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HemoglobinЧAn Inspiration for Research In Coordination Chemistry.

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[36] P. Finn, W L. Jolly, Inotg. Chem. 11, 893 (2972).
[37] F. Halsboer, W Beck, H . D. Bartunik, J. Chem. S o c . Dalton Trans.
1973, 1828.
[38] C.-C. Su, J. W Faller, J. Organomet. Chem. 84, 53 (1975).
[39] C.-C. Su, J. W Faller, Inorg. Chem. 13, 1734 (1974).
[40] J . Chatt, B. L. Shaw, J. Chem. SOC.1959,705.
[4l] J . Chatt, R . G . Wilkins, J. Chem. SOC. 1952, 273; K. Jensen, Z. Anorg.
Allg. Chem. 229, 225, 250 (1936).
[42] J. Chatt, B. L. Shaw, A. E. Field, J. Chem. SOC. 1964, 3466.
[43] J . Chatt, N. P . Johnson, B. L. Shaw, J. Chem. SOC.1964, 2508.
[44] J . Chatt, A. E. Field, 8. L. Shaw, J. Chem. SOC.1963, 3371.
[45] J . Chatt, R. G . Hayter, J. Chem. SOC. 1961, 896.
[46] J . Chatt, B. L. Shaw, 1. Chem. SOC. A 1966, 1437.
[47] J. Chatt, N. P . Johnson, B. L. Shaw, J. Chem. SOC. A1967,604.
[48] J. Chatt, R . H. Crabtree, E. A. Jeffery, R. L. Richards, J. Chem. SOC.
Dalton Trans. 1973, 1167.
[49] W Hieber, V Frey, P. John, Chem. Ber. 100, 1961 (1967).
[SO] J . Chatt, N. P . Johnson, B. L. Shaw, J. Chem. SOC.1964, 1662.
[51] J . Chatt, A. A. Williams, J. Chem. SOC.1951, 3061.
[ 5 2 ] J . Chatt, B. L. Shaw, J. Chem. SOC.1962, 5075.
[53] J . Chatt, R. G . Hayter, J. Chem. SOC.1961, 2605.
[54] J. Chatt, R. G. Hayter, J. Chem. SOC. 1961, 5507.
[55] W Bathelt, quoted by P. John, Chem. Ber. 203, 2178 (1970).
[56] H. Tengler, quoted by P. John in [55].
[57) W Hieher, H. Tengler, Z. Anorg. Allg. Chem. 318, 136 (1962).
[58] J. Chatt. B. L. Shaw, J. Chem. SOC. A 1966, 1811.
[59] R . K Adams, J . Chatt, N . E. Hooper, G . J . Leigh, J. Chem. SOC.
Dalton Trans. 1974, 1075.
Hemoglobin- An Inspiration for Research In Coordination Chemistry
By Johann Walter Buchler [‘I
Dedicated to Professor Heinrich Noth on the occasion of his 50th birthday
Hemoglobin transports oxygen in the blood and is responsible for its red color. Being
one of the most closely studied proteins, it is entitled an “honorary enzyme”. This admirable
natural substance invites chemists to copy it, imitate it, and vary or modify it. The first
means a total synthesis of the original molecule, but such reproduction does not increase
our knowledge of its function. In the case of imitation, the biochemical effect of the “original”
(i.e. hemoglobin) is achieved in full or in part with simpler molecules of similar structure,
i.e. with models. Research is here directed at the function of hemoglobin. In the case of
variation or modification the original molecule is changed to various extents, which reveals
the factors underlying its action. In all three cases-reproduction, imitation, and modificationhemoglobin serves as an inspiration for research. The aim of the present review is to summarize
recent investigations inspired by hemoglobin in the field of coordination chemistry. A brief
outline of the coordination chemistry of the porphin system serves as an introduction.
1. Introduction: The Coordination Chemistry of the
Porphin Ligand
Porphin [H,(P); (I)], which forms the parent substance
of all porphyrinsI’], contains four pyrrole rings linked into
a macrocycle by methine bridges (see Fig. 1 and Table 1).
Of the four inner nitrogens, two that are diagonally opposite
each other carry labile protons that can be split off with
bases. The resulting porphin dianion (P)’- has four pairs
of free electrons pointing inward. Owing to its aromatic character, this ion forms a rigid, planar, closed, quadridentate
chelate ligand system whose center can be occupied by metal
ions of suitable
This process, called metalation, is
shown in reaction (a) for the important Fernion. This reaction,
which is generally slow because of the rigidity of the porphin
system, follows a complicated mechanism, since many bonds
have to be broken and formed in its course[5,61.
H,(P) + Fe(OAc)*
HOAc, 110°C
(1)
+
HCI
Fe(P) + 2HOAc
(2)
[*] Prof. Dr. J. W. Buchler
lnstitut fur Anorganische Chemie der Technischen Hochschule
Templergraben 55, D-5100Aachen (Germany)
Angew. Chem. I n t . Ed. Engl. 17, 407423 (1978)
The character of a rigid, closed chelate also explains the
remarkable stability of porphyrin complexes. Thus, a formation constant of at least 10l6 has been reported for a Zn”
porphin, related to the Fe” p~rphin[~‘l.
Nevertheless, many
metal ions can be abstracted from porphyrin complexes with
the aid of strong acids. Thus, dilute hydrochloric acid is sufficient for such demetalation in the case of the Fe“ ion in
the reverse of reaction (a).
The formation of the planar chelate Fe(P) ( 2 ) , an “inner
complex salt” in the classical sense, by no means exhausts
the possibilities offered by this system in coordination chemistry. In compound ( 2 ) the four nitrogens of the porphin ligand
occupy the corners of a square, seen from the side in A
(Figs. 1 and 2). This square in ( 2 ) can form the base of
a pyramid B after the addition of a neutral donor ligand
L, while after the addition of two donor molecules it can
form the equatorial plane of a more or less tetragonally distorted octahedron C (Fig. 2). In the complexes B and c,
formed in reaction (b), the donor molecules L act as “axial”
ligands.
Fe(P)
A
-1-t
Fe(P)L
B
Fe(P)LZ
C
(b)
407
Fig. I . Formulas of porphin ( I ) , the unsubstituted parent substance of
all porphyrins, and of porphinatoiron (iron porphyrin) ( 2 ) , the parent substance of all hemes.
Table 1. Abbreviations.
tionchemistry. This field is treated systematicallyin the appropriate sections of recent monographs and reviewsf3- 71.
The intensivework on porphyrins, illustrated by the publication of 44 articles in the Journal of the American Chemical
Society in 1975 alone, stems from the great interest of chemists
in heme proteins responsible for the transport of molecular
oxygen in the body and for a wide variety of oxidation processes[14J.Yet this area itself is not so popular among chemists
at present. The present review will treat hemoglobin as an
inspiration for the chemistry of metal porphyrin complexes,
without discussing the other heme proteins.
General symbols
M : central metal ion, L: axial donor ligand (neutral or anionoid), X: monovalent anion, H,(P): unsubstituted porphin ( 1 )
2. The Main Characteristics of Hemoglobin and Myoglobin
Special symbols
a) Hemoglobins
[Hb]: monomeric hemoglobin, [Mb]: myoglobin
b) Metal-free porphyrins (examples)
H2(proto): protoporphyrin-IX [cf. (3a)],
Hl(meso-DME): mesoporphyrin-IX dimethyl ester [cf. ( 3 d ) I .
H ,(TTP): iiirso-tetra(p-tolyl)porphyrin[cf. f6,i)I.
Hl(OEP): octaethylporphyrin [ct (7a/];
H,(Pc): phthalocyanine
c)
Organic solvents or axial ligands or their corresponding acids
Py: pyridine, Hlm: imidazole, I-MeIm: 1-methylimidazole, 2-MeIm: 2methylimidazole, THF: tetrahydrofuran, DMF: dimethylformamide,
MeCN: acetonitrile, PR3: triorganylphosphane, HOAc: acetic acid,
H(acac): 2,4-pentanedione (acetylacetone)
While the d6 electron configuration of the Fe" ion favors
the formation of coordination type C, which is very common
also with other central metal ions, the dzz orbital of metal
ions with configurations d7, d', and d9, which is partly or
fully occupied and lies in the axial direction, repels axial
donor ligands, so that coordination type A predominates in
the case of Co", Ni", Cu", and ions that are isoelectronic
with these and are in the same groups of the periodic table[3-91.
1
\,:
/
M-L
I
I
I
I'
A
B
C
D
:
t i t
3.
M
L-M-L
Human hemoglobin is a globular protein with a molecular
weight of 64500, which gives the erythrocytes their red color
(see Fig. 3) and enables them to transport ~ x y g e n [ l ~ - ' ~ ~ .
The structure of hemoglobin with various axial ligands has
been determined on single crystals by X-ray crystallography
at a resolution of 2A[18].Hemoglobin consists of four associated peptide chains (two u- and two 0-chains), and its composition in the ligand-free state can be written as [Fe(proto)GI4, where G is the apoenzyme globin and Fe(proto) is
the coenzyme heme ( 3 a ) , the latter being the iron@) chelate
of protoporphyrin IX (see Table 2).
Myoglobin has a molecular weight of 17000 and takes
up oxygen in the muscle cells on its way to the mitochondria,
thus accelerating its diffusion. In composition and structure
it differs only slightly from one of the subunits of hemoglobin,
specifically in the globin component, and can therefore be
represented as [Fe(proto)G] (see above).
L
''
Fig. 2. The most important coordination types of metal porphyrins A: square
[see ( 2 ) ] ; B: square pyramid; C: distorted octahedron (trans configuration);
D: cis configuration in the addition of bidentate chelate ligands L-L (See
Section 7.1 ).
As will be seen later, the possibility of adding on axial
ligands is in fact essential for the biological function of iron
porphyrins.
sigAfter Richard Willstiitter's"'] and Hans Fischer's",
nificant contributions and the blossoming of organometallic
chemistry after 1950, all metals and boron, silicon, germanium,
and phosphorus have now been inserted into the porphyrin
s y ~ t e m [ ~ -Research
~].
in this field makes extensive use of
physical and instrumental techniques[3,41, particularly X-ray
structure analysis['*] and electron spin resonance spectroscopyr''I. As a result of this work, the coordination chemistry
of metal porphyrins has grown into a separate field of coordina408
I
400
k50
500
A [nml
I
---550
600
650
Fig. 3. Electronic absorption spectrum of oxyhemoglobin [Hb.0z]4 (-1,
deoxyhemoglobin [Hb]., (--), and carbonylbemoglobin [Hb.C0I4
at pH 7 and 20°C (see Fig. 4). The longest-wavelength absorption maximum
is called the ''a band" (after [IS]).
