivative of 7, using ferroceneboronic acid
with the conditions of Ward and co-workers,25 was unsuccessful
due to degradation of the starting complex at the high reaction
temperatures required. With the desired ligand in hand,
cyclomanganation with BnMn(CO)5 proceeded in good yield
to afford target 2.
Finally, compound 3, incorporating the redox-active moiety
in the first coordination sphere of the metal, was synthesized via
a Negishi coupling to afford ligand 9 in 74% yield before
cyclomanganation with BnMn(CO)5 to give 3.
Single crystals of 1, 2, and 8 suitable for X-ray diffraction
were obtained, either by layering pentane on a concentrated
dichloromethane solution of the product (1) or by slow
evaporation of a chloroform solution (2 and 8). Thermal
ellipsoid plots are shown for target complexes 1 and 2 in Figure
3; a thermal ellipsoid plot for 8 is provided in the Supporting
Information, along with summary data tables for all three
structures.
Comparison of 1 and 2 with other Mn(I) phenylpyridine
complexes shows the same slight distortion from the idealized
octahedral structure at manganese, due to the rigidity of the 2-
phenylpyridine system.38 The structures also suggest that the
cyclomanganation of 8 forces the pyridyl and phenyl rings to
become planar in complex 2, having been twisted slightly in 8,
the torsion angle increasing from −8.9(6)° in 8 to −20.3(2)° in
2.
RESULTS AND DISCUSSION
■
Compound 1, which accommodates the ferrocenyl group in the
most remote location relative to the Mn(I) center, was
synthesized by employing the versatile alkynyl building block
6 (Scheme 1).
Complex 6 could not be synthesized directly by cyclo-
manganation of the corresponding terminal alkyne. On the
basis of work by Nicholson and co-workers,40 we hypothesized
that addition of the alkyne into the Mn(I) center could
compete with coordination of the pyridyl nitrogen directing
group. The poor functional group tolerance of such a side
reaction to bulky silyl substituents on the alkyne was exploited
as a protecting group strategy, affording TIPS analogue 5 in
88% yield. Deprotection affords alkyne 6, a readily
functionalizable building block for the synthesis of remotely
conjugated modular CORMs complementary to the current
libraries. Alkyne 6 was shown to be a viable reagent in a copper-
catalyzed azide−alkyne cycloaddition (CuAAC) reaction.
Reaction with azidoferrocene afforded the triazole product 1
in 61% yield after flash column chromatography. An alternative
route may be envisaged whereby the click conjugation takes
place before the cyclomanganation, although we anticipate that
this would present a challenge for the inclusion of more-water-
soluble derivatives, due to the nonpolar solvents typically
employed in the cyclomanganation step. Compound 2
(Scheme 2), in which the ferrocenyl group is conjugated to
the 2-phenylpyridyl ligand, was accessed via a Suzuki−Miyaura
Complexation of the ligands to manganese was also
evidenced by NMR and infrared spectroscopies. The 1H
NMR spectra of 3 and 9 in CD2Cl2 (Figure 4) showed a
significant change in the region of the ferrocenyl protons on the
substituted Cp ring. The two triplets at δ = 4.92 and 4.40 ppm
were replaced by three resonances each corresponding to a
single proton, reflecting the deprotonation and desymmetriza-
tion of this ring upon cyclomanganation. Smaller changes in
chemical shifts were also observed for the protons on the
unsubstituted Cp ring and the pyridyl ring.
E
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Figure 5. Cyclic voltammogram of a 1 mM dichloromethane solution
of 1. The electrolyte was tetra-n-butylammonium hexafluorophos-
phate, present at a concentration of 1 M, and the scan rate was 100
mV s−1.
gram, the separation between the anodic and cathodic peaks
was comparable to that of the ferrocene/ferricenium calibration
run, although solution resistance led to these values being
higher than the ideal 59 mV, up to 170 mV.42
The midpoint potentials (E1/2) are compiled in Table 1.
