A comparative study of tricarbonylmanganese photoactivatable CO releasing molecules (PhotoCORMs) by using the myoglobin assay and time-resolved IR spectroscopy

Article abstract of DOI:10.1002/ejic.201200115

Tricarbonylmanganese(I) complexes of the ligands tris(imidazol-4-yl) phosphane (4-tip^H), tris(1,4-diisopropylimidazol-2-yl)phosphane (2-tip^iPr2), tris(pyridin-2-yl)phosphane (tpp) and tris(N-methylimidazol-2-yl)carbinol (2-tic^NMe) were prepared. These act as N,N,N tripodal chelators. The solid-state structure of [Mn(CO) ₃(tpp)]OTf was determined by X-ray diffraction. The potential of these complexes to act as photoactivatable CO-releasing molecules (PhotoCORMs) was studied with the UV/Vis spectroscopy-based myoglobin assay as well as by time-resolved IR spectroscopy. Within the series of compounds prepared, the steric bulk of the imidazolyl groups seems to significantly influence the CO-release kinetics and stoichiometry when using the myoglobin assay. In contrast, the time-resolved IR data suggest release of all carbonyl ligands upon irradiation. This effect points to a much closer association of myoglobin and PhotoCORMs than previously thought and will require further investigation.

Full text of DOI:10.1002/ejic.201200115

FULL PAPER
DOI: 10.1002/ejic.201200115
A Comparative Study of Tricarbonylmanganese Photoactivatable CO Releasing
Molecules (PhotoCORMs) by Using the Myoglobin Assay and Time-Resolved
IR Spectroscopy
Wilhelm Huber,[a] Rolf Linder,[b] Johanna Niesel,[c] Ulrich Schatzschneider,[c]
Bernhard Spingler,[d] and Peter C. Kunz*[a,e]
Keywords: Manganese / Carbonyl complexes / CO releasing molecules / IR spectroscopy / Phosphanes
Tricarbonylmanganese(I) complexes of the ligands tris(imid-
azol-4-yl)phosphane (4-tipH), tris(1,4-diisopropylimidazol-2-
yl)phosphane (2-tipiPr2), tris(pyridin-2-yl)phosphane (tpp)
and tris(N-methylimidazol-2-yl)carbinol (2-ticNMe) were pre-
pared. These act as N,N,N tripodal chelators. The solid-state
structure of [Mn(CO)3(tpp)]OTf was determined by X-ray dif-
fraction. The potential of these complexes to act as photoac-
tivatable CO-releasing molecules (PhotoCORMs) was
studied with the UV/Vis spectroscopy-based myoglobin as-
say as well as by time-resolved IR spectroscopy. Within the
series of compounds prepared, the steric bulk of the imid-
azolyl groups seems to significantly influence the CO-release
kinetics and stoichiometry when using the myoglobin assay.
In contrast, the time-resolved IR data suggest release of all
carbonyl ligands upon irradiation. This effect points to a
much closer association of myoglobin and PhotoCORMs than
previously thought and will require further investigation.
well as coagulation processes associated with transplan-
tations.[2]
Introduction
Until quite recently, carbon monoxide (CO) was mostly
seen as a dangerous air pollutant due to its properties as an
odourless and colourless gas with high toxicity to humans
caused by its interference with oxygen transport in the
blood. It has, however, since then become clear that carbon
monoxide is endogenously produced in the human body at
a rate of a few millilitres per day by tightly controlled enzy-
matic heme degradation and serves as an important small-
molecule messenger, much like nitric oxide and hydrogen
sulfide.[1] In addition, the deliberate application of CO to
biological systems was found to give rise to a number of
beneficial physiological effects due to its antiinflammatory,
antioxidative, and antiapoptotic activities. In animal experi-
ments, it was also shown to affect ocular hypertension as
Since CO itself is a difficult to dose and highly toxic gas,
there is currently significant interest in the application of
metal carbonyl complexes as a solid storage form for car-
bon monoxide. An increasing number of such CO releasing
molecules (CORMs) has been studied to optimise their CO
release characteristics and achieve sufficient water-solubility
for therapeutic applications.[3] While Motterlini et al. have
pioneered the use of carbonylruthenium complexes, with
tricarbonylchloro(glycinato)ruthenium(II) (CORM-3) as
the CO releasing molecule most commonly employed in
biological studies,[4] more recently iron and carbonyl(pyr-
one)molybdenum complexes (CORM-F7 and CORM-F10)
have also received considerable attention.[5] In these com-
pounds, CO release is usually triggered by ligand exchange
reactions in aqueous solution. As an alternative approach,
the light-induced liberation of carbon monoxide from dark-
stable carbonylmanganese complexes has been explored.