(F-)
Angew. Chem. Int. Ed. Engl. 1 7 , 4 0 7 4 2 3 (1978)
The characteristics of hemoglobin that are considered essential
by inorganic chemists will merely be outlined here, with what
might seem ludicrous brevity, by representing the fundamental
chemistry of a monomeric hemoglobin [Hb] in Fig. 4, this
scheme referring both to a single subunit of human hemoglobin
and to myoglobin [Mb].
Table 2. Composition ofmetal porphyrins (3) of natural origin. (For abbreviations see Table 1.)
M
L
Fe
Fe
Fe
Fe
Fe
Fe
Fe
co
co
Yb
L‘
R
R
Abbreviation
CH=CHz
CH=CH2
CH=CH2
CZHS
H
CZH5
CH=CH2
CH=CHZ
CH=CHz
CZH5
H
H
CH3
CH3
CH3
H
C2H5
CHj
H
CHa
Fe(proto)
Fe(proto-DME)
Fe(meso-DME)
Co(proto)
The term hemoglobin is also used nowadays in the broad
sense as a generic name for all heme proteins that add on
oxygen reversibly and transport it[’6]. It is very confusing
for outsiders that in physiological chemistry the abbreviations
Hb and Mb are used for ligand-free hemoglobin and myoglobin, irrespective of their state of association, while there are
also some hemoglobins that consist of a single peptide
In contrast, the state of association will always
be specified here, with the aid of the following abbreviations
in square brackets:
human hemoglobin
hemoglobin subunit
myoglobin
[Hb]4 = [Fe(proto)GJ,
[Hb] = [Fe(proto)G]
[Mb] = [Fe(proto)G]
Buse has given a protein chemist’s account of the structure
and function of hemoglobin, with special reference to the
globin component“ ‘I. Changes in the quaternary and tertiary
structure (allosterism) are brought about by “allosteric effectors”, low-molecular substances reacting with the protein.
Allosterism is the basis of e. g. the Bohr effect (the pH-dependence of the overall oxygenation equilibrium shown [reaction
(c)], with hydrogen ions as the effectors) and of the “cooperative” nature of the oxygen uptake, where the bound oxygen
itself acts as an effector; a condition for this is an association
of the subunits, e.g. to [Hb],. Contrary to expectation, there
is much less driving force behind the first step of the oxygen
uptake [reaction (d)] than behind the last step [reaction (e)],
which ensures that the bound oxygen is released more easily
in an oxygen-deficient medium a long way from the lungs.
Finally, [Hb], also takes care of about 60% of the reverse
transport of COz formed in cell respiration back to the lungs,
but heme itself is not involved in t h i ~ [ ’ ~ - ’ ~These
I.
effects
cannot be discussed here in further detail.
(4c), [Hh.COj
-N-F.e-N
-N-F.e-X
(4d), [Hb.NO]
f 4 f L 1Hh.W
Fig. 4. Schematic representation of the essential chemistry of a hernoglobin
unit [Hb] or myoglobin ([Mb] is then used instead of [Hb]). The letter
G symbolizes the protein component, i.e. globin.
2.1. The Coordination Chemistry of Hemoglobin
In deoxyhemoglobin [Hb], [cf. (4a)], the iron(n) ion is
pentacoordinated (type B, Fig. I), has an effective magnetic
moment perf= 5.4 B.M.“’], and protrudes from the plane of
the protoporphyrin[’*~’*]by about 50-60pm. The heme component Fe(proto) ( 3 a ) is held in the “pocket” of the globin
by van der Waals forces and the dative coordinate bond
of the nitrogen atom shown in (4a). This nitrogen belongs
to the imidazole part of what is called the “proximal” histidine,
which is not absolutely essential for fixing the heme in the
globin but has a fundamental effect on the binding of ligands
and probably also transmits the allosteric effects. “Distal”
histidine, which is on the opposite side of the heme disk
and is not shown in (4a), cannot form a coordinate bond
with the iron in heme because it is too far away; distal histidine
is not essential for the binding of Oz, but seems to influence
theentry of the ligand to the site of the bond
Under physiological conditions (37 “C), [Hb], reacts with
molecular oxygen to give oxyhemoglobin [Hb.O2I4 [cf. (4 b),
while with carbon monoxide and nitric oxide it forms respectively carbonylhemoglobin [Hb. CO], [cf. (4 c)] and nitrosylhemoglobin [Hb,NO], [cf. ( 4 d)]. These reversible reactions
cause characteristic changes in the visible spectra (Fig. 3).
The association constants (Kass) for the equilibria of the
monomers have approximately the following relative magnitudes at comparable pH:
K , , . 1 4 < 1 1 * f 4 h l K , . , ( 4 ( 1 ) ~ ( 4 1i h , . . ( 4 ( 1 ) * / 4 d )
= 1 :4 x 10’ 5 x 10” [IS]
The binding of CO or NO is therefore favored over the
uptake of 0 2 . This is true for [Hb],, [Mb], and numerous
Angew. Chem. f n t . Ed. Engl. 17, 4 0 7 4 2 3 (1978)
409
other heme proteins in the Fe” form, and is the reason for
the high toxicity of CO and NO. Since [Hb.C0I4 and
[Hb.N0I4 dissociate much more slowly than [Hb.02]4[201,
a chain-smoker can easily render 10% of his hemoglobin
useless, owing to the carbon monoxide in the smoke[”*. The
adducts [Hb.02f4 and [Hb.COI4 are diamagnetic, while
[Hb14 is not, and [Hb.N0I4 has an unpaired electron. The
adducts are therefore in the low-spin state[’g1.
In the crystalline product, and to a small extent also under
normal metabolic conditions in the blood, the oxygenation
of [HbI4 to [Hb.O2I4 is followed by oxidation to “methemoglobin” [Hb.OHI4 [(cf. 4e)], which carries an OH on each
Fe”’ ion, and these OH groups can be protonated to give
an aquo complex called “acid methemoglobin”. With anions
X- (X = F, OAc, CN, N3 etc.), [Hb. 0 H l 4 gives a series of other
ferrihemoglobins [Hb.XI4 [cf. (4f)], whose magnetic
moments show a pure high-spin state for X=OH or F, an
intermediate spin state for X=N3, and a low-spin state for
X=CN[”]. In the blood [Hb.OHI4 is constantly reduced
again to [Hb14 by the “repair enzyme” methemoglobin-reductase[”]. When a dangerous level of [Hb.0Hl4 has built up
in the blood (“methemoglobinemia”) under abnormal metabolic conditions, such as nitrite poisoning, [Hb’OH], can be
converted back into [Hb14 by an intravenous injection of
redox mediators such as methylene blue or toluidine blue[”].
Incidentally, sperm-whale metmyoglobin [Mb.OH] was the
first protein whose crystal structure was determined by X-ray
~rystallography[~~1.
All the X-ray structure analyses[’*] so far carried out on
carbonylhemoglobins point to the presence of a bent Fe-CO
unit with an Fe-C-0
angle of about 145”.This is unusual
in complexes and was first found by Huber in his work on
the [Hb.CO] of the insect Chironomus t h ~ m n i [ ~Otherwise
~].
a bent M-C-0
unit has so far been found only in a single
; the
carbonyl complex, namely in Mnz(AsMez)(CO)6C5H5
bent shape of a terminal Mn-CO group is attributed to
steric hindrance due to neighboring groups[’ 51. Distal histidine
in globin is likewise so oriented that it is in the way of
a CO or CN ligand attached to the iron normally to the
porphin plane; as a result, either the F e C - 0 unit is bent,
asin (4 b), or the Fe-C-0
axis is tilted from the perpendicular line of the porphin plane, but one cannot yet distinguish
between these possibilities. On the other hand, bent diatomic
or triatomic ligands, such as azide or hydroxide, fit better
into the heme pocket[”]. Figure 4 shows these aspects and
thus anticipates the results for [Hb.O2I4 and [Hb.N0]4 to
be discussed in Sections 2.2 and 4.
2.2. Nature of the Dioxygenyliron Group in Oxyhemoglobin
The structure and the distribution of the valence electrons
in the dioxygenyliron unit in [Hb.O2I4 or [Mb.02] have
long been the subject of lively disputelZ6-321, but this cannot
be described here in detail. Unfortunately, it has not yet
been possible to investigate the oxygenated forms by X-ray
crystallography, because autoxidation to [Hb.OHI4 takes
place during the lengthy process of data collection. In addition,
the resolution of the structure analysis is not high enough
to allow the determination of the space coordinates of the
410
atoms next to iron with the accuracy that can be achieved
with low-molecular complexes.
P’
M
P
P
M
E
F
0
O
?,
M
G
Therefore, in the case of a hemoglobin a decision is not
yet possible between the three conceivable configurations of
the FeO2 unit in (4b), namely the bent monodentate (E),
the linear monodentate (F), or the bidentate arrangement
(G).The bent structure E selected in Figure 4 was proposed
by Pauling as long ago as 1949[261.
The form G, first discussed
by Grifith in 1956[271,would be a n-complex of Fe” or a
peroxo complex of FeIV.There are no examples of the linear
arrangement F in inorganic chemistry.
H
K
The experiments described in Sections 5 and 6 show that
the synthetic O2adducts of mononuclear iron(@and cobalt(I1)
complexes have a bent structure of type E, so that the latter
is also likely for (4b) itself. The adducts of O2 (like O 2
itself)cannot be formulated unambiguously with valence signs.
