Synthetic Oxygen Carriers Related to Biological Systems
ROBERT D. JONES, DAVID A. SUMMERVILLE, and FRED BASOLO"
Department of Chemistry, North western University, E vanston, lllinois 6020 1
Received September 29, 1978
Confenfs early part of 1978, no attempt has been made to totally cover all aspects of the problem. Rather we have tried to approach the I. Introduction 139 subject in such a way as to complement the other reviews al- II. Nomenclature 139 ready available.2-18Specifically we have largely restricted our 111. Nature of 02 139 attention to the synthetic approaches that have been made to IV. Nature of Bound Dioxygen 140 observe metastable metal-dioxygen complexes of biological V. Natural Oxygen Carriers 143 importance. A. Heme-Containing Proteins, Hb and Mb 143 B. Hemerythrin 146 /I. Nomenclafure C. Hemocyanin 146 VI. Synthetic 02 Carriers 147 The terminology used in this review, referring to oxygen in its A. Porphyrins 147 various forms, is similar to that used by Vaskai5 in his recent B. Schiff Bases 148 review. The term molecular oxygen as used here refers only to VII. Cobalt-Dioxygen Carriers 148 the free uncombined O2 molecule. Unless otherwise specified, A. Early Work 148 it will be used to mean the ground (32g-)state of the molecule. 6. Recent Studies on Cobalt-Dioxygen Complexes The term dioxygen has been used as a generic designation for in Nonaqueous Solutions 149 the O2 moiety in any of its several forms, and can refer to 02 in C. Cobalt-Dioxygen Complexes in either a free or combined state. The only criterion for use of this Aqueous Solution 160 term is the presence of a covalent bond between the oxygen D. Solid-state Structures 164 atoms. Thus a metal-dioxygen complex refers to a metal con- VIII. Iron-Dioxygen Carriers 166 taining the O2 group ligated to the metal center. In using this term, IX. Manganese-Dioxygen Carriers 172 no distinction is made between neutral dioxygen or dioxygen in X. Dioxygen Carriers of Other Metals 174 any of its reduced forms. A metal-superoxide or metal-peroxide XI. Addendum 174 complex is one in which the coordindated dioxygen resembles XII. Abbreviations 174 a superoxide (02-)or peroxide (OZ2-) anion, respectively. The XIII. References 175 incorporation of 02 into a metal complex to form a metal- dioxygen compound is called oxygenation (eq 1). Deoxygenation 1. lnfroducfion is the reverse of this process. Certain metal complexes provide the delicate balance re- quired to form adducts with dioxygen without the metal (M) or 111. Nature of O2 the ligands (L) being irreversibly oxidized. Such systems, known Molecular oxygen is a paramagnetic molecule, having a triplet, as oxygen carriers, are biologically utilized in the transport and 32g-ground state. The two lowest lying electronic excited states storage of molecular oxygen. The equation for adduct formation are the singlet state, 'A, and 'A,+, lying 22.53 and 37.51 (eq 1) is written as an equilibrium process. To be classified as kcal/mol above the ground state, respectively. A molecular an oxygen carrier, it is necessary that the reverse reaction, Le., orbital description of the ground state, 32,- level is the dissociation of the dioxygen complex to give M(L) and 02, be observable. In practice this process can be observed by O~KK(~SU,)~(2~0, *)2(2p~g)2( ~PT,)~(~PT, ) '( ~PT, )' lowering the partial pressure of 02,by heating the complex, or where the KK term indicates that the shells of the two oxygen by the addition of a ligand capable of replacing the bound 02. K atoms are filled. The two unpaired electrons in the 32,- ground nM(L) i-02 + [M(L)1"(02) (1) state are found in the two degenerate antibonding 2prg" orbitals (Figure I), leaving O2 with a formal bond order of two. The n=lor2 electronic configurations for O2 in its three lowest lying states The study of compounds capable of reversibly binding mo- is shown in Figure 2. lecular oxygen has received a great deal of attention for several The MO description for molecular oxygen shows a vacancy years. Several of these compounds, like the Vaskal complex, for the addition of a single electron in both of the antibonding Ir(PPh3)2(CO)(CI),involve the addition of O2to group 8 metals. 2p~,* orbitals. The addition of one or two electrons to a neutral Although the chemistry of these compounds embraces a fas- dioxygen molecule results in formation of the superoxide (Oz-) cinating and worthwhile area of investigation, this review is and peroxide (OZ2-) anions, respectively, leaving superoxide limited to a discussion of those synthetic dioxygen complexes with a bond oraer of 1.5, and the peroxide 0-0 link with a rormal that are of specific interest as models of natural oxygen carriers. bond order of one. Consistent with this assignment of bond or- Per force, this review deals largely, but not exclusively, with ders, both the 0-0 bond lengths and 0-0 bond energies fall in complexes containing the elements iron, cobalt, and manga- the order O2 > 02- > 022-.Some of the salient physical data nese. for 02,both in its neutral and ionic forms, are summarized in In writing this paper, which reviews the literature through the Table I.
0009-266517910779-0139$05.0010 @ 1979 American Chemical Society 139 140 Chemical Reviews, 1979. Vol. 79, No. 2 Jones, Summervllle, and Basolo
I .o
0
2PUq v1 -c >0
2s 2s -1.0 *2sup
0 02 0
Figure 1. The molecular orbital energy-level description for 02.
- 2.0
[OO]+ [om]
-2 -I 0 Cool- [oo] Oxidation Number Figure 3. Frost diagram for the reduction of O2 to H202. [DO]- [@a] TABLE 1. Some Properties of the Dioxygen Moiety
0-0 bond bond distance, energy, VO-0, [oo] order compde A kcal/mol cm-I 02+ 2.5 OnAsFs 1.123’ 149.4’ 1858‘ 02 2 02 1.207* 117.2 15154.7~
[@@I + [oo ] oz(’4 2 02 1.216e 94.7‘ 1483.58 02- 1.5 KO2 1.28 1145h 022- 1 NazO2 1.49 48.8 842)
L J. C. Abrahams, Q. Rev., Chem. Soc., 10,407 (1956). Reference 23. J. Shamir, J. Beneboym, and H.Classen, J. Am. Chem. Soc., 90,6223 Figure 2. The electronic configurations for the unpaired electrons in H. the 2rg orbitals of O2 in its three lowest lying states. The lower con- (1968). Reference 23. M. Kasha and A. U. Khan, Ann. N. Y. Acad. Sci., figuration represents O2 in its 38g-state, the middle ’Ag, and the upper 171, 5 (1970). ‘Calculated from the data in footnote d. 8 L. Herzberg and the 8,+ state. G. Herzberg, Astrophys. J., 105, 353 (1947). J. A. Creighton and E. R. Lippencott, J. Chem. My$.,40, 1779 (1964). S. N. Fonw and R. L. Hudson, J. Chem. Phys., 36, 2676 (1962). I J. C. Evans, J. Chem. SOC. 0,682 The primary fate of molecular oxygen in the higher biological ( 1969). organisms is its reduction to form water. This process, which occurs with the overall transfer of four electrons (eq 2), be attributed to the rather small difference in bond energies O2 + 4H+ + 46 4H20 between HOZ-and H202 to = 1.23 V, AGO = -113.5 k~al/mol~~ (2) HOP. + H+ + e F+ H202 to = 1.68 V22 (4) is highly exothermic, both under standard conditions ([Hf] = compared with the energetically favorable formation of the 0-H 1.0 M) and at biological concentrations of H+ (pH 7.4,20 t = 0.79 bond, as can be seen by a comparison of the 0-0 bond energies V, AG = -72.9 kcal/mol), making molecular oxygen a powerful (kcal/mol): oxidizing agent. O2Z3 117.2 The reduction of 02to H20proceeds, in general, via a series of one- or two-electron transfer processes. The monodynamic H02.22 55.5 nature of these processes can be seen by examining a Frost H202“ 34.3 diagramz1(Figure 3) for the 02to H20reduction in acidic media. IV. Nature of Bound Dioxygen From this diagram it can be seen that although the overall re- duction is highly exothermic, the one-electron reduction pro- In 1936, Pauling and C0ryeI1*~published their now classic cess paper on the magnetic propertiesof oxyhemoglobin. In this paper they noted that “the oxygen molecule undergoes a profound H+ e + HOz- EO = -0.32 VZ2 Oz+ + (3) change in electronic structure on combination with hemoglobin”. is quite endothermic, owing primarily to the large reduction in Since that time, the manner in which dioxygen is bound in metal 0-0 bond strength on going from O2to H02. The highly favorable complexes has proven a matter of considerable interest and reduction of the hydroperoxyl radical (H02.) to H202(eq 4) can controversy. Synthetic Oxygen Carriers In Biological Systems Chemical Reviews, 1979, Vol. 79, No. 2 141
TABLE II. Properties of Some Metal-Dloxygen Complexesa
type of complex M:O structure example YO-0,cm-l
0 superoxide-like 1:l o.H Co(bzacenXpyXO2) 1128b Fe(TpivPPXI-MelmXO2) 115SC la MI Cr(TPPMpyXO2) 1 142d range 1130-1 195 Ib ,Oh / M [C02(NH3)10(02)1~+ 1122' MO [C~Z(CN)IO(~Z)~~- 1 104e range 1075-1122 peroxide-like Ila 1:l -0 Ir(COXPPhM302) 875 Ti(OEPXO2) 8980 v [Co2(CN)4(PMe2Ph)stO2)1 881 range 800-932 Ilb 2: 1 M [Co(NHdro(O2)l+ 808' M/o'o/ [CO~(CN)~O(~Z)~~- ... range 790-884 ionic dioxygen complexes K'02- 11451 2Na+, 022- 842 a The values UO-0are for the compounds listed and values for the range of VO-0were taken in part from the values given in Table Ill in ref 15. In addition, the classification scheme used is identical with that given by Vaska. Reference 35. Reference 145. K. by,Z. Anorg. Allg. Chem., 388, 209 (1970). e Reference 257. Reference 1. g Reference 396. J. Halpern, B. L. Goodall, G. P. Khare, H. S. Lim, and J. U. Pluth, J. Am. Chem. Soc., 97,2301 ff (1975). ' Reference 225. 1 J. L. Hoard in "Structural Chemistry and Molecular Biology", A. Rich and N. Davidson, Eds., Freeman and Co., San Francisco, 1968, p 573. F. J. Blunt, P. J. Hendra, and J. R. Machkenzie, J. Chem. SOC.,Chem. Commun., 278 (1969).