Initial studies used [Mn2(CO)10] (CORM-1) which, how-
ever, does not have good properties for biological applica-
tions.[6] In contrast, [Mn(CO)3(tpm)]PF6 [tpm = tris(pyraz-
ol-2-yl)methane] was shown to release CO upon UV exci-
tation and exhibit cytotoxic activity against cancer cells
while being inactive even after prolonged exposure in the
dark and it could also be conjugated to carrier peptides for
targeted delivery.[7] Very recently, iron carbonyl complexes
have also been reported which release CO upon irradiation
using visible light.[8] Although the number of studies on
metal carbonyl CORMs has significantly grown during the
[a] Institut für Anorganische Chemie und Strukturchemie I,
Heinrich-Heine-Universität Düsseldorf,
Universitätsstr. 1, 40225 Düsseldorf, Germany
Fax: +49-211-81-12287
E-mail: peter.kunz@uni-duesseldorf.de
[b] Institut für Physikalische Chemie I, Heinrich-Heine-Universität
Düsseldorf,
Universitätsstr. 1, 40225 Düsseldorf, Germany
[c] Institut für Anorganische Chemie, Julius-Maximilians-
Universität Würzburg,
Am Hubland, 97074 Würzburg, Germany
[d] Anorganisch-Chemisches Institut, Universität Zürich-Irchel,
Winterthurerstr. 190, 8057 Zürich, Switzerland
[e] Institut für Pharmazeutische und Medizinische Chemie,
Heinrich-Heine-Universität Düsseldorf,
Universitätsstr. 1, 40225 Düsseldorf, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejic.201200115.
3140
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Inorg. Chem. 2012, 3140–3146

Tricarbonylmanganese Photoactivatable CO Releasing Molecules
last few years, only very few systematic studies of the fac-
tors which determine the mechanism of CO release have
been carried out so far.[9]
In the present contribution, we report on the synthesis
and characterisation of a series of Mn(CO)3 complexes of
different imidazol-2-yl and imidazol-4(5)-yl phosphane li-
gands. Since the introduction of the tris(pyrazolyl)boranes
(tp) by Trofimenko, scorpionate ligands containing N donor
atoms have been intensively studied and are well known as
ligands for complexes used in biomedical applications.[10]
The tris(heteroaryl)phosphanes and carbinols used in this
study are neutral analogues of the tp ligand in which the
hydrolytically unstable B–N bonds have been replaced by
more stable P–C and C–C bonds, respectively.[11] To assess
the bioavailability of these new complexes, their distribution
coefficients in physiological media have been measured, fol-
lowed by an investigation of the light-induced CO release
from the Mn complexes.
Figure 1. Ligands used for the synthesis of the fac-Mn(CO)3 com-
plexes investigated in this study.
We recently reported on the light-induced CO release
from several tripodal tricarbonyl[tris(imidazolyl)phos-
phane]manganese(I) complexes. The substitution pattern of
the imidazolylphosphane ligand was found to determine the
number of CO molecules released. While the compounds
with the imidazol-2-ylphosphane liberate approximately
two equiv. of CO per mole of complex, those with the imid-
azol-4-ylphosphane release only one molecule of CO per
Mn(CO)3 unit.[12] Here, we report on a more detailed inves-
tigation of the CO release of fac-Mn(CO)3 complexes with
tripodal N,N,N ligands and the influence of the ligand sub-
stitution pattern on the number of CO molecules released.
Scheme 1. Synthesis of tris(imidazol-4(5)-yl)phosphane, 4-tipH (1):
(i) KI/I2, NaOH, H2O; (ii) MOMCl, KOtBu, THF; (iii) EtMgBr,
H2O, THF; (iv) EtMgBr, PCl3, HOAc(aq.)
.
the bromide ligand of pentacarbonylmanganese bromide in
acetone using silver triflate. After addition of the respective
ligand in acetone, the complexes [LMn(CO)3]OTf were ob-
Results and Discussion
Previously, we investigated the CO release characteristics tained in good yield (Scheme 2).
of different tris(imidazol-2-yl)- and tris[imidazol-4(5)-yl]-
phosphane ligands and observed that different amounts of
CO are released from the corresponding fac-MnI(CO)3
complexes. In order to elucidate the factors which deter-
mine the CO release, we have now expanded the series of
tripodal ligands and investigated the ligands tris(1,4-diiso-
propylimidazol-2-yl)phosphane (2-tipiPr,NiPr) and tris[imid-
azol-4(5)-yl]phosphane 4-tipH as well as tris(pyridin-2-yl)-
Scheme 2. Syntheses of Mn(CO)3 complexes.