Triazole 1 displays a relatively high redox potential of +220 mV
Table 1. Midpoint Potentials and Peak Current Ratios of
Ferrocenyl Mn Complexes 1−3 and Two Uncomplexed
a
Derivatives (8 and 9) in Dichloromethane
compd
E1/2 (mV)
ia/ic
Figure 3. X-ray crystal structures of compounds 1 (top) and 2
(bottom), with hydrogen atoms omitted. Atoms are displayed as
thermal ellipsoids at 50% probability.
1
2
3
8
9
+220
+31
1.05
0.94
1.04
1.03
0.97
−138
+48
The infrared spectra of the three complexes all show the
expected four carbonyl stretching bands for a CS or pseudo-C2v
symmetry (vide infra, Table 2). The carbonyl stretches for the
three complexes reflect the similarity of the first coordination
sphere of the manganese in each of the compounds.
+76
a
Peak currents were calculated by linearly extrapolating the baseline
current. The electrolyte was 1 M tetra-n-butylammonium hexafluor-
ophosphate. Potentials are referenced against the Fc/Fc+ redox couple.
Electrochemical characterization of the three Mn complexes,
along with starting materials 8 and 9, was carried out to
understand their redox properties. Cyclic voltammetry was
performed on solutions of each complex in dichloromethane.
An example voltammogram of 1 is shown in Figure 5.
For each compound, repeated scans showed a single
reversible one-electron redox reaction that was attributed to
the ferrocenyl portions of the molecules. In each voltammo-
vs Fc/Fc+, though this is consistent with other ferrocenyl
triazoles and is a result of the electron-withdrawing nature of
the triazole, which destabilizes the cation relative to the neutral
molecule.43 The midpoint potentials for 2 and 8 show a very
slight decrease in E1/2 of 17 mV upon cyclomanganation. This
suggests that the effect of cyclomanganation on the redox
properties of ferrocene in this position is small. A similar trend
1
Figure 4. A stack of 700 MHz H NMR spectra showing cyclomanganated complex 3 versus ligand 9. Spectra were recorded at 298 K in CD2Cl2
(the proton integrals are displayed as integers).
F
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Article
is seen upon the reaction of 9 to form 3, but the incorporation
of the ferrocenyl group into the first coordination sphere of the
Mn makes this effect much more pronounced with a lowering
of E1/2 from +76 to −138 mV, both vs Fc/Fc+. The change in
E1/2 implies that the effect of cyclomanganation is to stabilize
the cation more than the neutral molecule, so 2 and 3 are more
easily oxidized than their counterparts 8 and 9. It can therefore
be concluded that the electron density on the ferrocenyl moiety
increases as a result of cyclomanganation.
Repeated scans of each complex were performed, but no new
peaks were observed, and the peaks due to the complexes
remained, suggesting that 1−3 are all stable to repeated
oxidation and reduction.
This is consistent with a through-bond communication
between the two metal centers and suggests that redox-active
ligands should be incorporated into the first coordination
sphere of the manganese carbonyl. Consistent with the
reversibility of the single redox process in the voltammetric
results, the spectra show that the oxidized ferricenium cation of
each complex can be reduced back to the neutral form. There is
no electrochemically triggered CO release upon oxidation of
the iron center. Despite the lack of redox-triggered CO release,
these results demonstrate the communication between the iron
redox state and the bonding properties of the metal carbonyls.
The infrared stretches of the reduced and oxidized forms of the
three complexes are tabulated below (Table 2).
The response of the infrared stretches of the carbonyl
stretches to oxidation of the ferrocenyl moiety was assessed by
infrared spectroelectrochemistry. The results, shown in Figure
6, demonstrate the importance of the linker length in
a
Table 2. Infrared Stretching Frequencies for the Neutral
and Oxidized Forms of Complexes 1−3
compd
ν(CO) (cm−1
)
1
2076 (s), 1991 (vs), 1977 (vs), 1931 (s)
2076 (s), 1991 (vs), 1977 (vs), 1931 (s)
2074 (s), 1990 (vs), 1975 (vs), 1931 (s)
2078 (s), 1995 (vs), 1980 (vs), 1936 (s)
2077 (s), 1988 (vs), 1976 (vs), 1932 (s)
2089 (s), 2010 (vs), 2000 (vs), 1964 (s)
1+
2
2+
3
3+
a
Recorded in a dichloromethane solution.