This problem arises because the ligation of dioxygen to a dioxygen, as assigned from a classical definition of oxidation metal complex differs from the ligation of a simple neutral or states,26and the oxidation state that would be inferred from the anionic species, such as ammonia or the chloride anion, to a 0-0 stretching frequency. The problem of assigning numerical metal center. The addition of molecular oxygen to a metal oxidation states to metal-dioxygen complexes has been dis- complex (eq 1) could involve a formal oxidation of the metal cussed in a recent publication.*' center with a concomitant reduction of the coordinated dioxygen. Although a more complete description of the bonding of This arises from two factors: (1) that adduct formation between dioxygen to specific metal complexes will be covered in the molecular oxygen and metal complexes is only observed for appropriate section, a brief discussion of dioxygen bonding for complexes containing metals in a reduced oxidation state; and the classes of compounds listed in Table II will be presented (2) that there are readily accessible reduced oxidation states for here. the dioxygen species, i.e., 02- and 0z2-, Thus, depending on the stoichiometry of the oxygenation reaction and the nature of 1. Type la the metal, it is possible to envision the transfer of none, one, or two electrons from the metal to the coordinated dioxygen moi- It has long been believed that the bonding of dioxygen in ety. oxyhemoglobin and oxymyoglobin is of type la, and recently A comparison of the 0-0 stretching frequencies, obtained reported values for vo-o (1103 cm-1 for Mb0228and 1107 cm-l from metal-dioxygen complexes (Table II), with those observed for Hbo~*~)as well as single-crystal X-ray structural studies of for the compounds containing ionic superoxide or peroxide model compounds30make this almost a certainty. Synthetic type (Table I),shows that the metal-dioxygen complexes have 0-0 la complexes have been prepared from the reaction of molecular oxygen with metal complexes containing Cr(ll), Fe(ll), and stretching frequencies similar to those obtained from compounds containing ionic superoxide or peroxide, suggesting a substantial Co(ll). In terms of simple valence bond theory, bonding in these transfer of electron density from the metal center to the coor- complexes has been described in two ways. (1) The first ap- dinated dioxygen. That such a transfer of electron density is proach, first proposed by Pa~ling~~.~~to explain the diamag- required becomes apparent if one considers, for example, the netism of Hb02, assumes an even number of electrons about thermodynamics involved in the bonding of 02 to deoxymyo- dioxygen and is represented as a resonance hybrid of the globin. To be consistent with the observed diamagnetism of structures I and II: oxymyoglobin and oxyhem~globin,~~formation of a strictly neutral Fe(ll)-( lo2)bond would have to involve O2 coordinated in a singlet form. Since the lowest lying singlet state of O2 has (5) an energy of 22.53 kcal/mol above the ground state, and since AH for dioxygen bonding to myoblobin has been measured as I II 15 kcal/m01,~~this would require an unrealistic value for the -- It should be noted that, following the conventional method of Fe(II)-(102) bond energy of approximately 38 kcal/mol. Thus the coordination of dioxygen to a metal center involves some assigning oxidation states, the canonical forms I and II have electron delocalization from the metal to the dioxygen and, on valencies corresponding to Ml1(O2)and MlV(OZ2-)respectively. the basis of collective experimental evidence, the coordinated (2) The second approach, proposed by we is^^^ for the bonding dioxygen can be viewed as resembling either a coordinated of O2 in Hb02, assumes an odd number of electrons on the superoxide or peroxide anion. cdordinated dioxygen and is represented by the structures 111 and Before continuing further, we hasten to inject a word of cau- IV. For either of these two structures, the metal is in a +I11 oxi- dation state with the coordinated 02being formally 02-.For this tion. Although there exists a delocalization of electron density from the metal onto the dioxygen, and although it is often both useful and convenient to view the coordinated dioxygen as being either superoxo-like or peroxo-like, there may not be 1:l cor- respondence between the formal valency of the coordinated 111 IV 142 Chemical Reviews, 1979, Vol. 79, No. 2 Jones, Summervllle, and Basolo
is properly represented as Coii1(O2-). These experimental results agree with recent molecular orbital calculation^^^ that have been carried out on some cobalt Schiff base dioxygen complexes. These calculations show (1) bonding between Co and 02arises primarily from the overlap of a dioxygen KO** orbital with the dZz orbital of cobalt; (2) there is negligible Co-O2 r-overlap; and (3) the unpaired electron resides in the ro2*orbital. Unfortunately, the situation is not as clear for chromium- and iron-02 complexes. Experimental evidence has been collected on iron-dioxygen systems that has been interpreted in terms of an iron-dioxygen bond in which there appears to be a transfer of an electron from the Fe(ll) center to the dioxygen to form an Fe-O2 bond that can be approximated by the FeiIi(O2-) formal- ism. This evidence includes (1) the infrared stretching frequen- cies of the coordinated dio~ygen;~~.~~(2) the similarity between the optical spectra of oxyhemoglobin and alkaline methemo- gl~bin;~~,~~(3) the position of certain peaks in the resonance Raman spectrum of oxyhemoglobin that are characteristic of an iron(ll1) heme;39(4) the large quadrupole splittings observed in the 57FeMdssbauer resonance spectrum of oxyhem~globin;~~ (5)the tendency of certain tetraphenylporphyrinatoiron(l1)model systems to undergo oxygenation only in polar solvent^;^' (6) the \I release of free superoxide (02-)from the interaction of oxy- L,Fe(ll) 02 hemoglobin with certain anions (e.g., N3-);42 and (7) the recent measurements of the magnetic susceptibility of oxyhemoglobin (a ) (b) that have discovered a residual paramagnetism at low temper- Figure 4. A qualitative MO scheme for the bonding in iron-dioxygen ature indicative of a singlet-triplet eq~ilibrium.~~ complexes, showing both u and K interactions between iron and Despite the apparent strength of the evidence in favor of coordinated 02.This scheme is analogous to the Fe11(02)-Fe1V(022-) valance bond resonance hybrid when A > pairing energy. describing the system as a superoxide adduct, in which an un- paired electron resides on both the iron(ll1) and coordinated su- bonding model, the unpaired spins on Fe(lll) and 02- are repu- peroxide moieties, several worker~~~,~~have recently pointed tedly coupled, thus allowing for the observed diamagnetism of out that most of the experimental data can also be explained in the Fe02 system. terms of bonding models in which the electrons are totally paired. Other bonding approaches are, of course, possible. For ex- This interpretation, which is based on theoretical calculations, ample, Figure 4 shows a simplified molecular orbital scheme accounts for the experimental results in terms of a delocalization for the Fe-02 bond. From this scheme, two possible ground-state of paired electron density from the iron to the coordinated electronic configurations are possible: when the energy sepa- dioxygen and suggests a bonding scheme which is thus similar ration, A, is greater than the electron-pairing energy, the spin- to, but not identical with, the Fe(ll) - Fe(lV) formalism proposed paired electronic configuration (a)2(yz)2(d,)2(d,)2 which is by Pauling. The only data that are not consistent with this de- equivalent to the FeIi(O2)- FeiV(022-)resonance pair suggested scription, and which provide ineluctable evidence for an by Pauling, is obtained, whereas for A smaller than the pairing Feii1(02-)formalism, are the magnetic susceptibility measure- energy, the electronic configuration (u)2(yz)2dx,)2(dyr)1(r*I1, ments on oxyhemoglobin of Cerdonio et al.43 These workers having two unpaired electrons, is obtained. This configuration have observed a temperaturedependentmagnetic susceptibility can be considered similar to, but not equivalent to, the FeIii(O2-) between 25 and 250 K indicative of two antiferromagnetically valence bond pair 111 and IV.33 coupled S = '/2 systems having a singlet-triplet energy sepa- Although further, and more s~phisticated,~~~bonding treat- ration of 12J) = 146 cm-l. This work has, however, been ments can be proposed, and indeed may be required for the challenged recently by Pa~ling~~who feels that the magnetic fullest understanding of a la M-O2 linkage, the fundamental susceptibility measured by Cerdonio et al. may have arisen owing question of whether or not the ground-state electronic config- to experimental artifacts. At the moment the matter awaits fur- uration contains an unpaired electron located on the coordinated ther investigation. dioxygen moiety still persists. As we will discuss below, whereas The addition of O2 to low-spin, d4 Cr(ll) porphyrin complexes47 this question has been answered for the cobalt case, the nature of the type CrIl(Por)(B), where B represents a donor ligand such of the iron and chromium dioxygen bond remains in question. as pyridine, represents another example of type la complexes In contrast to the Fe-02 and Cr-O2 cases, the bonding picture (0-0stretching frequency for Cr(TPP)(py)(Op)is found at 1142 for dioxygen adducts of Co(ll) complexes is relative clear. cm-l). The resulting dioxygen complexes, which have been Oxygen has been observed to form la dioxygen adducts with a shown to have two unpaired electrons, can be treated in a large number of Co(ll) complexes, with the most common ex- manner similar to that given for the dioxygen adducts with Fe(ll). amples being the five-coordinate Schiff base complexes, Thus the dioxygen complexes can be written in terms of either CoIi(SB)(B), where B represents a neutral donor ligand, and a Cr(ll) - Cr(lV) or a Cr(lll) valency depending on whether we porphyrinatocobalt(I1)complexes, Co"(Por)(B). Magnetic sus- have an even or odd-oxygen electronic configurati~n.