phosphane (tpp) and tris(1-methylimidazol-2-yl)carbinole
(2-ticNMe) which are structurally similar to the previously
investigated ligands (Figure 1). The heteroaryl ligands
The IR stretching frequencies and, where applicable, the
2-tipiPr,NiPr, tpp and 2-ticNMe as well as complexes 1–3 and chemical shifts of the 31P NMR resonances of the new com-
8–12 were prepared according to published procedures.[12,13] pounds 4–7 are reported in Table 1. The IR spectra show
The synthesis of the new ligand 4-tipH, which is the par- two bands in the carbonyl region, typical for C3v-symmetri-
1
ent compound of the 4-tipR-class of ligands, was achieved cal M(CO)3 compounds. In addition, their H NMR spec-
by the reaction of 4-iodo-1-(methoxymethyl)imidazole, eth- tra show only one set of signals for the protons of the three
ylmagnesium bromide and phosphorus trichloride in equivalent imidazolyl rings. Although the phosphorus atom
dichloromethane. From the crude reaction mixture, colour- is not coordinated to the metal centre, upon coordination
less crystals of the magnesium complex [(4-tipNMOM)2Mg]- of the ligand to the M(CO)3 moiety, the 31P{1H} NMR
Br2 were obtained (see Supporting Information). The ligand signal of the P(III) atoms in 5 and 7 shifts to higher field
4-tipH was isolated as the acetic acid adduct after deprotec- by about 25 ppm. This shift is characteristic of complexes
tion in a mixture of ethanol and acetic acid (Scheme 1).
in which tip ligands are coordinated in an N,N,N
For the syntheses of the manganese complexes, fac- mode.[11,12,14] A similar shift was reported by Johnson for
[Mn(CO)3(solv)3]OTf was prepared in situ by abstraction of ligands of the type P(CH2NHR)3.[15]
Eur. J. Inorg. Chem. 2012, 3140–3146
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P. C. Kunz et al.
FULL PAPER
Table 1. IR and 31P{1H} NMR spectroscopic data and water/n- in the series according to 7 ϾϾ 4 ≈ 5 Ͼ 6. The lipophilicity
octanol distributioncoefficients(logD7.4)ofcomplexes [LMn(CO)3]-
of 4, 5 and 6 is within the range defined by the Lipinski
OTf (4–7).
“rule of five” for good drug candidates.[16]
Ligand
Compound δ(CO) / cm–1 δ(31P) / ppm
logD7.4
The structure of 6·0.5CH2Cl2 was determined by X-ray
diffraction analysis and is shown in Figure 2 with crystallo-
graphic data summarised in Table 2. The Mn atom is fa-
cially coordinated by the three carbonyl ligands and the tpp
ligand giving a slightly distorted octahedral coordination
environment. The metric parameters around the Mn atom
in 6·0.5CH2Cl2 are comparable with those of 1 and
9.[7a,12,17] The N–Mn–N angles in 6·0.5CH2Cl2 are slightly
larger than in complexes with ligands containing five-mem-
bered pyrazolyl or imidazolyl groups according to the
“bite” of the ligands.
2-ticNMe
4-tipH
tpp
4
5
6
7
2037, 1935
2033, 1911
2042, 1951
2029, 1923
–
0.87Ϯ0.02
0.83Ϯ0.05
–0.52Ϯ0.01
Ͼ5
–106.0
–9.5
–116.0
2-tipiPr2
The distribution coefficient logD was determined at pH
= 7.4 in order to assess the bioavailability of the new com-
plexes 4–7. As expected, 7, having six isopropyl groups, is
the most lipophilic compound. The lipophilicity decreases
CO Release Properties
In order to study the suitability of the compounds as new
photoactivatable CO releasing molecules (PhotoCORMs),
the manganese complexes 4–7 of the general formula
[LMn(CO)3]+ (L = 2-tipiPr2, 4-tipH, tpp and 2-ticNMe) were
investigated using the UV/Vis-based myoglobin assay.[6,18]
All compounds investigated do not release CO in the dark.
In Table 3, the number of CO equivalents released per mole
of complex nCO and the half-life t1/2 are summarised for
compounds 4–7 and compared with known Mn(CO)3 Photo-
CORMs incorporating N,N,N ligands. The steric bulk of
Figure 2. Solid-state structure of 6·0.5CH2Cl2. Cocrystallised sol-
vent molecules, the counter anion and hydrogen atoms are omitted
for clarity. Displacement ellipsoids are drawn at the 50% level. Se-
lected bond lengths [Å] and angles [°]: Mn1–C1 1.810(5), Mn1–C2
1.818(5), Mn1–C3 1.828(5), Mn1–N3 2.085(4), Mn1–N2 2.089(4),
Mn1–N1 2.090(4), C1–O1 1.149(5), C2–O2 1.142(5), C3–O3
1.138(5), N1–Mn1–C1 179.61(18), N2–Mn1–C2 179.5(2), N3– the N,N,N ligand seems to determine both nCO as well as
Mn1–C3 179.07(16), Mn1–C1–O1 177.3(4), Mn1– C2–O2 176.5(4),
Mn1–C3–O3 176.7(4).