As related Mn(I) tetracarbonyl complexes bearing 2-
phenylpyridine-derived ligands have previously been shown to
release CO photochemically,25 the light-triggered CO release
properties of ferrocenyl complexes 1−3 were assessed.
The results in Figure 7 show that 1 is stable in DMSO
solution in ambient light for >1 h, but degradation occurs with
a half-life of 21 min upon irradiation, as shown by the bleaching
of the peaks at 2076, 1990, and 1975 cm−1. The peak at 1931
cm−1 changes only slightly during the irradiation, suggesting
that another peak grows in near this wavenumber from the
photoproduct. New peaks rapidly grow in at 2012 and 1904
cm−1, indicating that a metal−carbonyl-containing photo-
product accumulates. The three bands are consistent with the
formation of a pseudo-C3v symmetric tricarbonyl species in
which a DMSO solvent molecule has substituted one of the
trans- carbonyl ligands. The sulfur−oxygen stretching mode for
a bound DMSO was not observed at the concentrations
studied. This intermediate then degrades over a longer time
scale, as another peak grows in at 1862 cm−1. A very similar
result was obtained for the degradation of complex 2,
suggesting that the triazole moiety of 1 does not coordinate
to the Mn as part of the degradation process.
Direct observation of CO release from 2 was carried out in
water using the well-established UV−visible myoglobin CO
release assay (Figure 8). Complex 2 is stable in water in the
absence of light, with CO release photochemically triggered by
400 nm LED irradiation. An assay using 40 μM 2 and ca. 45
μM deoxymyoglobin approached saturation of the myoglobin
after 240 min. The slow time scale of CO release may be due to
the poor water solubility of 2. This must be accounted for when
comparing the CO release kinetics of this complex with
analogous CORMs. The relatively poor water solubility of the
ferrocenyl group could be overcome by further functionaliza-
tion of the 2-phenylpyridine coligand or oxidation to the
ferricenium salt with a water-soluble anion. However, the
concentrations of CORM used in the myoglobin assay (tens of
micromolar) are still very high for practical therapeutic use and
Figure 6. Infrared spectroelectrochemistry of complexes 1−3 (panels
A−C, respectively). Experiments were performed in dichloromethane
at 298 K, at a concentration of 5.0 mM in the presence of 1.0 M tetra-
n-butylammonium hexafluorophosphate as the electrolyte. Spectra
were recorded 240 s after the potential was applied to allow complete
electrolysis of the solution to occur. All spectra are subject to a single-
point baseline correction at 2050 cm−1. (D) Selected spectra from the
oxidation step of panel C showing the isosbestic points.
determining the extent of communication between the iron
and manganese centers. The carbonyl bands in complex 1
(Figure 6A), showed no change upon oxidation, confirming
that the oxidation is that of the iron center. Complex 2, with
the less remote reporter group (Figure 6B) shows a small
increase of around 5 cm−1 in each carbonyl band when
oxidized. Complex 3 (Figure 6C) shows much larger shifts of
the bands, ranging from 12 to 32 cm−1. Overlaying a series of
spectra during the oxidation of 3 (Figure 6D) shows that the
oxidized and reduced species share isosbestic points at 2081,
1994, 1968, and 1949 cm−1, suggesting that no other metal
carbonyl-containing species are present during this conversion.
This remains the case for the reduction back to the neutral
species, the spectra for which have been omitted for clarity.
The observed increase in stretching frequency is consistent
with the removal of electron density from the manganese,
resulting in weaker π-back-bonding to the carbonyl groups.