~~As with ceptibility measurements on the cobalt-dioxygen adducts formed the iron-dioxygen complexes the matter has yet to be re- from these low-spin d7 Co(ll) complexes the presence solved. of only one unpaired electron. On the basis of frozen solution EPR spectra,35 it has been concluded that the majority of the unpaired electron spin density (>80%) resides on the dioxygen. 2. Type /la Further EPR studies36employing 170-labeled O2 have confirmed A large number of type Ila metal complexes have been pre- this conclusion, finding the electrgn spin density on the coordi- pared, and a review of type Ha complexes containing group 8 nated O2 to be close to 100%. On this basis, the unpaired metals is available.E Although complexes of this type arising electron clearly resides on the dioxygen moiety and the complex from the addition of O2to low-valent, coordinately unsaturated Synthetic Oxygen Carrlers In Biological Systems Chemical Reviews, 1979, Vol. 79, No. 2 143 organometallic complexes have recently undergone a great deal complexes, which are not strictly type Ilb complexes since there of investigation, numerous examples of Ila complexes containing is multiple M-(O2)-M bridging and the coordination number of the early transition metals, e.g., CT(O~)~~-,have been recognized oxygen is higher than two, the predominance of synthetic type for many years3 Among the salient differences between this Ilb complexes contain cobalt metal centers. type of bonding and the bonding observed in la complexes are The literature dealing with dimeric (Ilb) cobalt complexes is the coordination geometry, with the dioxygen being bound to the vast and has been reviewed several The earliest metal center in a symmetric, triangular fashion, similar to that known synthetic dioxygen complex is probably [(NH3)5-Co- proposed by Griffith49for the bonding of O2 in oxyhemoglobin, 02-C0(NH3)5] '+, characterized by Werner and Myli~s.~~The and the VO-~values, which are similar to those observed for free dimeric peroxo complex is often more stable than the mono- peroxide ion. meric complex and will generally form unless its formation is The only synthetic oxygen carriers of biological interest in inhibited. This inhibition can be accomplished sterically by having which this type of bonding has been implicated are the porphy- bulky ligands and/or kinetically by the use of low tempera- rinatomanganese-dioxygen complexes, Mn(Por)(02),which arise tures. from the reaction of O2 with Mn"(Por)(B), in noncoordinating The cobalt dimers are readily formed by the addition of oxygen organic solvents at low temperature (see section IX). Although to solutions of the parent cobalt compounds. In the case of some neither the 0-0 stretching frequencies nor single crystal X-ray cobalt-Schiff base complexes, the dimeric species can be structures have been determined for these complexes, the formed in the solid state. These complexes are diamagnetic with bonding of O2 is believed to occur in a Griffith geometry on the the oxygen being viewed as "peroxide like" with a concomitant basis of EPR evidence and the chemical behavior of the com- oxidation of the metal centers to low-spin d6 Co(lll). The parent plexes. cobalt compounds vary from classical Werner-type complexes, There exist four other metalloporphyrin complexes which [Co"(CN)5I3-, to Schiff base, Co"(salen)(py), to cobalt-porphyrin have the dioxygen bond in a symmetrically triangular fashion. complexes, CO~~(PPIXDME)(~~). These are the complexes Ti(MOEP)02,50 T~(TPP)(OZ),~O The X-ray and infrared data on the 0-0 bond lengths and YO-0 Ti(OEP)(02),50,51and Mo(T(~CH~)PP)(O~)~.~~The complexes of Ilb complexes are consistent with the bound dioxygen being are synthesized by the reactions of their corresponding titanyl regarded as "peroxo-like". The 0-0 bond lengths vary between and molybdenyl porphyrin complexes with organic peroxides. 1.31 and 1.49 with the average being 1.44 A. The vo-o span a The titanium-porphyrin complex, Ti(OEP)(02),has in the solid range of 790-844 cm-l with an average value of 810 cm-'. state the two oxygen atoms eclipsing two of the nitrogens of the Recently La Mar53has reported on the existence of a p-peroxo porphyrin moiety with an 0-0 bond length of 1.47 (3) A. In so- iron porphyrin. From NMR and magnetic data La Mar postulates lution there is rapid equilibration between the two eclipsing that the intermediate observed is dimeric with a bridging diox- positions for all three of the titanium-porphyrin-dioxygen ygen. From the magnetic data he believes the best formalism complexes. The complexes all exhibit strong infrared 0-0 is PorFe"'-02-Fe"'Por (where Por is T(mCH3)PP or OEP) with stretches. The values obtained were 898, 895, and 855 cm-l the dioxygen being peroxo-like. for Ti(OEP)(02), Ti(TPP)(Op), and Ti(MOEP)(02),respectively. The molybdenum-porphyrin complex, Mo(T(~CH~)PP)(O~)~,also has V. Natural Oxygen Carriers the dioxygens eclipsing the porphyrin nitrogens, with a bond Biological oxygen carriers are of three main types: the length of 1.399(6) A. The IR spectrum of the complex displays heme-containing proteins such as myoglobin (Mb) and hemo- an intense band at 964 cm-l. globin (Hb); the hemerythrins; and the hemocyanin^.^^ These complexes utilize either iron or copper to bind the dioxygen 3. Type Ib group. A vanadium-containing protein, haemovanadin, capable At the present time the only complexes of type Ib charac- of reversibily binding dioxygen, has been found in the 1.5 to 2 terized are those that contain cobalt. These green complexes N H2S04solution found in the vacuoles of the blood cells of are readily prepared by the one-electron oxidation of the p- certain ascidians (tunicates). It is felt that the protein may be peroxo species. The chemistry of these complexes have been involved in oxygen transport. Little is known, however, about the extensively revie~ed.~,~-~*'~,~~ nature of the vanadium complex. The partial pressure necessary The cobalt complexes are paramagnetic with p GZ 1.6 BM. to oxygenate one-half of the available sites, the PlI2O*, for the Their room-temperature EPR spectra are well-defined isotropic cells has been found to be about 2 Torr.59A summary of some spectra consisting of 15 lines, with Aiso 10 G. This is the ex- of the characteristics of these biological oxygen carriers is given pected spectrum if the two cobalt nuclei were magnetically in Table Ill. equivalent with the majority of the unpaired spin density residing on the dioxygen bridge. Experiments employing A. Heme-Containing Proteins, Hb and Mb 170are consistent with these EPR results. The Ib complexes of cobalt can be looked at as having two Hemoglobin and myoglobin60combine reversibly with diox- low-spin Co(lll) metal centers containing a bridging 02-.Bond ygen in the blood and tissues of numerous vertebrates and in- lengths for these complexes range between 1.24 and 1.35 A, vertebrates by virtue of a heme (iron" porphyrin) prosthetic group. with an average value of 1.31 A. In agreement with these bond The proteins bind one O2 for each ferrous ion. For this class of lengths are the YO-0values of 1075-1 195 cm-', with an average respiratory pigments, the iron(l1) is chelated to the four core ni- of 1125 cm-'. Both values support the formalism of Co(lll)- trogen atoms of the protoporphyrin IX dianion (see Figure 5). The op--co(lll). only exceptions are the oxygen-carrying hemoproteins, the chlorocruorins, found in some species of polychete worms of the phylum Annelida. Rather than having a vinyl group at position 4. Type Ilb 2 on the porphyrin ring, as found for protoporphyrin IX, chloro- The bonding of dioxygen in Ilb complexes is believed to be cruoroporphyrin or Spirographis porphyrin has a formyl group similar to that of the natural systems of hemerythrin and hemo- (Figure 5). cyanin. Bonding of dioxygen in these natural systems involves In the heme proteins of vertebrates the porphyrin is embedded two metal centers with the bound dioxygen being in a reduced in a polypeptide chain having a molecular weight of 16 000 to "peroxide-like'' state with a concomitant 0ne:electron oxidation 18 000. Myoglobins are monomeric, being composed of only of both metal centers. one of these protein chains, while most vertebrate hemoglobins With the exceptions of some rhodium55and molybdenum56 are tetrameric containing four such polypeptide subunits held 144 Chemical Reviews, 1979, Vol. 79, No. 2 Jones, Summervllle, and Basolo