Pauling has suggested formula Hrz61, in which the iron is
divalent, and which explains the apparent diamagnetism of
the adduct. Formula K, introduced by Weiss[28], shows
[Fe(proto)Oz.G] as a neutral complex of the hyperoxide ion
[O,] . (In these formulas circles denote d electrons of iron,
and points and lines denote valence electrons and valence
electron pairs of dioxygen.) In the case of the structure K
it is difficult to understand how the two unpaired electrons
at the Fe”’ ion and the terminal 0 atom can couple to form
a diamagnetic system. The latest and very accurate measurements of the magnetic susceptibility show that [Hb.OZl4
exhibits residual paramagnetism, whose temperature dependence between 3 and 30K indicates an exchange interaction
with a coupling constant of J = 12K between the two (S=
systems of an Fe3+ ion and an 0;
Formula K gives a correct description of some other properties of (4 b) and is therefore preferred at present. For example,
the weak light absorption in the near infrared region at 900IlOOnm that is observed with (4b), (4e), and (4f) but not
with (4a) and (4c) points to the presence of Fe”’ in the
first set of hemoglobin derivatives, i.e. in (4b), (4e), and
(4f). Furthermore, the IR spectrum of [Hb.O2I4 and
[Mb.02] exhibits an 0-0 stretching vibration with a frequency of about 11OOcm-’, characteristic of the coordinated
hyperoxide ion[30a-30cl.Besides, when C1- reacts with
[Hb.O2I4 in an aqueous solution, it is possible to detect
the hyperoxide ion (or HOz radical) that is displaced from
the heme in a nucleophilic substitution [reaction (f), with
X = Cl]. This explains the continuous formation of methemoglobin in the blood mentioned above. The hyperoxide released
here is also made harmless by enzymatic means. Other methemoglobins [Hb. XI4 [cf. ( 4f), with X = N3,SCN, OCN, F]
Angew. Chem. I n t . Ed. Engl. 17, 4 0 7 4 2 3 (1978)
can also be prepared directly by an exchange of the anions
according to reaction (f)[30d330e1.
ride and acetone[34! The intact globin can be isolated with
dilute hydrochloric acid in acetone at -20°CI’5]. Hemin
remains in solution in both cases. The process is as shown
in reaction (g).
According to recent quantum-mechanical ab-initzo calculations, the Pauling configuration F has as much as 55 kcal-mol-’
less energy than the Griffith configuration G. However,
the calculated electroneutrality of the O 2 ligand points to
a predominance of the electron configuration H[3’’. The calculations involve a great deal of simplification, NH3 being used
as the base trans to the O 2 molecule; this might not take
sufficient account of the contribution of imidazole to the
rc-bonds, which has been observed experimentally[’’I.
The special effect of the porphyrin and the globin components can be seen by comparing the behavior of the Fe“
ion in hemoglobin and in water at pH 7: in hemoglobin
there is a rapid reversible oxygenation, while in water there
is an extremely slow and irreversible autoxidation (it is considerably faster in an alkaline medium). This difference is
explained to some extent by the syntheses in which hemoglobin
is modified and imitated and which will be discussed later,
after the following notes concerning a reproduction of hemoglobin.
[Fe(proto)OH-G] + HC1
3. Copying: Remarks on the Total Synthesis of Hemo-
( 4 e ) = [Hb-OH]
cleavage
’ [Fe(proto)CI] + G + H * O (g)
reconrlllUliOn
(3b)
“Reconstitution”, i. e. the recombination of heme ( 3 a ) and
intact globin, was first achieved by Hill and Holden in 1926‘351.
The overall process starts with the reversal of reaction (g),
after which the resulting [Hb.OH] ( 4 e ) is reduced to complete
[Hb] ( 4 a ) (see also Section 4).In a weakly alkaline medium
(pH 7.2-8.0), the equilibrium in reaction (g) lies entirely
to the left[’51.
A total synthesis of the apoenzyme has not yet been described, but it seems feasible at the present state of protein
research. The modification of globin is provided in uivo by
the existence of many species-specific globin variants or
mutants, which exhibit characteristic deletions or substitutions
in their amino-acid sequence, leading to changes in the function
of the m o l e ~ u l e [ ’ ~ * ’ ~ ~ ~ ~ 1 .
4. Variation I: Removal of the Globin ComponentCoordination Chemistry of Heme and Hemin
globin
The total synthesis of a natural product, i. e. its nonenzymatic
reproduction in uitro, does not explain its mode of operation
but provides us with the necessary methods for modifying
and imitating the molecule and thus for discovering the way
it acts in nature. With the total synthesis of hemin ( 3 b ) ,
and thus also heme (3a), Hans Fischer succeeded in 1929
in “copying” or reproducing the coenzyme of
However, it is easier to extract hemin ( 3 b ) from blood than
to synthesize it. For this, the blood is first treated with citrate
to bind the calcium ions and to make it uncoagulable by
suppressing fibrin formation. The erythrocytes are then made
to burst (hemolysis) by producing an osmotic shock with
water. After centrifuging, [Hb.OH], is obtained in the
aqueous phase if the work is carried out in air. Globin is
denatured and precipitated by the addition of strontium chlo-
The modification of the globin component on the basis
of mutants occurring in nature belongs to the field of protein
chemistry[’6,36J. Although this field is also instructive for
inorganic chemists,we shall discuss here only one modification,
namely the complete elimination of globin. Figure 5 shows
the essential chemistry of heme ( 3 a ) , which exists preferentially as a complex Fe(P)L2 [reaction (b)] when mixed with
donor-solvent molecules L such as THF, DMF, and pyridine.
These hemochromes (earlier called hemochromogens) (5 a ) ,
carbonylhemes ( 5 g ) , and hemins (5f) have long been
known[’], whereas the other species were first isolated and
characterized spectroscopically in the last decade.
Owing to the strongly polar carboxyl groups and the labile
vinyl groups, it is not practical to use protoheme ( 3 a ) , which
can be obtained from the blood via hemin ( 3 b ) . It is better
to convert it into the dimethyl ester [Fe(proto-DME)] ( 3 c )
Fig. 5. Schematic representation of the essential chemistry of the heme Fe(P), especially iron(I1)
protoporphyrin Fe(proto) (3 a ) or the corresponding derivative of tetraphenylporphyrin Fe(TTP)
(6a), or octaethylporphyrin Fe(0EP) (7a). The coordination types are designated as (5a)-f5j).
Angew. Chem. Int. Ed. Engl. 17, 407-423 (1978)
411
or to hydrogenate it further to the mesoporphyrin derivative
[Fe(meso-DME)] (3 d). The labile vinyl groups are often eliminated completely, and the dimethyl ester of deuteroporphyrin-IX ( 3 e ) is used for further work. To avoid these steps
and the asymmetric arrangement of substituents which leads
to complicated spectra, one can use either cheap tetraphenylporphyrin [H2(TPP)], which can be prepared from pyrrole
and benzaldehyde in a single step[3s4,371,
or octaethylporphyrin [Hz(OEP)], which is expensive but is the most convenient to use. The incorporation of iron in reaction (a) or
with the aid of iron(I1) 2,4-~entanedionate[~~
381 gives the heme
Fe(TPP) ( 6 a ) or Fe(0EP) ( 7 a ) (see Tables 3 and 4). In
solution, all hemes are very sensitive to air and are readily
autoxidized to hemins (Sf), which are usually isolated after
the insertion of iron. A very convenient way to incorporate
the iron, described by Hans Fischer"], is to use FeC13 in
boiling glacial acetic acid and sodium acetate. The porphin
is dissolved out of an extraction thimble in the course of
about a day, and the chlorohemin Fe(P)Cl [(Sf) with X = CI]
crystallizes on cooling.
to the hemin solutions, the solvent is evaporated, and the
solid hemochromes ( 5 a ) are i ~ o l a t e d ~ ' - ~These
].
hemochromes react with carbon monoxide and nitric oxide, giving
the similarly crystallizable carbonylhemes (5g)" - 4 * 391 and
(7)
Table 4. Composition of metal octaethylporphyrins M(0EP)LL ( 7 ) . (For
the abbreviations see Table 1 .)
M
L
Fe
Fe
Ru
0s
Ti
-
0 s
0s
0s
0 s [a1
A
L
co
co
co
M
L
L
0 s
OMe
N2
NO
NO
PY
NO
PY
MeCN
MeCN
OMe
DMF
NO
OMe
PY
OMe
PY
MeCN
MeCN
0s
0s
0s
Ru
0
Ru
0
N2
PY
PY
Fe
Ru
0s
[a] Cationic 0s"' complex.
v
R
Table 3. Examples of metal tetraarylporphyrins (6). (For abbreviations see
Table 1.)
M
Fe
Fe
Fe
Fe
Fe
co
co
Mn
Cr
0s
0s
Ru
R
L
H
H
H
H
H
OMe
H
H
H
Me
Me
H
-
L'
co
NO
NO
2-MeIm
PY
-
PY
PY
-
-
NZ
THF
PY
co
More care is needed for the introduction of iron into the
much more labile H2(proto), i. e. into the iron-free (3a). For
this, a solution of Hz(proto) in pyridine is combined with
a solution of (NH4)zFe(S04)2
. 6 H 2 0 in maximum-purity glacial acetic acid in the absence of air and the mixture is heated
to 80°C for 1 h. The resulting Fe(proto) ( 3 a ) is oxidized
by air in the cold and is converted into hemin ( 3 b ) by treatment with HCI[Z,3*34b1.
After treatment with reducing agents, such as sodium dithionite, hydrazine, chromium(n) 2,4-pentanedionate, NaBH,,
or palladium/calcium hydride, the required neutral ligands
L, such as pyridine or 1-methylimidazole (I-MeIm), are added
412
nitrosylhemes ( 5 h)[40-431, respectively. In nitrosylhemes
(Sh), only the ligand L trans to the nitrosyl group can be
easily split off, giving (5 i). This has recently also been observed
with [Hb.N0]4i40b.40c1.
X-Ray crystallographic analysis has
elucidated the structures of the carbonylheme Fe(TPP)CO(Py)
(6b)r3'g1 and nitrosylhemes Fe(TPP)NO (6c) and
Fe(TPP)NO(l-MeIm) (6d)i411. Unlike [Hb. CO],, the FeC-0 group is linear and oriented normally to the porphin
plane. According to Scheidt, the F e N - 0 unit is bent, the
Fe-N-0
angle being 149" in ( 6 ~ ) ' ~ and
' ~ ' 140" in (6d)[41c].
These angles agree with the assumption that nitric oxide is
basically a neutral ligand here. The donor action of the imidazole system in the trans position in (6d) imparts a partial
anionoid character to the NO, as can be seen from the widening
of the angle on going from (6c) to (6d). Since Fe(protoDME)NO(I-MeIm) (dissolved in 1-methylimidazole, VNO =
1618cm-') and [Hb.NOI4 (vNO= 1615cm-') exhibit virtually the same NO frequency, it can be assumed that
the FeNO unit has a bent configuration in [Hb.NO], as
The complexes of the type ( 5 a ) , ( 5 g ) , and ( 5 i ) , which
are fairly stable in the solid state in air, readily undergo
autoxidation in solution, particularly in the absence of an
excess of ligands. As expected, (5 a ) and (5 g) are diamagnetic,
while (5i) has an unpaired electron and takes on a further
NO reversibly at - 196°C to form the dinitrosyl complex
( 5 j)f4'1.