t1/2. While complexes with sterically less demanding ligands
like 1–4, 6 and 10–12 liberate approximately two moles of
CO per mole of complex, complexes 7–9 with the bulkier
ligands release only one mole of CO per mole of Mn(CO)3
unit. Interestingly, in complex 5 with the small ligand 4-
Table 2. Crystallographic data for 6·0.5CH2Cl2.
tipH, an average of only 1.37 mole CO per mole of complex
is found. The release of different amounts of CO from the
complexes should result in at least transient occurrence of
CO-containing intermediates. We thus choose to investigate
the photoinduced CO release of selected complexes by time-
dependent IR spectroscopy.
Empirical formula
Formula weight
Crystal system
Space group
a [Å]
C19.5H13ClF3MnN3O6PS
595.75
orthorhombic
Pnn2
23.8743(9)
11.9146(3)
b [Å]
c [Å]
8.1976(3)
2331.84(14)
4
1.697
0.906
Volume [Å3]
Z
Density (calculated) [Mgm3]
Absorption coefficient [mm–1]
F(000)
Table 3. Photoinduced CO-release of complexes [LMn(CO)3]+ with
tripodal N,N,N ligands, half-life time (t1/2) and number of CO mo-
lecules released (nCO) as determined by myoglobin assay.
1196
Crystal size [mm]
Crystal description
Index ranges
0.23ϫ0.05ϫ0.02
colourless needle
–15 Յ h Յ 32
–13 Յ k Յ 16
–11 Յ l Յ 7
10408
Complex
L
t1/2 / min
nCO
Ref.
[7a]
[12]
[12]
1
tpm
20
25
21
19
32
17
13
30
27
20
20
20
1.96
1.82
1.83
1.61Ϯ0.29
1.37Ϯ0.08
2.28Ϯ0.01
1.04Ϯ0.28
0.83
0.96
1.59
Reflections collected
2
2-tipH
Independent reflections
Reflections observed
Completeness to theta
Max. and min. transmission
Data/restraints/parameters
Goodness-of-fit on F2
4597 [Rint = 0.0470]
2657
99.9% to 29.13°
0.9821 and 0.9308
4597/3/330
3
2-tipNMe
2-ticNMe
4-tipH
4
this work
this work
this work
5
6
2-tpp
7
2-tipiPr2
4-tipiPr
4-tipoiPr
bpma
this work
[12]
0.815
8
[12]
[19]
[19]
[19]
Final R indices [I Ͼ 2σ(I)]
R indices (all data)
R1 = 0.0443, wR2 = 0.0680
R1 = 0.0893, wR2 = 0.0748
–0.04(2)
9
10
11
12
Absolute structure parameter
bpmea
Bpmvba
2.65
1.65
Largest diff. peak / hole [eÅ–3]
0.807 / –0.367
3142
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Tricarbonylmanganese Photoactivatable CO Releasing Molecules
Time-Resolved Irradiation Experiments
tensity of the A1 and E bands was observed and after ex-
tended irradiation, they have completely disappeared for
complexes 7–9 having bulky ligands while no new bands
show up, whereas in complexes 3–6 and 10 as well as 11
with sterically less demanding ligands, a new band of very
low intensity at 1840–1860 cm–1 emerged. This can be ra-
tionalised if one assumes that one carbonyl ligand is ex-
changed by a solvent methanol. Substitution of the π ac-
ceptor ligand CO by the σ donor ligand CH3OH results in
a strengthening of the remaining Mn–CO bonds. In the re-
lated compound [CpMn(CO)2(thf)], the CO-stretching vi-
brations are found at 1930 and 1861 cm–1.[20] This might
explain why we just see one new band since the second one
should then be obscured by the E band of the tricarbonyl
complex. As such, dicarbonyl complexes are also photola-
bile, they are only transient species, which might explain the
low intensity of the band at 1840–1860 cm–1.[21] In the cases
of [Mn(CO)3(tpm)]OTf (1) and [Mn(CO)3(tpp)]OTf (5), the
highest intensities of the newly formed band can be ob-
served. Thus, we performed a band separation on the bands
at ca. 2050 cm–1 showing a shoulder. Indeed, the separated
bands showed an intensity ratio of about 2:1 (E and A1
band of the corresponding tricarbonyls) as well as two
bands of relative intensities of about 1:1 (see Supporting
Information). This clearly shows the intermediate forma-
tion of dicarbonyl complexes, at least under the conditions
of the IR measurements. These findings are in good agree-
ment with the IR experiments performed by the groups of
Kurz and Westerhausen on MnI and FeII carbonyls in
which, depending on the ligands used, transient decarb-
onylation species were observed.[8,9a] Interestingly, com-
pounds 5, 7 and 8 which should release only one equivalent
on CO per complex do not show the transient formation of
a dicarbonyl species.