TABLE 111. Properties of Naturally Occurrlng Oxygen Carrlers TABLE IV. O2 Affinities for Monomerlc Hemoproteins
hemoproteins protein source P11202, Torra hem- hemo- Hb Mb erythrin cyanin Hb, a chain human 0.46 Hb, p chain human 0.40 metal Fe Fe Fe cu Mb whale 0.51 oxidation state of I1 II II I horse 0.70, 0.65d . deoxygenated human Mb I, I1 0.65e,‘ form human reconst. 0.72e metakdioxygen ratio 1Fe:102 1 Fe: lo2 2Fe:102 2Cu:102 Aplysia 2.7b magnetic-electronic a At 20 OC and pH 7-7.4, unless otherwise noted. M. Brunori, R. W. properties Noble, E. Antonini, and J. Wyman, J. Biol. Cbem., 241, 5328 (1966). From deoxy hs., S = hs., S = h.s., S = die, S = Table 9.1, ref 60a, p 221. H. Theorell, Biocbem. Z.,268,46 (1934). e A. L 2 2 0 Rossi-Fanelli and E. Antonini, Arch. Biocbem. Biopbys., 77, 478 (1958). OXY diamag- diamag- weft T- diamag- ‘Found at DH 8. netic netic depen- netic dent diamag- netic ground state p1/2200,Torr 2.5a 0.65 4c 4.3d subunit-subunit yes no slight yes interaction major function transport storage storage transport no. of subunits 4 1 8 variable a p1/2 is the partial pressure of O2 in Torr at which 50% of the sites are oxygenated. Data for human Hb, pH 8.0, in 0.15 M phosphate buffer taken from Figure 7 of E. Antonini, J. Wyman, M. Brunori, C. Fronticelli, E. Bucci, and A. Rossi-Fanelli, J. Bid. Cbem., 240, 1096 (1965). For human Mb, pH 8.0: A. Rossi-Fanelli and E. Antonini, Arch. Biocbem. Biopbys., 77, 478 (1958). Taken from data on hemerythrin from spinunculid S. nudus, pH 7.0, 0.15 potassium phosphate buffer: G. Bates, M. Brunori, G. Amiconi, E. Antonini, and J. Wyman, Biocbemisfry, 7,3016 (1968). dAt 20.6 OC, pH 8.2 for hemocyanin from Levantini biefsolima; 2. Er-el, N. Shaklai, and E. Daniel, J. Mol. Bid., 64, 341 (1972).
Figure 6. The structure of the 6 chain of Hb as determined from X-ray data. The helical regions are denoted A to H, beginning from the amino end. The nm-helical region bridging the helical regions are labeled AB, BC, . . . , etc. The heme prosthetic group can be seen lying between \--I the E and F helices. Both the prosthetic group can be seen lying between the E and F helices. Both the proximal (F8) and distal (E7)histidine residues are clearly shown (from ref 61). CH,-COOH In the deoxygenated state the ferrous ion is found to be five- coordinate; four of the coordination sites of the Fe(ll) are satisfied by the porphyrin moiety while the fifth, axial position is occupied by the imidazole group. The remaining axial position is vacant in the deoxygenated protein. In this conformation the iron has R= -CH =CH2 ~ Protoporphyrin Ix been shown to be in the high-spin, S = 2, configuration, and X-ray analysis indicates that the metal lies out of the plane of the R= -CHO : Chlorocruoroporphyrin porphyrin, toward the coordinated imidazole by several tenths Figure 5. Structures of natural and synthetic porphyrins. of an angstro~q.~~,~~On oxygenation, the sixth coordination sites is occupied by 02 and the iron is situated in a pseudooctahedral together in a tetrahedral array. Each molecule of normal adult environment. The effects of this new environment are sufficient human hemoglobin contains two subunits known as the cy chains to both stabilize a low-spin, diamagnetic ground state64for the and two subunits called the @ chains. Although the primary iron-dioxygen complex and to place the iron in the mean plane structures of the various myoglobins and hemoglobin subunits of the porphyrin ring.65 show distinct variations, the tertiary structures are in general The binding of O2to Mb or isolated monomeric subunits of Hb quite similar. The structure of the @ subunit of Hb as deduced shows the behavior expected for simple 1: 1 association between from X-ray data is shown in Figure 6.61The protoheme prosthetic dioxygen and protein. The affinities of various myoglobins for group lies in a crevice between the E and F helices of the poly- O2 lie within a fairly narrow range. peptide, being held in place by nonbinding interactions with the protein. The single covalent attachment of the heme to the protein-Fe + O2 protein-Fe-02 (7) protein occurs by coordination of the heme iron to the imidazole Table IV indicates P11202values (equal to 1/Ko2 from eq 7)for nitrogen of the F8, or so-called “proximal” histidine residue. several Mb’s as well as data for oxygen binding to isolated Hb Synthetic Oxygen Carriers in Biological Systems Chemical Reviews, 1979, Vol. 79, No. 2 145 subunits. The monomeric heme proteins obtained from mam- malian sources generally yield P,/202 values in the range 0.4 to 0.7 Torr. The equilibrium uptake of O2 by tetrameric hemoglobin turns out to be more complex than for the case of the heme-protein monomers. The affinity of a subunit in Hb to add a single mole- cule of O2 is apparently dependent upon the number of other subunits oxygenated in the tetramer. Typical plots of equilibrium 02 uptake data for normal human Hb and the isolated (Y chain are shown in Figure 7. Analysis of such data reveals a number of salient fea- tures.60 (1) The data for 02uptake by either the isolated Hb subunits or Mb show behavior typical of a straightforward 1:l association between the heme and 02:
KO2 (protein-Fe) + nO2 (protein-Fe)(OZ), Such behavior is precisely described by the Hill equation66(eq I 9) with n = 1. I
Y = fraction of sites oxygenated Po, = pressure of O2 II Thus the total oxygen curve in Figure 7 can be reconstructed for the simple monomeric heme proteins from the KO, which is equal to (P1/202)-1. (2) In contrast to the hyperbolic curve obtained from the data for the monomeric hemes, the data obtained for Hb shows 0 IO 20 30 Po2 (mm Hg) "sigmoidal" behavior, indicative of interaction between the Figure 7. L. F. Ten Eyck, Cold Spring Harbor Symp. Biol., 36, 295 subunits. While of no physical significance, the data obtained (1975).Fraction of sites oxygenated (Y) vs. the partial pressure of O2 from Hb between ca. 10 and 90% oxygenation can be ade- for human Hb and the isolated a chain at -20 OC. Data for Hb taken quately, albeit empirically, fitted to the Hill equation to give values from ref 50a, pp 162. of n - 3 for normal human Hb. A careful analysis of the binding curve (Figure 7) for Hb at low partial pressure of 02,where substantially less than one-fourth changes the equilibrium between the T and R states. As Hb picks of the sites are oxygenated, shows that the equilibrium constant up oxygen, the equilibrium shifts toward the R state. Thus the for binding the first 02to the fully deoxygenated complex is about more O2 molecules bound to Hb, the higher the probability that a factor of 100 less than the equilibrium constant for binding O2 Hb will be in the R state. As the oxygen affinity of the R state is to an isolated subunit. Thus the association of the monomeric approximately the same as that of an isolated subunit, the 02 units to form the Hb tetramer results in a large decrease in the affinity of almost completely oxygenated Hb should be ap- affinity of the protein toward dioxygen, without changing the proximately equal to that of the isolated chains. nature of the axial imidazole ligand bound to the heme. The intimate mechanism through which the heme-heme in- (3) Although fully deoxy-Hb has a markedly reduced affinity teraction occurs is still a matter of some controversy. Perutz for 02,addition of 02to a Hb sample which is largely (>go%) (following the suggestions of Hoard71aand william^^'^^^), using oxygenated proceeds with an affinity that is approximately equal both experimental results from studies on hemoglobin combined to the affinity observed for the isolated subunits. Thus the effect with studies on model heme systems, has postulated a "trigger" of adding successive molecules of 02to Hb relaxes the inhibition mechanism for the cooperative interaction. On oxygenation, the toward O2 binding that arises from the aggregation of the subunits heme iromthat is originally above the porphyrin plane undergoes to form the tetramer. a spin change and moves into the mean plane of the porphyrin The dependence of the 02 affinity of Hb on the degree of ox- ring. This is accompanied by the movement of the covalently ygenation is known as the hom~tropic~~or heme-heme inter- linked proximal F8 histidine residue of the globin. The movement action. From X-ray data and molecular models, Perutz66has of this residue causes a change in the structure of the protein. proposed a stereochemical mechanism for the cooperative, It is this structural change which occurs in the binding of the heme-heme interaction based on the earlier two-state allosteric dioxygen to the heme that resiilts in the decrease in the stability model of M~nod~~and Rubin and Change~x.