Like the reversible reactions of [Hb],, the conversions of
globin-free hemes start from a pentacoordinate species of
type B, such as (5b)r431,these compounds being formed mainly
by the dissociation of the hexacoordinate complexes ( 5 a).
When a sterically hindered axial ligand like 2-methylimidazole
(2-MeIm) is used, ( 5 b ) can also be prepared in the crystalline
state. Thus, Collmnn et al. have isolated Fe(TPP)(2-MeIm)
(6e)C4,1, and even managed to crystallize the bare heme
Anqew. Chem. Int.
Ed. Engi. 1 7 , 4 0 7 4 2 3 (1978)
Fe(TPP) ( 6 a ) with the established square geometry
However, Hans Fischer et a/.['] and C a ~ g h e y ' had
~ ~ ]prepared
such bare hemes before; for example, Fe(proto-DME) ( 3 c )
or Fe(0EP) (7a) are also formed when the hemochromes
( 5 a ) are heated in high v ~ c u u ~ [ ~ ~ ~ * ~ ~ ] .
It has only recently been found that the reversible oxygenation is not restricted to [Hb14 and [Mb]. Thus, the existence
of oxygen adducts ( S c ) , formed analogously to ( 4 b ) (see
Figs. 3 and 4), has been demonstrated for a number of hemes,
such as ( 3 ~ ) [ ~ (3d)[481,
'],
and (6a)[39'i, with the aid of lowtemperature absorption spectroscopy in solution at - 50°C.
When heated to room temperature, these adducts undergo
autoxidation to the binuclear iron(111)complexes ( 5 e ) at a
rate that depends on the solvent
It is generally
assumed that the autoxidation starts with an attack of a
second heme (5 6 ) on the dioxygen complex ( 5 c), as a result
of which a p-peroxo complex ( 5 d ) is formed. This might
then change into ( 5 e ) by symmetrical cleavage to (P)FecO
and by the further reaction of this iron(1v) species with excess
iron(]]) porphyrin ( 5 6 ) . In this series of reactions ( 5 b )
-+ (5c) -+
( 5 d ) -+ ( 5 e ) , the axial ligands L are lost. The
NMR spectroscopic monitoring of the autoxidation of Fe(P)
in
[P =meso-tetra(o-toly1)porphyrin) into (P)Fe@-Fe(P)
toluene at - 30°C does indeed indicate an intermediate, which
is probably the p-peroxo complex (5d)1491.
The end products of the autoxidation, the p-0x0-bis(iron(111)porphyrins) ( 5 e ) , are identical with hematins, to which the
formula Fe(P)OH [(Sf), with X = OH] was previously
ascribed. The approximately linear Fe-@-Fe
bridges present
in them according to crystal structure analyses['2*501 cause
an antiferromagnetic interaction between the two Fe"' ions,
which leads to magnetic moments that are abnormally low at
room temperature and disappear altogether at - 250"C[50.511.
Unlike [Hb. OHI4 [cf. (dell, mononuclear globin-free
hydroxoiron(ii1)porphyrins ( 5f), with X = OH, do not
exist as isolable substances. Attempts to obtain them by the
alkaline hydrolysis of a hemin Fe(P)X (5f) are invariably
followed by condensation to ( 5 e ) according to reaction (h)
(but see Section 8).
2 Fe(P)X *+
(Sf)
2 HX
2 Fe(P)OH
3( P ) F e O - F e ( P )
i
II,O
f5e)
The binuclear nature of hematins would have certainly been
noticed before if the elementary analysis had been extended
to ~ x y g e n ' ~ . ~ ~ !
The last remarkable phenomenon to be mentioned here
is the reverse reaction of the hemin type ( 5 f ) with electrochemically produced hyperoxide ions to form the dioxygen adduct
(5c) in reaction (i), observed by H i [ / in DMF at -50"C[521.
This reaction is the reversal of the formation of methemoglobin
in reaction (f) and is a further indication of the hyperoxide
character of the bound O2molecule.
Fe(proto-DME)OC103 + 0 ; + DMF +
Fe(proto-DME)DMF.O,
+ C10;
(i)
It appears from all this that the iron ion in hemoglobin
has, pictorially expressed, two "garments": under the globin
"cloak, it wears the red "gown" of porphyrin.
Angew. Chem. In t. Ed. Engl. 17,407-423 (1978)
Each plays a part in affecting the reactivity of the iron
ion. First of all, the inner envelope ensures that the formation
of insoluble polynuclear hydroxo and p-oxo-iron(lI1) complexes, which is dangerous in the biological medium (aqueous
system, p H z 7, air) is restricted to the formation of binuclear
p-0x0 complexes ( 5 e ) , which readily decompose according
to reaction (h). The contribution of the porphyrin ligand to
this is an acceleration of the exchange of the axial ligands
on the Fe"' ion. As a result, the solvent exchange in DMF
is faster with the complex ion [Fe(TPP)(DMF)2]+,which
probably exists in it, than with the cation [Fe(DMF)6]3+[531.
A labilization of the axial ligands is also assumed for the
Fe" porphyrin system, because Cr"', Co"', and Ru" porphyrins
also have rates of substitution that are not normally expected
for inert complexes of these ions with d3 or d6 configurati or^(^^* 551. This labilization, which was first noted by
F l e i ~ c h e $and
~ ~is~ very important for the rapid establishment
of the oxygenation equilibrium (c), is attributed to the additional n-acceptor function of the porphinate ligand, which
is brought about by the delocalized x-electron system and
which becomes effective when the central metal ions possess
occupied d,, or dyzorbitals, from which some of the electron
density can diffuse to the unoccupied eg(n*)molecular orbitals
of the porphyrin s y ~ t e m [ ~ -This
~ ] . removes the degeneracy
of the d,,, 4,, and d, orbitals that leads to the inert character
of systems in the d3 or d6 configuration. This type of information comes mainly from studying porphyrin complexes with
central metals other than iron (see Sections 6 and 7).
However, globin, which forms the second envelope of
hemoglobin, constitutes an effective system only in the blood.
Porphyrin has conferred the above-mentioned reaction advantages on the iron ion, but-owing to its own hydrophobic
nature-has not made this ion water-soluble at all; this can
only be done by combination with globin, which has a hydrophilic periphery, making dissolution in water possible. On the
other hand, the hydrophobic inside space of globin shelters
heme properly. The low dielectric constant of this inner
medium makes it difficult for the dioxygen adduct to dissociate
into a hyperoxide ion and methemoglobin in reaction (f).
However, this shell has another, and quite fundamental, effect
in that it inhibits the attack of a second heme on the already
oxygenated heme and thus also the step ( 5 c ) - + ( 5 d ) (Fig.
5), which starts the irreversible autoxidation of heme in a
nonpolar medium. The longer life of oxyhemoglobin ( 4 b )
in comparison with dioxygenylheme (5c) is thus due to an
inhibition of the subsequent reactions of oxygenation, which
is confirmed by the investigations described in Section 5.
As mentioned before, globin is also responsible for the
cooperative effects. Besides, it is worth mentioning that the
oxidation potential of the iron(]]) ion in [Mb] (0.05V) is
very close to zero, and thus the driving force behind the
autoxidation to [Mb.OH] is relatively small[15*561. Finally,
globin provides as an axial ligand an imidazole group that
can act simultaneously as a o-donor, n-donor, and n-acceptor,
and thus it facilitates the addition of dioxygen, and also carbon
monoxide, in the trans position. Whereas the o-donor/n-acceptor effect is well known[". 56b1, the important n-donor effect
has only emerged from recent analyses of the cis- and trans
effects, which were carried out on metal porphyrins but which
will not be discussed here[39'*571.
413
5. Imitation of Hemoglobin: Iron-containing Myoglobin Models
A complete simulation of all the functions of hemoglobin
by a given metal complex calls for numerous characteristics,
of which it suffices to mention the following:
1) The formation of an O2adduct ( 5 c ) from ( 5 b ) should
be reversible.
2) The adduct ( 5 c ) should be stable in a liquid phase,
i.e. in solution, at 37"C, so that it can be transported in
a pipeline system of conduits.
3) The adduct ( 5 c ) should be incorporated in a water-soluble protein, for only then can blood serve as a transport
medium, and the adduct would not be excreted by the
kidneys[14a].(It is not taken into account here that [Hb-O2I4
is in turn incorporated in the erythrocytes, which also impedes
excretion.)
4) It should be possible to adjust the affinity of ( 5 b ) for
oxygen to the prevailing physiological and biological conditions (different O2 partial pressures), which means that it
should be possible to control the system through allosterism.
The first requirement is fulfilled even by solid model substances, while the second calls for a soluble species. The third
and fourth requirements are of a typically physiological nature.
The designation "myoglobin models" is intended to indicate
that one cannot expect a simulation of the cooperative effects.
3-chloropropyl groups was then replaced by the imidazole
group. This was followed by the addition of Fe(TPP) ( 6 a )
as the heme component, and the resulting heme, fixed on
the silica gel, was finally brought into the active form of
type ( 5 b ) denoted by (8) by drying at 250°C in high vacuum.
System (8) is capable of chemisorption of molecular oxygen
that is weak at room temperature, strong at -78"C, and
irreversibleat - 127°C.No autoxidation to the p-0x0 complex
of type ( 5 e ) was observed. Carbon monoxide is also taken
up at room temperature and is only given off again at 160°C
in a current of helium.
It has also been possible to immobilize heme in solution
by fixing Fe(TPP) ( 6 a ) as the heme component on partially
quaternized poIy(4-~inylpyridine)~~'~J.
The heme-polymer
adduct thus obtained was stable to oxidation in a mixture
of DMF and water, but it absorbed oxygen, which could
be displaced from it by CO as in the case of ( 4 b ) and (5c).
However, no reversible binding of O2 was observed, and
the identification of the presumed adduct of type ( 5 c ) is
incomplete.