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Figure 7. In situ infrared spectroscopic monitoring of compounds 1 and 2 in DMSO. The start of continuous irradiation with a 365 nm LED
drawing a power of 5.0 W is indicated on the graphs. (A) Selected spectra of a 12 mM solution of compound 2 after irradiation began. (B) Peak
height, fitted to a two-point baseline, of selected peaks over time of compound 2. (C) Selected spectra of a 20 mM solution of compound 1 after
irradiation began. (D) Peak height, fitted to a two-point baseline, of selected peaks over time of compound 1.
protonation, rather than oxidation, by H+ is responsible for the
decomposition observed. The results are consistent with NMR
spectroscopic studies that clearly show formation of protonated
ligand 9. This result demonstrates that 3 is sensitive to protons
and its CO release rate could therefore be modulated on the
basis of pH.
CONCLUSIONS
■
Redox-tagged ferrocenyl-CORMs have been synthesized and
fully characterized. The ferrocenyl moiety is a validated isostere
of the phenyl group in drug discovery and for the first time this
has been incorporated into the structure of a CORM class.
Compounds 1 and 2 display photochemical degradation at the
same wavelengths as analogous Mn(I) tetracarbonyl com-
plexes,26 while compound 3 additionally releases CO in water
in the dark, a process which appears to be triggered by
protonation.
The versatility of alkynyl building block 6 has been
showcased in a CuAAC functionalization reaction, enabling a
series of compounds to be made analogously to other modular
CORM classes.
Each redox-tagged CORM exhibited a single-electron
reversible redox couple due to oxidation of the ferrocenyl
moiety, while the Mn(I) tetracarbonyl moiety was redox silent
within the electrochemical window assessed (up to a potential
of +590 mV vs Fc/Fc+). However, previous studies on Mn(I)
tricarbonyl systems have shown that an irreversible oxidation of
the Mn(I) center does occur at very strongly oxidizing
potentials.44,45
Infrared spectroelectrochemistry revealed the effect of
ferrocene oxidation upon the Mn center as being dependent
on the linker length between the two metal centers.
Comparison of CORMs 1−3 showed that a substantial shift
in the metal carbonyl stretching frequencies took place only
when the ferrocenyl moiety was in the first coordination sphere
of the Mn(I) center. Although the perturbation to the structure
of the complexes on oxidation was not sufficient to promote
CO release, these observations provide motivation for further
incorporation of redox-active groups into the first coordination
sphere of CORMs with the ultimate goals of triggering and
monitoring CO release electrochemically in a tunable and
predictable manner.
Figure 8. Myoglobin CO release assays. Irradiation from a 400 nm
LED drawing 5.0 W power began where indicated. Irradiation was
performed in cycles of 2 min on, 3 min off. Left: A 40 μM assay of 2.
Right: A 10 μM assay of 3.
such a high concentration of CORM in solution is unlikely to
be required.
Complex 3, in which the ferrocenyl group is closest to the
manganese, was also assessed using the myoglobin assay
(Figure 8). In this case, slow conversion of myoglobin to
carboxymyoglobin was observed in the dark. Irradiation of a
solution of 3 with a 400 nm LED accelerated CO release, but
the complex also displays significant thermal release.
It was hypothesized that the thermal CO release behavior of
3 was due to the susceptibility of the Mn−Cp bond to
protonation in protic solvents. To test this, a solution of 1 was
prepared in dichloromethane, and aliquots of the non-
coordinating proton source [HNMe2Ph]BF4 were added via
syringe. The resulting decomposition of 3 was monitored using
in situ infrared spectroscopy (Figure 9). The electrochemical
and infrared spectroelectrochemical results have demonstrated
that 3 does not degrade upon oxidation on the same time scale
as it does during addition of [HNMe2Ph]BF4, suggesting that
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.7b00509.
■
Figure 9. Effect of successive additions of the proton source
[HNMe2Ph]BF4 to a 20 mM solution of 3 in dichloromethane
solution. Left: Changes in the infrared bands with the total
[HNMe2Ph]BF4 stoichiometry. Right: Evolution of selected bands
over time.
S
H
DOI: 10.1021/acs.inorgchem.7b00509
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Inorganic Chemistry
General synthetic procedures of known compounds,
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Davidge, K. S.; Cook, G. M.; Mann, B. E.; Poole, R. K.