~~(For recent re- of the T conformation relative to the R form and causes the ob- views of the heme-heme interaction, see ref 60e-g.) served cooperativity. However, it should be noted that other The basis of this model is as follows. Association of the CY and investigator^^^ have concluded there are some shortcomings, p subunits to form deoxy-Hb occurs with the formation of one or unresolved difficulties, with the trigger mechanism. of two possible quaternary structures: (1) a low-energy, or tense In addition to the effect that the bonding of a molecule of (T) state and (2) a high-energy, or relaxed (R) state. The two forms dioxygen to a heme site has on the oxygen affinity of the he- are present as an equilibrium mixture. With no O2 present, the moglobin molecule it has also been observed that bonding of T state is more stable than the R state and the Hb is thus found protons to a hemoglobin molecule affects the oxygen affinity. to be almost exclusively in the T form. The O2 affinity of Hb in This heterotropic ir~teraction,~~known as the Bohr effect, can the T state is much less than the 02affinity of Hb in the R state. be viewed either as a change of pH in bonding a ligand to the Thus, the initial 02affinity of Hb is significantly lower than that heme site or as the change in the affinity of the heme site toward observed for the individual subunits. Addition of O2 to deoxy-Hb binding the ligand as a function of pH. For a discussion of the 146 Chemical Reviews, 1979, Vol. 79, NO. 2 Jones, Summervllle, and Basolo
with ls0labeled dioxygen have shown the two atoms of the Myo\O,M bound O2to be in different environment^.^^ This would be con- sistent with structures VI1 and Vlll shown in Figure 8. P Magnetic susceptibility measurements on both oxy- and methemerythrin have shown the two Fe(lll) ions to be antifer- romagnetically coupled.78While this is believed to occur through the 022-for oxyhemerythrin,the coupling between the two iron centers in methemerythrin may occur through a bridging oxo anion. The magnetic, Mssbauer, and electronic absorption data obtained for methemerythrin have been interpreted as being consistent with a pox0 bridge arrangement.74 Despite the large number of studies that have been performed, the manner in which the iron is bound to the protein in hemer- ythrin in its deoxy, oxy, and met forms remains uncertain. Several recent low-resolution X-ray crystallographic studies on the protein still leave the matter unres~lved.~~ As it is generally found in the main body cavity of the organism the physiological significance of hemeGthrin appears to be 0 oxygen storage. While it is in oxygen transport that the physio- logical significance of the homotropic interaction and Bohr ef- M----’’ I fects become important, one might expect both of these effects ‘0 to be absent in hemerythrin. These interactions have been ob- Ix served to occur in hemerythrins to variable degrees. Hence, Flgure 8. Possible structures for the M202unit in hemerythrins and hemerythrin from the brachiopod Lingula exhibits both homo- hemocyanins. M = Fe(lli) for oxyhemerythrin and M = Cu(ll) for oxy- tropic and heterotropic interactions; both effects are absent in hemocyanin. hemerythrin from the sipunculid P. agassizii. Hemerythrin from the sipunculid S. nudus shows only a slight site-site interaction nature of the Bohr effect and the manner in which it is trans- and no Bohr effect. The manner in which these subunit inter- mitted, see ref 60 and 68. actions are transmitted is still in the speculative stage. B. Hemerythrin C. Hemocyanin hemerythrin^^^,^^ are iron-containing, oxygen-carrying pro- teins found in certain species of four invertebrate phyla: spi- Hemocyaninsso are nonheme copper containing proteins unculids, polychaetes, pripulids, and brachiopods. Like hemo- found only in some species of the phyla Arthropoda and Mol- cyanin (vide infra) the prosthetic group of hemerythrins does not lusca. Like hemoglobin and hemerythrin, the hemocyanin pro- contain a porphyrin moiety; rather the iron is bound directly to teins consist of a number of subunits. The size of these subunits the protein side chains. In general, hemerythrin occurs as an are phylum dependent: hemocyanins from arthropods have a octamer of molecular weight about 108 000; each subunit molecular weight of about 36 700 per copper atom, while the contains two iron atoms and binds one molecule of O2 per ratio for molluscs is about 25 100. As for hemerythrins, the subunit. manner in which the metal centers are bound to the protein is Magnetic measurements and Mossbauer spectra show not well understood, nor has the structure of the metal-dioxygen deoxyhemerythrin to contain high-spin (S = 2) Fe(11).74Moss- complex been well established. bauer spectra of deoxyhemerythrin from Golfingia gouldii indi- The copper in deoxyhemocyanin is present as Cu(l). Recon- cate that the two iron(l1) atoms in the subunits are in identical stitution of the apoprotein with cuprous salts leads to regener- environment^.^^,^^ Consistent with the pale yellow color, the ation of the activity of the protein. The color of the deoxygenated electronic absorption spectrum of the deoxy complex is rela- protein is almost colorless in keeping with the d10 Cu(l) center. tively clear down to 300 nm. Upon oxygenation, hemocyanin has a deep blue color, having The electronic spectrum of the red oxy form is quite similar absorption maxima in the visible at -345 nm (~CU- 500). The to that observed for the met[Fe(lll)] species. This has led to the similarity between these bands and those of known cupric pro- suggestion that the two iron centers in the oxy form are in the teins supports a Cu(ll) center in oxyhemocyanin. These ab- Fe(l1l) state with the O2moiety being of the peroxide-like 022- sorptions have been attributed to d-d transitions of Cu(ll) in a type. As indicated below, this interpretation is also consistent distorted tetragonal ligand field.8i with Mossbauer data. Hemocyanins absorb one 02 for every two copper atoms in Mossbauer spectroscopy of oxyhemerythrin from G. gouldii the molecule. Several geometries have been proposed for the shows the presence of two quadrupole doublets, indicating that copper-dioxygen center in hemocyanins (Figure 8), which are the environments of the two iron nuclei differ.7*p74v75The isomer analogous to those proposed for hemerythrin. shifts of both doublets, which can be related to the oxidation state Resonance Raman spectroscopy of hemocyanins from both of the iron and the degree of covalency of the complex, are arthropods (C. magister) and molluscs (8.canaliculafum) has similar to the met derivatives of hemerythrin. This again suggests found the 0-0 vibration at 744 cm-1 (C.mgisferj and 749 cm-l a formalism for the iron of Fe(ll1). The manner in which dioxygen (5. canaliculatum).These frequencies suggest a description of binds to the iron sites has still not been resolved. Several the 02 as a peroxide-type, or 022-, species.45This is consistent structures that have been suggested are shown in Figure 8. with a formal description of the copper as being in the (+II)ox- Resonance Raman spectroscopy has been used to reinforce idation state. The weakly paramagnetic nature of the oxy- the assignment of a peroxide-like, Oz2-, electronic state to the hemocyanin complex is apparently due to an exchange inter- bound 02.78 A peak at 844 cm-’ observed in the resonance action between the two d9 centers; magnetic susceptibility Raman spectrum of oxyhemerythrin has been assigned to the measurements place a lower limit on the exchange coupling symmetric 0-0 stretch and is similar to the value obtained for parameter (J) of 625 cm-I for the antiferromagnetically coupled VO-0for other peroxide-containing compounds. Further studies Cu(ll) dimersa3 using resonance Raman spectroscopy on oxyhemerythrin made From a recent resonance Raman study on oxyhemocyanin Synthetic Oxygen Carriers In Blologlcal Systems Chemical Reviews, 1979, Vol. 79, No. 2 147
2
Commund W DE FC,