\
0
/
I
CH2
5.1. The Concept of Immobilization
The first attempts to imitate hemoglobin by the use of
iron porphyrins date back about 20 years. Thus, Corwin and
BruckrSBa]
studied the oxygen uptake of the solid imidazolehemochrome Fe(meso)(HIm), (3f) at room temperature. At
60-65°C the adduct suffered a loss of weight in vacuum,
corresponding to the binding of 1 mol of 0 2 per mol of hemochrome. This indicated a reversibility of the O2 addition. Using
carbon monoxide, 1-phenethylimidazole, the diethyl ester of
obtained a carFe(proto) (3g), and polystyrene, Wangfs8bJ
bonylheme of type (5 g) embedded in polystyrene. Elimination
of the CO with an inert gas left behind a heme assumed
to be of type ( 5 b), which was capable of taking up O2 reversibly, as was indicated by the visible spectrum typical of ( 5 c )
and ( 5 b ) in the presence and the absence of Oz, respectively.
Both these studies were based on the concept of "immobilization" of the heme. When in the solid state or bound to a
matrix, the heme molecules are not suficiently mobile to
form the p-peroxo complex ( 5 d).
Returning to the concept of immobilizing heme, Basolo
et a1.[591
have recently obtained a heme with the partial formula
(8), fixed in a silica gel matrix. For this purpose, 3-chloropropyl groups were first introduced on the silica gel surface
with 3-chloropropyltrimethoxysilane,
and the chlorine in these
414
C'I,
/
I
CH2 $HZ
CH-
\
CH2
\
6
\
C,H2
\
Much more sensational is Buyer and Holzbach's publication
about synthetic heme polymers,describing e. g. the preparation
of the macromolecule (9)[60b1.In (9), the heme carries not
carboxyl groups as in ( 3 a ) but amide functions, coming from
3-(1-imidazolyl)propylamine and terminal histidine groups,
two of which complete a chain of polyethylene glycol bis(g1ycine ester) with an amide-type bond. Besides the immobilization of heme in the polymer coil, other concepts were also
involved here, which have already been worked out on lowmolecular myoglobin models, such as the fixing of an imidazole
residue on the heme to simulate the proximal histidine [cf.
( I I)]; the distal histidine has also been simulated (see Section
5.2).
In fact, the macromolecule ( 9 ) resembles [HbI4 in many
respects: It can go through a number of oxygenation cycles
in aqueous solution and gives an S-shaped oxygen sorption
isotherm. In view of the binuclear nature of this heme complex,
this second effect, which points to a cooperative character,
Angew. Chem. I n t . Ed. Engl. 17, 407-423 (1978)
is not entirely unreasonable [formula ( 9 ) shows only one
heme terminus of the polymer chain completed by two heme
units], but the visible spectra of ( 9 ) in various ligand states
indicate that the species are not uniform, and further experimental details need to be reported.
from (12) by freezing and the application of vacuum, and
from ( 1 3) by flushing with nitrogen. The dioxygenyl complexes
(1 2) and (1 3 ) have even been isolated as pure solid substances.
5.2. Monomolecular Myoglobin Models
The model substances described in Section 5.1 have the
short-coming that the heme envelope in them is by no means
“tailor-made”. Therefore, we cannot expect the heme package
to have a long life in these systems. Another idea is to link
heme firmly to its envelope by introducing steric hindrance
on heme itself with the aid of bulky substituents strongly
bonded through C-C bonds. In 1973-75 numerous authors
competed to be the first to prepare such monomolecular soluble myoglobin models.
(13)
Baldwin and Hufl6l1 described in 1973 the first synthetic
iron(u) complex ( l o ) , which is a rigid macrocyclic chelate
similar to heme but can be oxygenated reversibly only at
low temperatures. Chang and Traylor[621were the first to
show with the peripherally modified heme (1 1 ) that globin-free
hemes can also be reversibly oxygenated at low temperatures.
The coordination type B is stabilized in (11) on account
of the chelate effect, because the imidazole ligand is firmly
connected with one of the porphyrin side chains. However,
the stabilization of type B, i. e. of the complex ( 5 b ) analogous
to deoxyhemoglobin ( 4 a ) , is not necessary for reversible oxygenation, since the usual hemes (3c), ( 3 d ) , and ( 6 a ) also
givethe reaction(5b)r),(Sc) at -50”C[39’~47~48~(seeSection
4).Nevertheless, heme ( 1 1 ) and related systems are still useful
for studying the reaction mechanism and the bonding of small
molecules in
though this will not be discussed here.
The first systems that can be reversibly oxygenated at room
temperature were prepared by B a l d ~ i n ~Collman[6s-6’]
~~],
and
their associates; these are Baldwin’s “capped heme” ( 12 )
(crown hemec6])and Collman’s “picket fence heme” (13).
Both of these have been given the formula (5c), which is
analogous to ( 4 b ) . The globin pocket is in these compounds
to some extent fused with the porphyrin system. One of the
sides of the porphyrin disk is covered by bulky substituents
in such a way that no irreversible autoxidation can take
place as long as the other side is occupied by axial ligands,
such as 1 -methylimidazole, that favor reversible oxygenation.
It has thus been possible to carry out “several” cycles of
reversible oxygenation at 25°C with (12) and (13) [at least
three with ( 1 2 ) ] without any notable irreversible oxidation
taking place. After the addition, the oxygen was cleaved off
Anyew. Chem. l n t . E d . Engl. 17,407-423 (1978)
For ( 13), crystal structure analysis has indicated structure
E, i.e. a monodentate, bent dioxygen chain bound to the
although it should be mentioned that this analiron
ysis did not have the accuracy attainable nowadays, owing
to the mediocre quality of the crystals and the disordered
arrangement of the bound oxygen molecule. After initial difficulties, the typical IR bands of the F e 0 2 system have been detected (at 1159cm-’), and the magnetic data and the Mossbauer spectra of (13) agree with those of [Hb.O2I4, so that
the Pauling structure E is also valid for [Hb.02]4[66y671.
The sterically hindered porphyrin ligangs in (12) and (13)
were prepared by conventional methods of organic chemisThe key compound forming (12) was the pyromellitate
tetrakis[2-(2-formylphenoxy)ethyl]-1,2,4,5-benzene tetracarboxylate, which condensed with pyrrole to give the meso-substituted porphyrin that gave the heme component in ( 1 2 )
after the incorporation of iron[641.The decisive step in the
synthesis of (13) was the chromatographic separation of the
atropo-isomers of a,f!,y,S-tetrakis(2-aminophenyl)porphyrin.
The isomer that had all the amino groups on the same side
of the porphyrin disk was acylated with pivaloyl chloride
and converted into the heme component (13) by the incorporation of iron[6s.661.
However, (12) and (23) have a limited lifetime in solution,
because the detachment of the imidazole ligand can start
an autoxidation and p-0x0 complex formation at the lower,
unprotected side of heme. In hemoglobins, however, the axial
ligand trans to the O2 molecule, the proximal histidine, is
also supplied by the enveloping globin [ ( 4 b ) , ( 4 c ) l . The
415
number of cycles can be raised to 200 by making use of
6.1. Development of Coboglobin
immobilization, i e . by the reversible formation of (23) in
the solid state. The thermodynamic data for this reaction
A cobalt(I1) chelate-salcomin (24a), first prepared by
show a remarkable agreement with those of r n y ~ g l o b i n ~ ~ ~ ~ lPfeiffer
.
in 1933[721-was incidentally the first reversibly oxyThe use of a rather aprotic medium is important for a
genable metal complex
However, a complex does
long life of the dioxygen complex, as can be seen from the
not have to be a planar chelate to be capable of reversible
fact that, when the pivaloyl amide groups in (23) are replaced
oxygenation, as has since been proved by many investigaby the more strongly acidic p-toluenesulfonamide groups, the
tions[701.Most adducts are diamagnetic pperoxodicobalt(1Ir)
corresponding 0 2 adduct cannot be detected[66! The presence
complexes of type M, which are much more stable than the
corresponding iron complexes ( 5 d). C a l d e r ~ z z dfirst
of unsubstituted imidazole in the solution has the same
~ ~ de~
641.
scribed the preparation of a mononuclear 1 :1 chelate complex
( 1 4 b ) in 1969. Basolo and H ~ f l r n a n studied
[ ~ ~ ~ at the same
The synthesis of the sterically hindered hemes (12) and
time the formation of the analogous complex (15) at 0°C
(13) has stimulated many other laboratories engaged in porin DMF. The ESR spectra of ( 1 5 ) and of numerous similar
phyrin synthesis to prepare further porphyrins with bulky
side chains or side chains bonded like cyclophane[681,but
these variants have not yet supplied coordination chemists
with any fundamentally new results.
None of the models discussed here fulfils all the requirements
for a perfect imitation of hemoglobin. They possess only the
first two necessary characteristics, i. e. reversible adduct formation and transportability. In contrast, the well characterized
model substances (12) and ( 1 3 ) are not soluble in water
R
L L'
I
L
and have a low molecular weight, so that they would be
(14a) H
- M
removed from the blood by renal ultrafiltration and are there(146) OMe O2 Py
fore unsuitable as blood substitutes, not to mention the allosteric effects, which must be absent in the case of a monomolecular model. Nevertheless, the synthesis and structure analysis
compounds have been ascribed to the Co"' hyperoxide species
of such model substances are highly instructive and fruitful
having structure E. This has been proved correct by the deterfor hemoglobin research and for preparative coordination
mination of the crystal structure of (25)[751 and of a large
number of corresponding ad duct^[^^- 711.
chemistry.