Time-resolved IR spectroscopy was used to follow the
course of the CO release upon irradiation of compounds 1,
3, 5–8, 10 and 11 in methanol. Relevant sections of the IR
spectra taken after 0, 3 and 6 min of irradiation are shown
in Figure 3. The two bands of the fac-Mn(CO)3 moiety de-
crease in intensity and a new band appears in the region of
1840 to 1860 cm–1 for some of the compounds. In any case,
after prolonged irradiation (ca. 90 min) all bands in the
carbonyl region of the IR spectra completely disappeared.
For compounds [Mn(CO)3(2-tipNMe)]OTf (3) and
[Mn(CO)3(tpp)]OTf (6), we also followed the change of the
band intensities in the carbonyl region with variation of the
excitation wavelength. No CO release was observed above
a threshold of 400 nm, which corresponds to an irradiation
into the low intensity high wavelength tail of the UV/Vis
band of compounds 3 and 6. Additionally, we investigated
the influence of the intensity of the light which was mea-
sured at the site of the cuvette using a calibrated optical
powermeter. Freshly prepared methanolic solutions of com-
pounds 3 and 6 (1 wt.-%) were irradiated at 360 nm for
3 min. As expected, higher intensities lead to a more pro-
nounced decrease in band intensity of the carbonyl bands
(Figure 4). Thus, extreme caution has to be taken when
comparing release rates and half-lives reported for Photo-
CORMs if experimental details of the irradiation setup have
not been reported in sufficient detail. In particular, the ab-
solute intensity of the light source in Einstein/s has to be
Figure 3. Time-dependent changes in the IR spectra of methanolic
solutions of a: [Mn(CO)3(tpm)]OTf (1), b: [Mn(CO)3(tpp)]OTf (6),
c: [Mn(CO)3(2-tipNMe)]OTf (3), d: [Mn(CO)3(4-tipH)]OTf (5), e:
[Mn(CO)3(2-tipiPr2)]OTf (7), f: [Mn(CO)3(4-tipiPr)]OTf (8), g:
[Mn(CO)3(bpma)]OTf (10) and h: [Mn(CO)3(bpmea)]OTf (11); ir-
radiation at 360 nm (150 μW).
If one assumes a step-wise CO release of one or two quoted to facilitate comparison, as can be determined, for
equiv. of carbon monoxide, as observed in the myoglobin example, by actinometry.
assay, the appearance of one (monocarbonyl complex) or
We did not detect free CO in any experiment. The signal
two (dicarbonyl complex) new bands in the carbonyl region is expected to appear at 2140 cm–1 but usually is very weak
of the IR spectra would be expected. However, in the time- in the IR and therefore could not be observed in our mea-
resolved IR spectra of all compounds, a decrease in the in- surements.[22]
Eur. J. Inorg. Chem. 2012, 3140–3146
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P. C. Kunz et al.
FULL PAPER
the myoglobin as has also been recently observed for
[Mn(CO)4{S2CNMe(CH2CO2H)}].[9b] This discrepancy be-
tween the results of the myoglobin assay and the IR investi-
gations has recently been studied in detail by Kurz and Be-
rends on closely related Mn(CO)3 complexes.[9a] Although,
for a detailed understanding of the CO release mechanism
in complex biological medium, a combination of different
spectroscopic techniques like UV/Vis, IR and Raman spec-
troscopy as well as mass spectrometry and EPR will be re-
quired, since they can easily and quickly be carried out,
the myoglobin assay will remain indispensable for an initial
screening of CO activity to selected compounds worth a
more detailed investigation as outlined above.
Experimental Section
General: All reactions were carried out in Schlenk tubes under an
atmosphere of dry nitrogen using anhydrous solvents purified ac-
cording to standard procedures. The ligands 2-tip ,
iPr,NiPr [13b] tpp[13a]
and 2-ticNMe[13c] as well as 4-iodo-1-methoxymethylimidazole[23]
were prepared according published procedures. The metal com-
plexes were prepared using N2-flushed solvents. All chemicals were
1
purchased from commercial sources and used as received. H, 13C
and 31P NMR spectra were recorded on Bruker DRX 200 and 500
1
spectrometers. The H and 13C spectra were calibrated against the
residual proton signal of the solvent serving as an internal reference
Figure 4. Carbonyl region of solutions of a) [Mn(CO)3(2-tipNMe)]-
OTf (3) and b) [Mn(CO)3(tpp)]OTf (6) in methanol (1 wt.-%) after
irradiation for 3 min at 360 nm using intensities of 50, 100, 150 and
200 μW.