Ru(CO)3Cl(Glycinate) (CORM-3): A Carbon Monoxide-releasing
Molecule with Broad-spectrum Antimicrobial and Photosensitive
Activities Against Respiration and Cation Transport in Escherichia
coli. Antioxid. Redox Signaling 2013, 19, 497−509.
representative NMR spectra, UV−visible spectra, electro-
chemical results, and a summary tables of X-ray data
(PDF)
Crystallography data for 1, 2, and 8 in CIF format (CIF)
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Monoxide-releasing Molecule, CORM-3 (Ru(CO)3 Cl(Glycinate)),
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AUTHOR INFORMATION
Corresponding Authors
*J.M.L. e-mail: jason.lynam@york.ac.uk.
*A.P. e-mail: alison.parkin@york.ac.uk.
*I.J.S.F. e-mail: ian.fairlamb@york.ac.uk.
■
(9) Pena, A. C.; Penacho, N.; Mancio-Silva, L.; Neres, R.; Seixas, J.
D.; Fernandes, A. C.; Romao, C. C.; Mota, M. M.; Bernardes, G. J. L.;
̃
Pamplona, A. A Novel Carbon Monoxide-releasing Molecule Fully
Protects Mice From Severe Malaria. Antimicrob. Agents Chemother.
2012, 56, 1281−1290.
ORCID
Benjamin J. Aucott: 0000-0002-1213-1839
Alison Parkin: 0000-0003-4715-7200
Ian J. S. Fairlamb: 0000-0002-7555-2761
Present Address
J.S.W.: Department of Chemistry, Durham University, Lower
Mountjoy, South Road, Durham, DH1 3LE, United Kingdom.
(10) Foresti, R.; Hammad, J.; Clark, J. E.; Johnson, T. R.; Mann, B.
E.; Friebe, A.; Green, C. J.; Motterlini, R. Vasoactive Properties of
CORM-3, a Novel Water-soluble Carbon Monoxide-releasing
Molecule. Br. J. Pharmacol. 2004, 142, 453−460.
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Releasing Molecules for the Delivery of Therapeutic CO in Vivo.
Angew. Chem., Int. Ed. 2014, 53, 9712−9721.
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Carbon MonoxidePhysiology, Detection and Controlled Release.
Chem. Commun. 2014, 50, 3644−3660.
(13) Motterlini, R.; Clark, J. E.; Foresti, R.; Sarathchndra, P.; Mann,
B. E.; Green, C. J. Carbon Monoxide-Releasing Molecules: Character-
ization of Biochemical and Vascular Activities. Circ. Res. 2002, 90,
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(14) Clark, J. E.; Naughton, P.; Shurey, S.; Green, C. J.; Johnson, T.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the BBSRC (BB/F017316/1) and EPSRC
(EP/M506680/1) for supporting Ph.D. studentship funding for
J.S.W and B.J.A. We thank the funding contribution from the
Wild fund to the Ph.D. studies of J.M. The project was
underpinned by investments made in equipment as part of the
EPSRC “ENERGY” grant (EP/K031589/1) and supported by
a TARGeTED Project (University of York Antimicrobials)
grant on CO-RMs. Christopher Morrell is thanked for initial
experiments toward the synthesis and characterization of
complex 3. Chemistry Department workshops (C. Mortimer,
Dr. C. Rhodes, and A. Storey) are acknowledged for the design
and manufacture of equipment for the photochemical and
electrochemical studies.
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and Design of Photochemical CO Releasing Molecules and the Efforts
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ABBREVIATIONS USED
■
CORM, carbon monoxide-releasing molecule; DSC, differential
scanning calorimetry; HO, heme oxygenase; Mb, myoglobin;
Mb-CO, carbonmonoxymyoglobin; OCP, open-circuit poten-
tial
(19) Ward, J. S.; Lynam, J. M.; Moir, J.; Fairlamb, I. J. S. Visible-
Light-Induced CO Release from a Therapeutically Viable Tryptophan-
Derived Manganese (I) Carbonyl (TryptoCORM) Exhibiting Potent
Inhibition Against E. coli. Chem. - Eur. J. 2014, 20, 15061−15068.
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