It was now an obvious step to the porphyrin system, and
Walkert76]and the teams of James and I b e r ~ [ ' ~discovered
]
almost simultaneously, by electronic absorption spectroscopy
6. Variation 11: Coboglobin and Other Metalloglobins
and ESR spectroscopy, the reaction ti) with various cobalt(I1)
porphyrins Co(P)L such as ( 3 h ) and (Sf), proceeding to
In the description of work aimed at imitating the biological
a small extent at room temperatureand readily at temperatures
function of hemoglobin in the previous section we deliberately
below
-20°C.
ignored the publications dealing with the reversible oxygenation of metal complexes containing neither iron nor porphyrin
Co(P)L + 0 2 F! CO(P)L(O2)
ligands. The aim was to adhere closely to the original example,
ci)
although basically any reversibly oxygenable metal complex
In the presence of an excess of base, there is autoxidation
is an imitation of hemoglobin at the simplest level. The whole
to the cobalt(m) species in this case as well. These experiments
field of reversible oxygenation of metal complexes is very
established the analogy with iron-porphyrin chemistry (see
large and is covered comprehensively in many reviews, some
of them giving even the more recent r e s ~ l t s [ ~so~ that
~ ~ ~ - ~ Sections
~ ~ , 2, 4,and 5), and the results obtained with the two
systems mutually confirmed each other.
we shall deal here only with data of direct relevance to our
This analogy between iron and cobalt received its ultimate
topic.
demonstration in the work of Hoffman et al., who "reconstiWe shall examine in this section the possibility of varying
tuted coboglobins from Co(proto) ( 3 j ) and globins by
the central metal in hemoglobin, i. e. examine which other
methods described in connection with the heme Fe(proto)
metals can be incorporated in hemoglobin instead of iron
( 3 a ) (see Section 3). These cobalt analogs of myoglobin
without suppressingits main biological function, uiz. the trans[CoMb] or hemoglobin [CoHb14 show an amazing similarity
port of oxygen. According to Vaska, only certain complexes
to [Mb] or [Hb],. Thus, both these analogs take up oxygen
of manganese, copper and all Group 8 metals react with
reversibly at room temperature ! However, the formation conmolecular oxygen17'l. Besides iron, only cobalt (which lies
stant of the "original", [Mb.02], is almost a hundred times
next to iron and has one more d electron) forms complexes
higher than that of [CoMb.02]. Furthermore, [CoHb14 too
that bind O 2 in a demonstrably monodentate manner. In
exhibits allosteric effects such as the Bohr effect (see Section
the case of manganese this arrangement is not yet certain.
2) and the cooperative behavior in the O2 uptake, although
All the others hold the O2 in a bidentate manner as in G
to a smaller
The cobalt analog of (13) has also
and can, in a simplified way, be regarded as peroxo complexes.
been found in the meantime; the equilibrium mixture contains
There is no question here ofan imitation of [Hb.02], because
about 25 % of this adduct besides the starting material (type
of their structural and electronic difference from it, even if
B) in toluene at room temperature[791.
they can take up oxygen in a reversible manner.
"k
416
Angew. Chem. Int. Ed. Engl. 17, 407423 (1978)
Although coboglobin has a much lower affinity to oxygen,
it surpasses its "original" in one respect of ecological interest:
it does not take up carbon monoxide. Therefore, living
organisms that have coboglobin instead of hemoglobin should
be capable of existing in an atmosphere containing more
CO, since the latter would be only physically dissolved in
their blood. Besides, Co" porphyrins also give only a limited
reaction with CO. Wayland et aE. have shown that Co(TPP)
( 6 g ) takes up CO in reaction (k) only at very low temperatures
and only in the absence of a nitrogen or phosphorus donor["'].
Since coboglobin contains a nitrogen donor in the form of
the proximal histidine, it is inert to carbon monoxide.
Co(TPP)+ CO *Co(TPP)CO
(k)
In contrast, Co(TPP) and coboglobin add on nitric oxide
to the same
The additional electron in the dZ2
orbital of the Co" ion evidently repels CO, but pairs off
with an unpaired electron of the radical-molecule O2 or NO;
Co(TPP)NO is diamagnetic, contains a bent Co-N-0
unit,
and is isoelectronic with the corresponding F e 0 2
6.2. Other Metalloglobins
As mentioned at the beginning of this section, according
to Vaska not only Co" but also Mn" might function as a
central metal ion in place of the Fe" ion in hemoglobin.
In fact, the reversible oxygenation of Mn(TPP)Py ( 6 h ) in
reaction (I) has recently been detected at low temperatureds21.
On the other hand, Cr(TPP)Py ( 6 j ) adds on oxygen irreversibly, presumably with the formation of a hyperoxide
Since the relatively large high-spin Mn" ion in Mn(TPP) is
not coplanar with the porphyrin
and reaction (1)
follows the stoichiometry given, it is concluded that pyridine
is replaced by O2 in a frontal attack. Accordingly, the "manganoglobins" [MnHb]4 and [Mn. Mb] prepared by several
teams cannot add on oxygen, since in the reconstituted system
the O2 would have to displace the relatively immobile proximal
hi~tidine["~861. H owever, manganoglobins are still interesting: [MnHbI4 exhibits a Bohr effect and, when binding NO,
the allosteric cooperative effects known for [Hb]4[861. Unlike
O2 and CO, the NOrx7,""] can therefore be bound, because
only the particularly strong x: acceptor NO can effect a transitionof the Mn" ion into the low-spin state during the addition.
In this state the Mn" ion is smaller and capable of assuming
the octahedral configuration C, as for example in
Mn(TPP)NO(L)(L =4-methylpiperidine)[871,which must also
be present in [MnHb.N0I4. The constitution of Mn(TPP)02
formed in reaction (1) is still unclear. Basolo suspects a peroxo
complex of Mn'" (structure G)[82bl,while Leoer["'] assumes
the formula of a hyperoxomanganese(i11)complex (structure
E) for his O2 adduct obtained from manganese(r1)-phthalocyanine Mn(Pc).
The metalloglobins obtained by "reconstitution" from
Cu(proto) or Z n ( p r o t ~ ) are
~ ~ unsuitable
~ ~ ~ ' ~ as O2 carriers,
since Cu"and Zn" normally cannot donate any more electrons.
Angew. Chem. Int. Ed. Engl. 1 7 , 407-423 (1978)
In addition, Cu" porphyrin has a fully occupied dzZ orbital,
which allows only a weak interaction with axial ligands (see
Section 1).This also rules out nickel porphyrins for reconstitution. On the other hand, pentacoordinate Zn" porphyrins
are known[l21. In fact, the optically excited triplet state has
been detected in [ZnHbI4 and [ZnMb] by ESR spectroscopy,
and differences have been noted between the porphyrin-globin
interaction here and that in hemoglobin and myoglobin["!
Even a lanthanoid porphyrin, Yb(meso-DME)(acac), with
the composition ( 3 j ) , has recently been reconstituted with
apomyoglobin. Being a shift reagent, the paramagnetic ytterbium ion should facilitate the analysis of the NMR spectra
ofglobin["'. However, since ( 3 j ) very probably has a different
structure from that shown in ( 3 ) (see Section 7.1), the results
cannot be simply applied to myoglobin itself.
7. Variation 111: Exotic Metal Porphyrins
The idea of varying the central metal in hemoglobin can
be taken further, but we shall mention here only two types
of metal porphyrins, namely the complexes of some d-electrondeficient ("early") transition metals, and the ruthenium and
osmium derivatives, with the heavier central atoms from the
same group in the periodic table as iron, examples being
the carbonylmetal porphyrins ( 7 c ) and ( 7 d ) , which are analogous to carbonylheme ( 7 b ) but much more stable. From
a chemical point of view, these are "exotic" metal porphyrins,
which cannot be prepared by the usual methods such as
reactions (b), and have been reported only
Though equally interesting, the porphyrin derivatives of
technetium and rheniumr71,and of rhodium['21, are less relevant here, because the first two contain two metal ions per
porphyrin ligand (like the alkali metal porphyrinsr2-61)and
therefore do not belong to any of the coordination types
presently under discussion, while the rhodium derivatives are
more suitable as models for vitamin B1 than for hemoglobin.
This incidentally also applies to cobalt porphyrins, which
form a great variety of alkyl-metal and aryl-metal derivatives.
The early transition metals give unusual coordination geometries in their oxidation states being sometimes normal,
while osmium porphyrins display a larger variety of oxidation
states and axial ligands than their iron or ruthenium analogs.
7.1. Unusual Coordination Geometries
Figure 2 shows the coordination types A X , which are
"normal" for the porphyrin system. In principle. besides the
trans arrangement, a cis configuration D is also possible in
the presence of two axial ligands L. According to Schneehage,
the scandium p o r p h y r i n ~ [can
~ ~ Ibe obtained from tris(2,4-pentanedionato)scandium Sc(acac), and the corresponding porphyrin in molten imidazole by reaction (m), an example being
S~(0EP)(acac)['~
931. On the basis of the IR and NMR spectra,
the cis configuration N has been chosen for these scandium
complexes.
Sc(acach + H,(OEP) -+ Sc(OEP)(acac)+ 2 H(acac)
(m)
417
TiO(0EP) + H Z 0 2+ Ti02(OEP)+ H 2 0
(7e)
P
N
P
X-Ray crystallographic investigations have shown that the
peroxotitanium(1v) porphyrin Ti02(OEP) has configuration
P[lol],which corresponds to D or N. Particularly remarkable
is the bis(peroxo)molybdenum(VI) compound Mo(O&(TPP)
with configuration Q, which has also been proved by X-ray
crystallography.
The complex is obtained from oxomolybdenum(v) porphyrins[', 93,
'04] described before, by oxidation and ligand
exchange as in reaction (n)['Ozl.This complex is the trans
analog of octacoordinate zirconium porphyrins (Fig. 6). The
two peroxide ligands are staggered (S4 symmetry) when the
molecule is viewed normally to the porphyrin surface and
are ecliptic to the N atoms of the porphyrin system.
P and Q are the first examples of porphyrin complexes
that exhibit structural elements of the Griffith configuration
G of the dioxygenylironsystem. The complexes can be formally
regarded as mono- or bis(dioxygen) adducts of Ti(0EP) or
Mo(TTP), but these derivatives of Ti" and Mo" are as yet
unknown, and O2 cannot be detached from P and Q. It
is strange though that P and Q have come to light just now
as more and more arguments are being found against the
presence of G in [Hb.02].
According to the IR spectra, the lanthanoid porphyrins
such as Yb(meso-DME)(acac)mentioned in Section 6.2 also
possess bidentate pentanedionate ligands and therefore exist
in a cis configuration D, like the scandium porphyrins whose
discovery prompted the synthesis of the lanthanoid derivative~[~''.
This is understandable in view of their large ionic
radii; even heptacoordinated species like Yb(meso-DME)(acac)HzO must be considered. However, a cis configuration of
the axial ligands lead to the formation of a metalloglobin
with a rather unnatural conformation in reconstitution experiments with apoglobins, even if the proximal histidine adds
on to the lanthanoid ion at all.