([D4]methanol): δH = 3.31 ppm, δC = 49.2 ppm; [D6]acetone: δH
2.05 ppm, δC = 29.9 ppm; [D6]DMSO: δH = 2.50 ppm, δC
=
=
39.5 ppm; D2O: δH = 4.80 ppm while the 31P{1H} NMR spectra
were referenced to external 85% H3PO4. The 13C resonances of
carbonyl carbon atoms are in general very hard to detect in this
class of compound and could not be identified in 4–7. The ESI
mass spectra were recorded on a Finnigan LCQ Deca ion trap API
mass spectrometer. Infrared spectra were recorded with a Bruker
IFS 66 FTIR spectrometer. The elemental compositions of the
compounds were determined with a Perkin–Elmer Analysator 2400
at the Institut für Pharmazeutische und Medizinische Chemie,
Heinrich-Heine Universität Düsseldorf.
Conclusions
Four new Mn(CO)3 complexes with tripodal N,N,N li-
gands bearing imidazolyl and pyridinyl substituents have
been prepared and characterised. CO-release investigations
using the myoglobin assay show that these compounds act
as photoinducible CO-releasing molecules (PhotoCORMs)
upon UV irradiation at 365 nm while they are stable
towards decomposition and do not liberate CO spontane-
ously in the absence of light. We have shown that even when
irradiated in the low intensity long wavelength tail at
400 nm of the absorption band of Mn(CO)3 complexes,
they do release CO. The CO release characteristics in terms
of half-lives and number of CO equiv. released per mole
of complex have been compared with related CORMs. The
results of the myoglobin assay show that Mn(CO)3 com-
plexes with sterically demanding ligands release approxi-
mately one equiv. of CO per complex while complexes hav-
ing sterically less demanding ligands release 2 equiv. of CO
per complex. This might also be relevant when such carb-
onyl compounds are employed as precursors for oxo-
bridged Mn-cluster compounds as the steric hindrance
might prevent close association.[9a] In contrast to the results
of the myoglobin assay, IR investigations in solution did
not provide any evidence of intermediate decarbonylation
products. Instead, they clearly support loss of all three CO
ligands upon irradiation. This indicates that there is proba-
Tris[imidazol-4(5)-yl]phosphane, 4-tipH: To a solution of 4-iodo-1-
(methoxymethyl)imidazole (6.66 g, 28 mmol) in tetrahydrofuran
(100 mL), was added ethylmagnesium bromide (3.0 m in ethyl ether,
9.3 mL, 28 mmol) dropwise at 0 °C. The reaction mixture was
stirred for 1 h at 0 °C and then phosphorus trichloride (1.23 g,
9 mmol) in tetrahydrofuran (5 mL) was added dropwise. The sus-
pension was stirred at ambient temperature for 16 h. All volatiles
were removed in vacuo and the residue was treated with dichloro-
methane and extracted with aqueous ammonium chloride solution.
The organic phase was collected and all volatiles were removed in
vacuo. The residue was dissolved in a mixture of ethanol (50 mL)
and acetic acid (10 mL) and stirred at 60 °C for 16 h. The volume
was reduced to 10 mL and the colourless precipitate collected by
filtration, washed with diethyl ether and dried in vacuo. The prod-
uct thus obtained was pure enough to be used for further reactions
1
without additional work-up; yield 1.28 g (33%). H NMR (D2O):
δ = 7.63 (d, J = 1.3 Hz, 3 H, Him), 8.85 (m, 3 H, Him) ppm.
31P{1H}NMR (D2O): δ = –81 ppm.
[Mn(CO)3(2-ticNMe)]OTf (4): Pentacarbonylanganese bromide
(101 mg, 0.37 mmol) and silver triflate (95 mg, 0.37 mmol) were
heated at reflux for 1 h in acetone (20 mL). The precipitate thus
formed was filtered off and the yellow solution added to a solution
bly a much more intimate interaction of the CORM with of 2-ticNMe (100 mg, 0.37 mmol) in acetone (10 mL). The reaction
3144 Eur. J. Inorg. Chem. 2012, 3140–3146
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Tricarbonylmanganese Photoactivatable CO Releasing Molecules
mixture was stirred for 4 h at ambient temperature and filtered.