Coisalen) -iCH2h- H H HH ’\=/ Co(3-MeOsalen) - (CH,), - CH,O H H H 65 Co(4, 6-MeZsalen) -(CHz)n- H CH, H CH, CoiFsalen) -iCHJ2- F H HH Coinapsalen) :C.“,%!z- H HH Coisaloph) H H HH Porphyrins 12 34 5 6 7 8 mesob Co(sal14 or im)bn) -CH-CH- H H HH I1 CH, CH, P P Me H Protoporphyrin IX Me V Me V Me CO(Sal(=)or (“pen) -CH-CH- H H HH Mesoprphyrin Me Et Me Et M? P P Me H lX b, C6H5 H H HH DeuteroporphyrinlX Me H Me H Me P P Me H Co(sal(+)or@)chxn) -CH-CH- \I Pyrropormyrin XV Me Et Me Et Me H P M? H (CH,), Coisaldpi) -(CH,),-NH-(CH,),- H H H H -meso-Tetramenylporpin H H H H H H H H Ph Coi3 -MeOsaldDt) -ICH.).-NH-ICH.).- CH.0 H H H Octaethylporphyrin Et Et Et Et Et Et Et Et H Coi5-MeOsaldpt ) -iCH;);-NH-(CH;);- H ’ H CH,O H Co(S-NO,saldpt) -(CH,),-NH-(CH,),- H H KO2 H P P Me H 2,4-Diacetyldeutero- Me COCH, Ms CDCH, M? Co(- -Mesaldpt) -(CH,).-NH-(CH,I.- H H H CH, porphyrin IX CoisalMedDti -ICH:):-NCH.-I~H.L- H H H H ’ Co(3-MzOialMedpt) -(cH;I:-NcH;-(cH;):- CH,O H H H aAbbreviations: Me, methyl, V, vinyl; P, propionic acid; Et, ethyl, Ph, phenyl CoiS-MeOsalMedpi) -(CH,),-NCH,-(CH,),- H H CH,O H Co(x-MesalMedpi) -(CH,).-NCH.-(CH,).- H H H CH, ‘The -, B, , and 1 psitions have the same substiluent Co(sa1-n-Prdpt i -(CH.)“-N(n-e H )I@H 1 - H H H H ~ Co(sal-;-Prdpl) -(CH2~-N(;-C3H*)-iCH~)~-H H H H Co(salBj.dpt) -iCH:):-N(cH2k ha)- H H H H (CH,),- CoisalPhdpt) -(CH2),-NiC,H,)-(CH,)J- H H H H Co(sal-p-MeOPhdp!) -(CH,),-N(pCH,OC,H,)- H H H H (CH,),- Coi5-BrsalMedapp) -(CH,),-FCH,-(CH,),- H H Br H Coi3-MeosalMedapp) -(CH,),-P€H,-(CH,),- CH,O H H H Coi5-Brsaldape) -(CHz)3-O-(CHz)3- H H BrH Coi5-Clsaldape) -iCHz)3-O-iCHz)3- H H CIH Coisaltmzn) -c -c - H H HH Commund V A B ikHA (hHJZ COisalW) -CH2-CH(CH,CH,C,H,N)- H H H H Coiacacen) H CoiMeacacen) CH, J J Co(Phacacen) CP5 f \ Co@enacen) CoiClbenacen) H Co(Brknacen) H Co(Meknacen) H Co(Me0benacen) H Co(bensacen)a H Co(Clbensacen)a H Co(Brbensacen)a H W Co(Meknsacen)a H Co(Meobenstcen)a H 3 Co(sacacen) H Co(sacacen)a H Co(sacsacpn)a H Compound J K Co amSen) H H H CoINOpmben) H NO, H CoiMeOamben) Me0 Co(cyen)c H H
~~~ +he oxygen atoms are replaced by sulfurs bThe benzene rmgs are replaced by naph- thalenes ‘There is an ethylene bridEe replacing the two protons on the nitrogens Figure 9. Names and structures of the porphyrins and cobalt Schiff base complexes.
using unsymmetrically labeled 160-i80,it has been suggested substitution patterns and trivial names of the porphyrin com- that the Cu202moiety adopts a nonplanar, p-dioxygen confir- pounds discussed in this review are listed. matiomE4 The porphyrins can be divided into two classes, the first class being the “natural” porphyrins that are derived either directly Cu“-O from, or by modification of, metalloporphyrin complexes ob- ‘o-cull tained from nature, and the second class being those porphyrins X which are obtained entirely via a synthetic route. Of the por- phyrins listed in Figure 5, protoporphyrin IX, mesoporphyrin IX, VI. Synfhefic O2 Carriers and deuteroporphyrin IX are “natural” porphyrins being prepared from chloroprotoporphyriniron(lII), known as hemin, which is A. Porphyrins obtained from blood hemoglobin. These propionic acid chains Porphyrins are macrocyclic compounds that contain four which are common in these three porphyrins at positions 6 and pyrrole or substituted pyrrole rings joined by sp2-hybridized 7 are often esterified to obtain the dimethyl or diethyl esters. carbon atoms. As such, they can be viewed as being formally Pyrroporphyrin XV is also a “natural” porphyrin, being obtained derived from the parent compound, porphine (Figure 5), by by chemical modification of the chlorin ring of chlorophyll. substitution of the hydrogen atoms at the peripheral positions Of the synthetic porphyrins the two most commonly studied of the macrocyclic ring. Although other forms of nomenclature are meso-tetraphenylporphyrin, TPPH2, and octaethylporphyrin, can be used to label the positions on the porphyrin ring, the OEPH2. Compared with the natural porphyrins these synthetic system of nomenclature used here is the same as that utilized porphyrins both have rather chemically inactive side chains and by both FalkS5and Smitha6in their books on porphyrin chemistry. provide a symmetric square-planar environment for a metal That is, the eight “&pyrrole” positions are labeled 1 to 8 with coordinated in the porphyrin core. the four “meso” positions labeled CY, @, 7,and 6. In Figure 9 the For use in model studies of natural systems, octaethylpor- 148 Chemical Reviews, 1979, Vol. 79, No. 2 Jones, Summervllle, and Basolo
pensity for planarity. The pentadentate chelates have a fifth axial ligand atom present in the amine or ketonic precursor. If the chain is flexible enough, the fifth ligating atom can coordinate to the metal center. The pentadentate chelates can adopt two different geometries around the metal center depending on the flexibility of the chelate and length of the chain between two of the coordinated atoms containing the fifth ligand atom. If the chain is small or the chelate rigid, the metal-chelate complex will have a square-pyrami- dal-type structure. If the chelate is flexible enough, the resulting geometry will be trigonal bipyramidal. In all cases the tetra- and pentadentate chelates carry 6 -2 charge when ligated, so that the resulting M2+ complexes are neutral overall. Various substituents can be introduced on the periphery of the ligand by appropriate use of different aldehyde or ketone precursors. The substitutions alter the electronic properties of the metal chelates and their solubilities. In general, the Schiff base complexes are less aromatic than the natural and synthetic porphyrins. Unlike the porphyrins, the Schiff base compounds do not have extensive conjugated P systems available for P B bonding to the central metal ion. This effect is noted, for instance, Flgure 10. Type A and B Schiff base complexes studied in the solid in that the classically inert Co(lll) and Cr(lll) metal ions in the state. complexes Cr"'(TPP)(C1)93-95and CO~"(TPP)(CI)~~*~~display anomalous lability. This increase in liability is said to be the presence of the extensive conjugated ?T system causing a loss phyrinato-metal complexes represent in general a better choice of d3 or ds character. than tetraphenylporphyrinato-metal complexes. Because of the ethyl substituents at positions 1-8 on OEPH2, the electronic properties of octaethylporphyrin are closer to those of the Vll. Cobalt-Dioxygen Carriers "natural" porphyrins than are those of tetraphenylporphyrin. A. Early Work Further, metalloporphyrin complexes of OEP are, in general, more soluble than those of TPP. However, the ease of synthesis The first report of a synthetic reversible cobalt-oxygen carrier of TPPH287compared with that of OEPH288has resulted in many was made by Tsumaki in 1938.98He showed that the darkening more studies being conducted with TPPH2. One advantage of that had been observed by Pfeiffer and co-workers in 1933,99 TPPH2 over both the natural type porphyrin and OEPHp in studying when red-brown crystals of the cobalt(l1) Schiff base complex the properties of metalloporphyrin systems is that the electron Co(salen) were exposed to the atmosphere, was due to the re- density on the metal can be varied by substitution of the phenyl versible absorption of molecular oxygen. While this represents rings of tetraphenylporphyrin. A number of phenyl-substituted the first report of a synthetic reversible oxygen carrier, cobalt tetraphenylporphyrins have been prepared and the effects of compounds containing bound dioxygen have been known for a this substitution on the reactivity and electronic properties of the much longer period. In 1852,Fremyioo reported that the expo- metal center in tetraphenylporphinato-metal complexes sure of ammoniacal solutions of Co(ll) salt to the atmosphere studied.89 resulted in the formation of brown salts which he called oxo- cobaltiates. They were later characterized by Werner and Myl- 6. Schiff Bases ius5' in 1898 as containing the diamagnetic ~ation[(H~N)~- CO(O~)CO(NH~)~]4+. These complexes, which are mainly ionic Schiff bases are macrocylic compounds that are formed by and water soluble, are discussed in section V1I.C. the Schiff base condensation reaction (eq lo), often, but not Since the initial discovery by Tsumakig8that SB chelates of R R Co(ll) are oxygen carriers, there has been a continued interest in this property of these complexes. The binding of dioxygen to ,C=O\ + H,NR --t \C=NAR + H20 (10) cobalt(l1) chelate complexes of Schiff bases has been studied R d both for heuristic interest and as a practical means of isolating necessarily, employing a metal ion as a template. A number of pure dioxygen from the atmosphere. For a short period during reviews on Schiff base syntheses are a~ailable.