Q
Initial IR-spectroscopic work['. 93, 941, followed by X-ray
structure analysis (Fig. 6)[951,
has demonstrated on bis(acetat0)zirconium(1v)porphyrinand bis(acetato)hafnium(1v)porphyrin
of formula M(OEP)(OAC)~
(M =Zr, Hf) that porphyrin complexes with a metal ion can also have a coordination number
higher than 6 (in this case 8). This high coordination number
had already been established by Lux and H ~ p p e [for
~ ~sand]
wich-type phthalocyanine derivatives such as U(Pc),, and it
is also typical of hafnium and thorium porphyrins such as
Hf(0EP)(aca~)~[~']
and Th(TPP)(aca~)&~~l.
Prompted by this
work, other authors demonstrated the coordination number
7, again with cis-axial ligands, in the case of two niobium@)
porphyrins, namely the complexes N~(TPP)O(OAC)[~~'
and
Nbz03(TPP)z194*99.1001.
It seems that this unusual geometry
can exist only in the presence of a transition metal ion of
the acceptor class A ("hard acid", early transition metal) and
a bidentate chelate ligand L-L, for which acetate and 1,3diphenyl-1,3-propanedionatehave been used besides 2,4-pentanedionate.
7.2. An Increased Variety of Axial Ligands in the Case of
Osmium Porphyrins
Up to 1971 all the known methods of metal insertion failed
to introduce osmium into the porphyrin system. Finally Rohbock succeeded in synthesizing the carbonylosmium(1r) porphyrin Os(OEP)CO(Py) ( 7 d ) [ 1 0 5 1by the dropwise addition
Fig. 6. Results of crystal structure analysis of an octacoordinate hafnium(1V)
porphyrin Hf(OEP)(OAc)2 [95]. Two of the pyrrole nitrogens are hidden
under the two carboxyl carbons of the acetate groups; the four nitrogens of
the porphyrin ligands and the four oxygens of the acetate ions form a
distorted square antiprism. The Hf" ion lies lOOprn above the porphyrin
plane.
If the "bite" is reduced, i.e. if the distance between the
L atoms in the chelate Ligand L-L is decreased, then not
only relatively large ions like Sc"', Zr'", and Nb" but also
smaller ones like Ti'" and Mo"' can enlarge their coordination
sphere in the porphyrin system. According to Fournari['oll
and Weiss['021,peroxide groups with a bidentate linkage can
smoothly replace double-bonded oxygen in these complexesOf hydrogen
in many OXo complexes-by the
as
peroxide, e. g. in reaction (n).
418
7d)
(7s)
(7hJ
1
1
4
1
#
N4&N=0
0
'
!
Me+o&~e
-.,
1
L-0p-L
I
'
I
I
I
(71)
(7m)
(7il
(7 ii
Fig. 7. Schematic representation of the essential chemistry of osmium porphyrins [Os(OEP) ( 7 ) ; for ( 7 d ) , ( 7 f ) - ( 7 j ) also with Os(TTP) ( 6 j ) l .
Angew. Chem. Int. E d . Engl. 1 7 , 4 0 7 4 2 3 ( 1 978)
of a cold solution of osmium tetroxide in diethylene glycol
monomethyl ether to a solution of octaethylporphyrin in the
same solvent, kept at about 200°C. The C O ligand was formed
by oxidation and decarbonylation of the primary hydroxy
groups of the solvent; pyridine was added at the crystallization
stage. Figure 7 shows the essential chemistry of osmium porphyrins, based on ( 7 d ) . The fundamental differences from
the chemistry of iron porphyrins (Fig. 5 ) are as follows:
1) Osmium can have more oxidation states (+2, + 3, + 4,
and +6) than iron ( + 2 and +3) in compounds stable in
air.
Os(OEP)CO-Py
(7d)
CH3C0,H/H20
CH,CI,/MeOH
+ THF
(4)
(7Y)
L= I-Melm, Py, MeCN, PR3
trans-Dioxoosmium(v1)porphyrin (7f)[’06], which can be
prepared from ( 7 d ) with peracetic acid in dichloromethane/
methanol/HzO as shown in reaction (o),was the first example
of the highest oxidation state of a metal that can be achieved
in a porphyrin; (7f) is an important starting material for
further reactions (Fig. 7).
2) The adducts of 0s” porphyrins formed with small nacceptor molecules are much more stable than those of the
Fe” analogs. This can be explained by the stronger n-donor
character of the 0 s ” ion and the consequently reinforced
metal-ligand back-donation, because its occupied 5d orbitals
extend further out and penetrate through the x* molecular
orbitals of the ligands better than do those of the Fe“ ion.
As a result, the carbonylosmiumporphyrin ( 7 d ) , for example,
is so stable that it can be vaporized at about 200°C in the
high vacuum of a mass spectrometer, and the molecular ion
can be detected[1051.The replacement of Fe” by 0s“ in hemoglobin is therefore pointless, because the “osmoglobin” would
absorb even traces of carbon monoxide, and would gradually
become irreversibly poisoned.
3. Owing to the stronger “penetration” of the d orbitals
into the x* level of the porphyrin ligand on the one hand
and of the axial ligands on the other, the spectroscopic effects
(cis and trans effects[39b,
57]) accompanying the changes in
the axial ligands are much more pronounced with 0 s “ porphyrins than with Fe” porphyrins, where they are just outside
the accuracy of the measurements. In this connection, 0 s ”
porphyrins permit a much more accurate study of the electronic interaction^^'^^], the results of which can be applied to Fe”
porphyrins.
The strong d, donor action of the 0s” ion e. g. in Os(0EP)CO(THF)[’051is also manifested in the very low frequency
of the CO stretching vibrations, namely vcoz 1900cm-’.
According to Chatt’s rule, in the case of such low values
one can expect the existence of dinitrogen derivatives that
are isosteric with the CO complexes and in which the Nz
molecule is accordingly bonded end-on[1081. Smith indeed
obtained the first isolable dinitrogen complex of a metal porphyrin by reducing the dioxoosmium(v1)complex (7f) with
hydrazine hydrate in THF as shown in reaction (p). The
resulting Os(OEP)Nz(THF) ( 7 9 ) can be kept in the solid
state in air for a few days, but undergoes rapid autoxidation
in solution, re-forming the 0s”’ porphyrin (7f); in methanol,
Angew. Chem. Int. Ed. Engl. 17,407-423 (1978)
’’
Os(OEP)Nz(THF)+ 2 L -+ Os(0EP)Lz + N2
OsOl(OEP)
(7f)
Os(OEP)02 + N2H4+ THF + Os(OEP)Nz(THF)+ 2Hz0
(7f)
f 79)
the autoxidation stops at the tetravalent osmium stage, with
the formation of the bismethoxide Os(OEP)(OMe)2(7j)[Io9’.
This again shows the labilizing effect of the porphyrin system
on the axial ligands, discussed in Section 5. The dinitrogenpentaamminoosmium(1i)cation [Os(NH3),N,]* +,which has been
known for a long time, is much more stable not only in
the salt-like solid state but also in solution“ ‘O1. Accordingly,
the displacement of the coordinated Nz molecule, so far the
only reaction of ( 7 g ) , could be used for preparative purposes
as shown in reaction (q)[’O9, ‘1.
(PI
This gave “osmochromes” such as Os(0EP)Pyz ( 7 h ) , which
are analogous with the hemochromes (5a) and are otherwise
difficult to obtain. Like the hemochromes, these can be oxidized electrochemically into cationic complexes-“osmichromesalts”, such as [Os(OEP)Pyz]PF6 (7i)l1111. In comparison with the hemochrome/hemichrome system, however, the
osmochrome/osmichrome system is much more resistant to
substitution of the axial ligands and can therefore be characterized better. As in the case of iron porphyrins, this gives an
opportunity to increase our knowledge of the mode of action
of cytochrorne~[~
71.
Two further dinitrogen complexes, Os(OEP)N,(DMF)
( 7 k ) [ l 1 l I and Os(TTP)N,(THF) ( 6 k ) [ ’ ” ] , have recently been
isolated. The order of the frequencies of the NN stretching
vibrations [vNN=2035cm-’ ( 7 k ) < 2042cm-’ ( 7 9 ) <
2050cm-’ ( 6 k ) l shows that, as a donor ligand in the trans
position, dimethylformamide increases the 0s-N back-donation, probably because of its n-donor action, which is more
pronounced than that of THF[57*771
(trans effect), while the
tetra(p-toly1)porphyrin ligand in ( 6 k ) decreases the O s N
back-donation (cis effect) owing to its n-acceptor capacity,
which is greater than that of the octaethylporphyrin system.
A strong trans effect has also been found in the case of
the nitrosyl complexes (71) and (7m)[’071.While the dinitrosyl
complex Os(OEP)(NO), (71), which can be prepared from
the carbonyl derivative ( 7 d ) in an aprotic medium. decomposes with evolution of N O when heated to above lOO”C, the
nitrosylmethoxo derivative Os(OEP)NO(OMe) (7m ), which
is obtained by reacting (71) with methanol, can be vaporized
without decomposition in the high vacuum of a mass spectrometer, giving a molecule-ion. The dinitrosyl complex (7 I)
can be chromatographed and crystallized at room temperature,
unlike its iron analog ( 5 j ) (Fig. 5), which has been detected
onlyat - 196°C; this shows again how much the replacement
of Fe” by 0s“ stabilizes adducts formed between small molecules and the metal porphyrin system. The diamagnetism
and the IR spectrum of (71) point to a rare trans arrangement
of both NO species, caused by the porphyrin system.
Another cis effect exerted on the visible spectrum embodies
the “rule of bathochromism” (see below), which serves to
identify the adducts of small molecules to metal porphyrins
and can be worked out particularly well in the case of the
osmium porphyrins, because of the particularly pronounced
effects in their
On going from hemochromes to car419
bonylhemochromes [sequence ( 5 a ) + ( 5 b ) -+ ( 5 g ) , Fig.
51, there is a 10-14 nm bathochromic shift in the absorption
maximum with the longest wavelength ("a b a n d , Fig. 3).
In contrast, the corresponding shift is by 30-33nm in the
carbonylosmium porphyrins ( 7 d ) and osmochromes (7h)i5'1.