The filtrate was then treated with n-pentane, the yellow precipitate
collected by filtration, washed with n-pentane and dried in vacuo;
Partition Coefficients (logD): The n-octanol/water partition coeffi-
cient of compounds 4–7 was determined using the shake-flask
method. PBS-buffered doubly distilled water [100 mL, phosphate
buffer, [PO43–] = 10 mm, [NaCl] = 15 m, pH adjusted to 7.4 with
hydrochloric acid] and n-octanol (100 mL) were shaken together
using a laboratory shaker (Perkin–Elmer) for 72 h to allow satura-
tion of both phases. Then, 1 mg of each compound was mixed in
1 mL of aqueous and organic phase, for 10 min using a laboratory
1
yield 176 mg (81%). H NMR (200 MHz, [D4]methanol): δ = 4.12
3
3
(s, 9 H, NCH3), 7.17 (d, JH,H = 1.4 Hz, 3 H, Him), 7.42 (d, JH,H
= 1.4 Hz, 3 H, Him) ppm. 13C{1H} NMR (125 MHz, [D4]meth-
anol): δ = 37.0, 78.4, 126.1, 132.0, 145.1 ppm. ESI-MS (MeOH):
m/z (%) = 411.1 (36) [M]+, 354.9 (12) [M – 2CO]+, 327.3 (100) [M –
3CO]+. C17H16F3MnN6O7S (560.3): calcd. C 36.44, H 2.88, N vortexer. The resultant emulsion was centrifuged (3000 g, 5 min) to
15.00; found C 36.75, H 2.55, N 14.86. IR (KBr): ν = 2044, 1936,
separate the phases. The concentrations of each complex in the
aqueous and organic phases was determined using UV/Vis spec-
troscopy at 260 nm. LogDpH was defined as the logarithm of the
ratio of the concentrations of the complex in the organic and aque-
ous phase (logD = log {[complex(org)]/[complex](aq.)}). The value
reported is the mean of three separate determinations.
˜
1907 cm–1. IR (CH Cl ): ν = 2037, 1935 cm–1.
˜
2
2
[Mn(CO)3(4-tipH)]OTf (5): Pentacarbonylanganese bromide
(66.7 mg, 0.12 mmol) and silver triflate (62 mg, 0.12 mmol) were
heated at reflux for 1 h in acetone (20 mL). The precipitate was
filtered off and the yellow solution added to a solution of 4-
tipNH·3AcOH (100 mg, 0.12 mmol) in acetone (10 mL). The reac-
tion mixture was stirred for 16 h at ambient temperature and then
filtered. The filtrate was concentrated to 5 mL and treated with
diethyl ether, the yellow precipitate collected by filtration, washed
with diethyl ether and dried in vacuo; yield 46 mg (42%). 1H NMR
(200 MHz, [D4]methanol): δ = 7.63 (s, 3 H, Him), 8.53 (s, 3 H,
CO Release Studies: All UV/Vis measurements were performed
with a Jasco V-670 spectrophotometer at room temperature in a
quartz cuvette (d = 1 cm). Horse skeletal muscle myoglobin (Fluka)
was dissolved in 0.1 m phosphate buffer pH = 7.3 and degassed by
bubbling with nitrogen. It was then reduced by the addition of an
excess of sodium dithionite in the same solvent and finally buffer
added to the cuvette to a total volume of 749 μL. To this solution,
1 μL of complex dissolved in dimethylsulfoxide was added to give
a final concentration of 20 μmolL–1 of metal complex and
75 μmolL–1 of myoglobin with A(557 nm) Ͻ 1. Solutions were then
either kept in the dark or irradiated for given time intervals under
nitrogen at 365 nm with a UV hand lamp positioned perpendicular
to the cuvette at a distance of 6 cm. Irradiations were interrupted
at regular intervals so that UV/Vis spectra could be recorded. All
the measurements were carried out in triplicate to assess the repro-
ducibility of the CO release.
H
im) ppm. 13C{1H} NMR (125 MHz, [D4]methanol): δ = 125.4 (d,
JP,C = 53 Hz), 133.2, 142.9 ppm. 31P{1H} NMR (81 MHz, [D4]-
methanol): δ = –106.0 (s) ppm. ESI-MS (MeOH): m/z (%) = 371.2
(24) [M]+, 287.3 (100) [M – 3CO]+. C13H9F3MnN6O6PS (520.2):
calcd. C 30.01, H 1.74, N 16.15; found C 29.66, H 1.89, N 16.70.
IR (KBr): ν = 2033, 1911 cm–1.
˜
[Mn(CO)3(tpp)]OTf (6): Pentacarbonylanganese bromide (103 mg,
0.38 mmol) and silver triflate (97 mg, 0.38 mmol) were heated at
reflux for 1 h in acetone (20 mL). The precipitate was filtered off
and the yellow solution added to a solution of TPP (100 mg,
0.38 mmol) in acetone (10 mL). The reaction mixture was stirred
for 4 h at ambient temperature and filtered. The filtrate was treated
with n-pentane, the yellow precipitate collected by filtration,
washed with n-pentane and dried in vacuo; yield 141 mg (67%). 1H
NMR (200 MHz, [D4]methanol): δ = 7.70 (m, 3 H), 8.19 (m, 3 H),
8.47 (m, 3 H), 9.59 (m, 3 H) ppm. 13C{1H} NMR (125 MHz, [D4]-
IR Spectroscopy: For the IR experiments, the samples were irradi-
ated using a xenon arc-lamp (75 W) as the light source. The mono-
chromated light (resolution 1 nm) was directed to an optical bench
by means of an optical wave guide (quartz). The position of the
liquid measurement cell (CaF2 windows, 0.1 mm Teflon™ spacer)
or the powermeter head (wavelength calibrated) was fixed on the
optical bench. A greywedge (quartz) was used to adjust the inten-
sity. The intensity at the cell position was measured using a New-
port corp. 835 optical powermeter. IR spectra were recorded on a
Bruker IFS 113 v IR spectrometer.