~~-~~The Schiff World War II, the U.S. Navy used these complexes'0i in the bases used in these studies are generally tetradentate ligands, production of pure dioxygen aboard a destroyer tender for use but some are pentadentate ligands. At least two of the ligating in welding and cutting. More recently, a cobalt Schiff base atoms are nitrogen atoms, with the others being nitrogen, oxy- complexio2 was to be used in the E1bomber to provide oxygen gen, sulfur, or a combination of the three. Schiff base compounds when needed to the aircraft crew. are commonly referred to by their mnemonic abbreviations. The Complexes of both type A and type B (Figure 10) can be iso- abbreviations are a combination of the ketone and amine pre- lated as solids in active and inactive forms.lo3 The oxygen cursors. For example, bis(acety1acetone)ethylenediimine be- binding characteristics of these complexes are very dependent comes acacen, and N,N'-bis(salicylidene)ethylenediaminebe- upon the preparation and pretreatment of the sample, as well comes salen. If there are substituents on the Schiff base com- as the purity of the starting materials. Complexes of type A ab- pound the mnemonic simply adds the group to the front; e.g., sorb up to 1 mol of 02/molof cobalt, whereas those of type B N,N'-bis(3-methoxysalicylidene)ethylenediamineis 3-MeOsalen can absorb up to 0.5 mol of 02/mol of Co. (Figure 9). Type A chelates are square planar, while type B chelates are The tetradentate ligands enforce a high degree of planarity trigonal bipyramidal. In the unoxygenated states both type A and to the metal chelates. Although chelating ligands such as acacen B complexes are paramagnetic,lo4with type A having a single (Figure 9)allow for some distortion away from planarity, the in- unpaired electron and type B having three unpaired electrons. clusion of an aromatic ring as an integral part of the chelate, as In the solid state, upon oxygenation type A complexes become in amben, or salen, stiffens the ligand and increases its pro- diamagnetic, while type B reduce their paramagnetism to one Synthetlc Oxygen Carrlers In Blologlcal Systems Chemical Reviews, 1979, Vol. 79, No. 2 149 unpaired electron. This magnetic behavior is consistent with type Earlier solution work by Harle and Calvinlo8 involved mainly A complexes forming pperoxo dimeric species (eq 1 l), with the type B cobalt chelates. They found at 0 OC that the oxygen the dioxygen being “peroxo-like”. The oxygenated type B uptake by types A and B complexes was reversible to some complexes are monomeric with the unpaired electron on the extent. For the complex used in the studies, Co(3-Clsalen) in dioxygen fragment (eq 12). The dioxygen moiety is superoxo- quinoline and ethyl benzoate, greater than 97% of activity re- like. mained after cycling once. Above 0 OC there was present in the experimental runs a slow irreversible uptake of oxygen. The slow 2Co(SB) + 02 --+ [CO(SB)]~OZ (11) uptake may be due to oxidation of the chelate. The type A compound Co(sa1en) at 0 OC, when exposed to an oxygen Co(SBL) + 02 -+ Co(SBL)02 (12) pressure sufficient to cause oxygenation in the solid state, does The cobalt chelates (types A and B) exist in several cyrstalline not oxygenate in solution. If the pressure is increased sixfold forms, some of which are active, whereas others are totally approximately one-fourth of the sample oxygenates. devoid of oxygen-carrying ability. Depending on the method of preparation and pretreatment, different crystalline modifications are obtained. lnterconversionamong crystalline forms is affected -B. Recent Studies on Cobalt-Dioxygen by heating in vacuo or grinding. In addition, oxygen uptake rates Complexes in Nonaqueous Solutions were dependent on these conditions. Research on simple iron complexes in solution to mimic the Calvin105interpreted the differing uptake rates as being due naturally occurring systems of hemoglobin and myoglobin was, to the exposure of differing lattice faces in the crystallite caused for many years, unsuccessful. Because of this and of the success by different activation processes. In line with this interpretation Calvin and co-worker~~~~~had with their studies of the inter- are the results of crystallographic studies. Type A cobalt Schiff actions of solid cobalt chelates with gaseous dioxygen, there base chelates in the solid state crystallize in layers.lo6 All the began a renewed interest in the solution studies of cobalt(l1) atoms of the basic Schiff base ligand lie in the same plane. Schiff base compounds. Recent interest in the reversible oxy- Substituents and the ethylenic hydrogens usually lie outside of genation of cobalt complexes received a pronounced impetus this plane. The holes between layers are large enough to allow from the work of Floriani and Caldera~zo~~and Basolo and for the passage of oxygen; the holes between chelates are Crumblis~~~~~’lo who discovered that, under the proper condi- slightly smaller yet still allow for the passage of oxygen. These tions in nonaqueous solutions, certain Schiff base cobalt(l1) “holes” are passages through the lattice shown by X-ray analysis complexes would reversibly bind one molecule of O2 per mol- to be present in all active compounds and absent in at least the ecule of cobalt. Floriani and Caldera~zo~~~’~’studied the be- inactive form of the parent compound. Calvin103b~105found that havior of derivatives of Collsalen in nonaqueous media and found the binding of dioxygen at measurably fast rates of cobalt Schiff in general an O2 uptake of 1 O2 per 2 Co. However, when pyri- base complexes in the solid state were indirectly correlated with dine solutions of (3-methoxysalen)cobaIt(ll)were exposed to O2 the existence of holes in the crystal lattice. He believed that such at 10.4 OC, an uptake corresponding to 1 molecule of O2 per holes allowed for the rapid diffusion of oxygen throughout the .molecule of cobalt was observed. The starting material was crystal and that the arrangement of the holes allowed the bridging regenerated by heating the dioxygen adduct in vacuo. of two cobalt atoms by an oxygen molecule without extensive Independent experiments by Basolo and Cr~mbliss’~~~’lo rearrangement of the structure. made use of N,N’-ethylenebis(acetylacetonato)(cobalt(ll) The oxygenation process can be reversed by either heating (Co(acacen)). At room temperature, in either a coordinating or evacuation. After continued cycling Calvin’07 et al. found that solvent (e.g., DMF) or in a noncoordinating solvent (e.g., toluene) for Co(salen)and Co(3-Fsalen)the amount of oxygen desorbed in the presence of a coordinating ligand (e.g., pyridine), a solution on each cycle slowly decreased with time, indicating a slow of Co(acacen) shows a slow nonstoichiometric uptake of O2 over concurrent decomposition of the chelate. Calvin attributed ir- a period of days (Figure 11). Under these conditions, it appears reversible oxidation as the most important cause of deterioration. that some oxidation of the organic ligand is occurring. At tem- They actually observed the fracturing of a C~(salen)’~~~crystal peratures of 0 OC or below, however, there is a rapid and re- during cyclization, though they did not ascribe the loss of oxygen versible uptake of O2 corresponding to the formation of a 1:l carrying ability to this process. It has been reported that fine- Co:02 complex. grained material is the most efficient oxygen carrier.lol With the discovery of the 1:l dioxygen adducts of cobalt- Berkelew and Calvin105studied the kinetics of oxygen uptake Schiff base complexes, it was apparent that parallel studies on for the type A complexes Co(salen), Co(3-Fsalen), and Co(3- cobalt-porphyrin compounds were in order, since metallopor- EtOsalen). For all three compounds the oxygenation reaction was phyrins are utilized in natural proteins. At this time the significant first order with respect to oxygen pressure. The complexes result of Perutz’ l2 that the dioxygen molecule travels through Co(salen) and Co(3-EtOsalen) were first order in complex, but a hydrophobic pocket to reach the coordination site on the iron Co(3-Fsalen) displayed second-order dependence on complex. atom in hemoglobin was well known. It followed that one might The first step is the formation (eq 13) of activated oxygen mol- simulate the hydrophobic environment on the protein by the use ecules (this condition exists when the oxygen is bonded to only of nonaqueous aprotic solvents, known to work for cobalt(l1)- one cobalt atom) followed by the formation of the dimeric Schiff base chelates. For this reason cobalt(l1)-porphyrin model species (eq 14). For first-order behavior, reaction 13 is rate systems were studied using solvents such as toluene or CH2CI2. The generality of the ability of cobalt(l1) chelates to reversibly A 4- 02 AO2’ * (13) bind dioxygen under such conditions was soon extended to AO2’ 4- A + A02A (14) complexes synthesized by the research groups of Bus~h,~~ Cummings,’ l3 and McLend0n.l l4 determining; for second order behavior, reaction 13 is a rapid Four-coordinate Schiff l5-lZ0 porphyrin,’ 18,121-125 equilibrium and reaction 14 is the ratedetermining step. The and macrocy~lic~~.~l4,lZ6complexes of cobalt(l1) in the presence P1/202values for type A chelates were on the order of 5 Torr at of a slight excess of a coordinating base normally form low-spin, 25 OC, whereas type B chelates exhibited P,/2O2 values greater five-coordinate base adducts. However, there are exceptions than 1 atm; in addition, type B chelates reach equilibrium very among certain Schiff base and macrocyclic complexes. Com- slowly. For the type A complexes studied, thermodynamic values plexes’ l5 such as Co”(amben), Co”(cyen), and Co”(Me0amben) of AHw -20 kcal mol-’ and AS N -50 cal deg mol-’ for the do not form base adducts. This is believed to be due to the fact oxygenation reaction were obtained. that in these low-spin complexes the odd electron resides in the 150 Chemical Reviews, 1979, Vol. 79, No. 2 Jones, Summervilie, and Basolo
8 I I I I I 70 71 72 Time (hours) Figure 11. Oxygen absorption by DMF solutions of CO(aCaCen), data collected at 6 OC and 760 Torr of O2pressure denoted by open circles; filled circles are data collected at 25 OC and 480 Torr of 02.Data from refs 109 and 110.