The greater is the n-acceptor capacity of the axial ligand,
the greater is this shift. Accordingly, there is a bathochromic
shift of the a-band in the series Os(OEP)Pyz ( 7 h ) , 510nm
< Os(OEP)N2(THF) ( 7 g ) , 523 nm < Os(OEP)CO(Py) ( 7 d ) ,
540 nm < Os(OEP)NO(OMe) ( 7 m ) , 567 nm, corresponding
to the series Py < N2 < CO < NO+ along which the
rc-acceptor strength
If this rule is applied to
thea bandsofhemoglobins [Hb] (555nm), [Hb.CO] (569nm),
CHb.021 (577nm, Fig. 3), and [Hb.NO] (575nm), we find
that the electron delocalization to the rc-acceptor ligands is
found to be about the same for NO and O2 and in either
case greater than with CO. This rule also holds for cobalt(tr)p~rphyrins[~
71.Goutemzan has provided the theoretical basis
of this rule by molecular-orbital calculations by the iterative
extended Huckel method" 'I.
The replacement of iron by osmium in hemoglobin to prepare an "osrnoglobin" seems highly problematic and troublesome, because the very drastic reaction conditions used for
the incorporation of osmium cannot be applied with the labile
protoporphyrin system, and besides they lead to the extremely
stable CO complex. However, in principle it is now possible
to prepare an "osmoglobin". The possibility cannot be altogether excluded that it might function as an N2 carrier.
7.3. Ruthenium Porphyrins and Their Comparison with Iron
and Osmium Porphyrins
Ruthenium porphyrins were first synthesized by
Fleischeri"4] in 1969and were then further investigated mainly
by
Ho1m[55c1,andWhitten["5s'161.However,
their axial-ligand chemistry is underdeveloped in comparison
with iron and osmium porphyrins[?. Only the carbonyl complexes e. g. Ru(TPP)CO(Py)(6Z)[" 1' , the ruthenochromes, e.g.
Ru(OEP)Py, (7n)[' 3 , l8], and the nitrosylmethoxide
complex Ru(OEP)NO(OMe) (7p), which also obey the "rule
of bathochromism"[" 'I, have been properly characterized.
The bathochromic shifts of the CI bands in the series
Ru(OEP)Py, (7n), 521 nm < Ru(OEP)CO(Py) ( 7 c ) , 549nm
< Ru(OEP)NO(OMe) (7p), 572x1111 lie between the corresponding values for the compounds of the Fe" and 0s" series.
The CO frequencies decrease from Fe(OEP)CO(Py) (7 b),
1967cm-' through Ru(OEP)CO(Py) ( 7 c ) , 1925cm-' to
Os(OEP)CO(Py) ( 7 d ) , 1902cm-'. Both results show that the
back-donation ability of the central metal ion and thus also
the bond strength for small n-acceptor molecules increase
along the series: Fe" < Ru" < 0s".
As regards their redox behavior, however, ruthenium porphyrins occupy a surprising position: the half-wave potentials
of themetal(tt/tIr)state, determined by cyclic voltammetry with
respect to a calomel electrode, rise in the series 0s" < Fe"
< Ru", i. e. Os(OEP)Py, ( 7 h ) -0.37 V['''], Fe(OEP)Py, ( 7 q )
- 0.15 Vi5', 1191, Ru(OEP)Py, ( 7 n ) - 0.02 V[579' '* '"1. This
effect, which is also exhibited by the carbonyl derivatives,
agrees with theoretical results based on molecular-orbital calculations" l 31.
'
'
420
The relatively high Ru"/Ru"' redox potentials mean that
Ru" porphyrins have a correspondingly weaker driving force
for autoxidation, and they should therefore be interesting
candidates for reversible oxygenation (see the closing remarks
in Section 4). Indeed, recent results indicate that a labile
bis(acetonitrile)ruthenochrome, Ru(OEP)(M~CN)~
( 7 r ) , is
capable of undergoing reversible oxygenation even at room
temperature['Z01!However, the dioxygen adduct of ( 7 r ) , postulated only on the basis of spectrophotometric and presumably also gas-volumetric findings, does not obey the "rule of
bathochromism": its a band shows an appreciable hypsochromic shift with respect to that of the carbonyl complex. This
does not mean that this adduct does not exist, but it conflicts
with a monodentate bent bonding state of its Ru02 unit
according to Pauling's model E. It is possible that we are
faced here with a peroxoruthenium(1v)system of configuration
G, which according to the results given in Section 7.1 for
metal porphyrins can no longer be disregarded and which,
according to Vuska[7'lis to be expected anyway for ruthenium,
together with the ability of liberating02again at room temperature. The product of autoxidation of ( 7 r ) , which is slower
than oxygenation, has not yet been identified. Owing to the
more highly negative redox
the kinetically more
stable 0s" analog Os(OEP)(MeCN), (7s) merely undergoes
irreversible autoxidation to OsOz(OEP) (7f)['"l.
The existence of nitrogen-carrying ruthenium porphyrins' ' ", l Z 0 l , postulated on the basis of spectrophotometric
findings only, should be viewed with skepticism since such
compounds also do not obey the "rule of bathochromism"
and purportedly exist as trans ligands in the presence of pyridine or other N-donors. (The latter also applies in the case
of the previously discussed, but still unknown Fe(protoDME)N2(Py)['2'1.) Since even dinitrogenosmium(i1) porphyrins are cleaved by any other N-donorr'09s112~'13~,
such
behavior would be all the more likely in the case of the
more labile Fe" and Ru" analogs which must therefore be
regarded-on the basis of experimental evidence thus far-as
doubtful species.
On the whole, what has been said about an osmoglobin
(Section 7.2) applies also to ruthenoglobin.
8. Variation IV: Iron Porphodimethenes
The final variation to be presented is the porphodimethene
system, a further, not only sterically but also electronically
modified porphinoid ligand system akin to an a,y-dihydroporphyrin. The synthesis of the configuratively important carbonyl(ol,y-dimethyloctaethylporphodimethenato)pyridineosrnium(11) (16a)['221might serve as example for the synthesis
of such complexes (see Table 5 ) by Puppe's reductive rnethylaaccording to reaction (r).
tion of porphin
Os(OEP)CO(Py)
(7d)
I . 2ee
3Os(OEPMe2)CO(Py)
(16a)
On the basis of crystal structure analysis,by Scheidt, the molecule ( 1 6 a ) carries the two newly introduced methyl groups
in a syn-axial position to the carbonyl group, like a chimney
on the tetrapyrrole system, which is folded like a roof, with
Angew. Chem. Int. E d . Engl. 1 7 , 4 0 7 4 2 3 (1978)
the pyridine molecule suspended under the ridge of the roof
(Fig. 8). Like the further structure analyses of nickel(l1)- and
titanylporphodimethenes[ 241, this picture immediately
prompts one to try-as is being done now by Lay-to introduce bulky substituents somehow at the iron center in place
of the methyl groups, in order to obtain myoglobin models
of the type described in Section 6.
116)
Table 5. Examples of porphodimethenes M(OEPR2)LL‘(16).
M
R
L
L
[a] p-0x0 complex of type ( S e ) .
Gz@
3) Thedecreased aromaticity lowers the 7c-acceptor capacity
of the porphinoid ligands and may thus make the oxygen
uptake irreversible”261by lowering the redox potential at
the porphodimethene-hemochrome [{I 6 b), -0.30 V with respect to a calomel electrode“ g]].
However, with the isolation of the di-tert-butylporphodimethene complex (1 6 c), the first mononuclear hydroxoiron(1ri) complex with a porphinoid ligand system has been
prepared in substance. The constitution of this complex has
been ascertained by chemical analysis, IR spectrum
(voH=3661cm-I), magnetic measurements (leff=5.7 B.M.),
ESR spectrum (gi = 5.83), and the Mossbauer spectrum[1271.
In the porphodimethene complex (16c) condensation with
the iron hydroxide group into a binuclear complex occurring
in the step ( S f ) + (5e) (Fig. 5 ) is inhibited on both sides:
at the top by the bulky tert-butyl groups, and at the bottom
by the roof-like folding of the ligand surface, which does
not even allow the formation of a greatly over-extended FeO - F e bridge.
On the other hand, (1 6d), a p-0x0 complex of cr,y-dimethylporphodimethene corresponding to type (5e), is easy to preparer’251.IR spectra and magnetic measurements[51b1indicate
that axial methyl groups impair its Fe-O-Fe bridge, but
this is not sufficient to prevent condensation.
Owing to its similarity to [Mb.OH] [cf. (4e)], the hydroxide ( I 6 c) can be regarded as a “partial metmyoglobin model”,
partial because there is no proximal histidine trans to the
OH group. An accurate analysis of the physical properties
of (16c) might be useful in the continuing investigation of
the physics of metmyoglobin[’9‘1.
’
This review was written while the author held a visiting
professorship at Munich Technical University in the summers
qf I976 and 1977. 7hemanuscript was read critically by Professor
Fuhrhop and Professor Gersonde. His own work, summarized in
Section 7 and 8, was made possible by effective contributionsfrom
the colleagues mentioned in the text and the literature, by
generous financial support from the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie, and by
thefact that Professor Inhoffen and Professor Pommer (BASF)
generouslysupplieda large sample of the expensiveoctaethylporphyrin. The author wishes to express his gratitude here to
all these research workers and institutions.
Fig. 8. Results of crystal structure analysis of a metal porphodimethene
complex Os(OEPMez)CO(Py)( 1 6 a ) [d(Os-C)= 183, d(C-0)= 115, d(0sN,)=223, d(Os-N,,,)=207pm].
However, it is very difficult to investigate the iron porphodimethenes, for two reasons:
1) Reductive ring alkylation does not work with Fe” porphyrins, so that the iron porphodimethenes must be synthesized in a different, complicated way, which is of no interest
to us here[’251.
2) The double interruption of the porphyrin chromophore
leads to much less informative visible spectra, which sometimes
exhibit only a broad band at about 460nm (this band is
reponsible for the orange color of the porphodimethenes).
For this reason, the complexing reactions corresponding to
those shown in Figure 5 cannot be monitored spectrophotometrically as in the case of Figure 3.
Angew. Chem. Int. Ed. Engl. 17,407-423 ( 1 9 7 8 )
Received: June 16, 1977 [A 216 IE]
Supplemented: March 13, 1978
German version: Angew. Chem. 90,425 (1978)
[I] H . Fischer, H.Orth: Die Chemie des Pyrrols. Vol: 11, Part I. Akadem.
Verlagsgesellschaft, Leipzig 1937.
[2] J . E. Falk: Porphyrins and Metalloporphyrins. Elsevier, Amsterdam
1964.
[3] K. M . Smith: Porphyrins and Metalloporphyrins (new edition of [2]).
Elsevier, Amsterdam 1975.
[4] D. Dolphin: The Porphyrins. Academic Press, in press.
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423
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