methanol): δ = 127.9, 137.8 (d, JP,C = 54 Hz), 141.4 (d, JP,C
=
16 Hz), 155.9 (d, JP,C = 15 Hz), 159.1 ppm. 31P{1H} NMR
(81 MHz, [D4]methanol): δ = –9.5 (s) ppm. ESI-MS (MeOH): m/z
(%)
= 419.4 (6) [M + –
O]+, 320.3 (100) [M 3CO]+.
Crystallography: Crystallographic data were collected at 183(2) K
on an Oxford Diffraction Xcalibur system with a ruby detector
using graphite-monochromated Mo-Kα radiation (λ = 0.7107 Å).
Suitable crystals were covered with oil (Infineum V8512, formerly
known as Paratone N), mounted on top of a glass fibre and imme-
diately transferred to the diffractometer. The program suite
CrysAlisPro was used for data collection, multi-scan absorption cor-
rection and data reduction.[24] Structures were solved with direct
methods using SIR97[25] and were refined by full-matrix least-
squares methods on F2 with SHELXL-97.[26] In the structure of
6·0.5CH2Cl2, bond lengths of a disordered dichloromethane mole-
cule had to be restrained. The structures were checked for higher
symmetry with help of the Platon program.[27]
CCDC-865300 (for 6·0.5CH2Cl2) and -865301 {for [(4-tipNMOM)2-
Mg]Br2} contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
C19H12F3MnN3O6PS (553.3): calcd. C 41.25, H 2.19, N 7.59; found
C 41.55, H 2.50, N 7.12. IR (KBr): ν = 2033, 1944, 1928 cm–1. IR
˜
(CH Cl ): ν = 2042, 1951 cm–1.
˜
2
2
[Mn(CO)3(2-tipiPr2)]OTf (7): Pentacarbonylanganese bromide
(56.8 mg, 0.21 mmol) and silver triflate (53 mg, 0.21 mmol) were
heated at reflux for 1 h in acetone (20 mL). The precipitate was
filtered off and the yellow solution added to a solution of 2-tipiPr2
(100 mg, 0.21 mmol) in acetone (10 mL). The reaction mixture was
stirred for 16 h at ambient temperature and filtered. The filtrate
was treated with n-hexane, the yellow precipitate collected by fil-
tration, washed with n-hexane and dried in vacuo; yield 98 mg
3
(60%). 1H NMR (200 MHz, [D6]acetone): δ = 1.38 (d, JH,H
=
=
=
3
3
6.9 Hz, 6 H), 1.58 (d, JH,H = 6.3 Hz, 6 H), 3.65 (sept, JH,H
3
1
6.9 Hz, 3 H), 5.36 (sept, JH,H = 6.3 Hz, 3 H), 7.74 (d, JP,H
4.1 Hz, 3 H) ppm. 13C{1H} NMR (125 MHz, [D4]methanol): δ =
23.7, 25.0, 52.6, 52.7, 117.8, 137.5 (d, JP,C = 15 Hz), 157.0 ppm.
31P{1H} NMR (81 MHz, [D6]acetone): δ = –116.0 (s) ppm. ESI-
MS (MeOH): m/z (%) = 539.5 (100) [M – 3CO]+, 387.5 (29) [M –
3CO – Im]+. C31H45F3MnN6O6PS·2(CH3)2CO (888.87): calcd. C Supporting Information (see footnote on the first page of this arti-
48.61, H 6.64, N 9.72; found C 49.02, H 6.58, N 9.69. IR (KBr): ν
cle): Preparation of 4,5-diiodoimidazole, 1-methoxymethyl-4,5-di-
iodoimidazole and 1-methoxymethyl-4-iodoimidazole, band sepa-
˜
= 2029, 1923 cm–1.
Eur. J. Inorg. Chem. 2012, 3140–3146
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
3145

P. C. Kunz et al.
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Acknowledgments
Part of this work was supported by the Deutsche Forschungsge-
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Published Online: May 23, 2012
3146
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Eur. J. Inorg. Chem. 2012, 3140–3146