5 TABLE V. Equiiibrlum Constants for the Blnding 01 an Axial Ligand to Cobalt(ii) Chelates: cO(L4) -t B -Co(L4)(B)
log KB, log, KB, compounda base T, OC M-' ref compounda base r, oc M-I ref
Co(salen) quin 25 -0.52' C 3,5-C12PY 25 2.28 127 PPh3 25 -0.82 C 4-Me02Cpy 25 2.70 127 2-Mepy 25 0 C 2,4,6-Me3py 25 1.83 127 2,6-Me2~~ 25 0.45 C IsoQ 25 2.81 127 OPPh3 25 .38 C quin 25 1.20 127 3-Mepy 25 0.57 C acr 25 <- 1 127 4-Mepy 25 0.85 C Im 25 3.15 127 4-EtCOOpyd 25 0.45 C Melm 25 3.37 127 3-EtNCOpye 25 0.57 C 5-CIMeim. 25 3.09 127 PY 25 0.57 C N-aclm 25 2.89 127 PY 20 1.1fJ h 1,2-Me21m 25 2.79 127 Co(sal(f)dpen) PY 20 0.53' h Bzlm 25 2.44 127 Co(sai("pen) PY 20 0.57 ' h l-SiMe~lm 25 3.14 127 Co(sal(f )chxn) PY 20 1.02' h PiP 25 3.39 127 Co(sal(m)chxn) PY 20 0.75' h Mor 25 3.20 127 Co(acacen) PY 23 1.8 115 quinuc 25 3.19 127 Co(Phacacen) PY 23 1.9 115 PIP 25 3.386 124 Co(MeaCacen) PY 23 1.9 115 PY 25 2.685 124 Co(benacen) PY 23 2.3 115 PiP 25 3.517 124 Co(benacen) 2,4,6-M%~~ 23 1.8 115 PY 25 2.742 124 Co(sacacen) PY 23 2.5 115 PIP 25 3.616 124 Co(PPIXDME) DMF 23 1.18 129 PY 25 2.880 124 4-CNpy 23 3.24 129 PY 25 2.972 124 PY 23 3.78 129 PiP 25 3.698 124 4-t-Bupy 23 3.85 129 PY 25 3.004 124 Co(PPIXDME) Im 23 3.64 129 PIP 25 3.937 124 Melm 23 3.70 129 PY 25 3.268 124 4-NHnPY 23 4.00 129 PiP 25 4.036 124 PY 23 3.83 129 PY 25 3.386 124 Bzlm 23 3.5 122 PPh3 26 1.48 125 Co(T(pMe0)PP) PY 25 2.69 127 P(*Bu)s 20.5 4.08 125 4-Mepy 25 2.90 127 P(OMe)3 25.4 1.65 125 3,4-Mepy 25 3.03 127 SMe2 26.0 1.35 125 4-Me2Npy 25 3.62 127 AsPh3 24.9 1.40 125
a Solvent is toluene unless otherwise noted. * Solvent is DMA. A. V. Savitski and N. K. Zheltukhin, Izv. Akad. Nauk SSSR, 222,348 (1973). Ethyl isonicotinate. e Nicotinic acid diethylamide. ' Solvent is CHC13. g Approximate value. E. Cesarotti, M. Gullotti, A. Pasini, and R. Ugo, J. Chem. SOC., Dalton Trans., 757 (1977). Synthetic Oxygen Carriers In Biological Systems Chemical Reviews, 1979, Vol. 79, No. 2 '151 n
Flgure 12. Energy level diagrams denoting the changes in energy levels Figure 13. EPR spectrum of Co(acacen)(py)in frozen toluene solution for the axial ligation of Co(SB4).The diagram on the left is for Co(SB,); at 77 K (from ref 35). that on the right is for Co(SB,)(B). to a square-pyramidal arrangement, raising the dZz orbital above d, d, orbital. Thus in order to bind an axial ligand it would be nec- the d, (Figure 12), thus resulting in the configuration essary to promote the dZ2 orbital above the d,. However, the (dxz)2(dyz)2(dxy)2(dz)1.This latter configuration appears to be a energy gained from binding an axial ligand is not enough to necessary prerequisite of oxygenation. Basol~~~~and co- compensate for the energy of rearrangement, and hence the workers have reported that five-coordinate complexes of the complexes remain four-coordinate. cobalt(l1) Schiff base Co"(benacen)(B),where B represents an Toluene solutions of cobalt(l1) porphyrins118~'21-'25~127-129N-donor ligand, readily bind dioxygen in toluene solutions at 0 in the presence of base rapidly form the five-coordinate com- OC (eq 16). For example, log KO*= -2.0 at 0 OC for B equals plexes CoIl(Por)(B). In the presence of a large excess of base (1-Melm) and the electronic configuration of the complex is the bis-base complexes, Co11(Por)(B)2,are formed. For example, (dxz)2(dyz)2(dxy)2(dzz)1~ in toluene solutions containing piperidine (>1 M) KO2 Co"(PPIXDME)(pip)2is formed. StyneslZ9et al. found that at room cO(sB4)(B)+ 02e cO(sB4)@)(02) (16) temperature the weaker coordinating bases such as pyridine and 4-tert-butylpyridine do not form bis-base complexes with Co"- However, only a small amount of the four-coordinate Coli- (PPIXDME). However, at -4OoC, formation of the bis-base ad- (benacen) (electronic configuration of (dxz)2(dyz)2(dz2)2(dxu)l) duct was observed for 4-tert-butylpyridine. Walker127noted that complex is oxygenated under 1 atm of O2 in toluene at -83 only strong a-donor bases such as quinuclidine, piperidine, or OC. n-hexylamine readily form 2: 1 complexes with Co"(T(pMe0)PP). The EPR spectra of Co"(L4)(B)and Co11(L5)35,130complexes Weaker binding ligands such as pyridine formed 2:l complexes typically have an eight-line hyperfine splitting (Figure 13) due only at high ligand concentrationsand bases such as pyrrole and to the 59C0(I = 7/2) nucleus in the high field, "parallel", direction. quinoline did not under any conditions form bis-base adducts. Several of these are seen to be split into equal intensity triplets Thermodynamic values for the addition of a base (eq 15) as a by the presence of the single nitrogen (I = 1) nucleus of a N- fifth ligand are given in Table V. donor base. EPR values for Co"(L4)(B)and Co"(L5) complexes
KB are given in Table VI. The Col1(SB4)(B)complexes typically have Co"(Por) -t B +Cotl(Por)(B) (15) EPR values for g1 of 2.30-2.45 and 911 of 2.01, 2.02, while Co(Por)(B) complexes have gi values of -2.33 and gii of There appears to be no direct correlation between log KBand 2.03. the pKa of the ligand, although Walker127did note that for Upon oxygenation the EPR spectra of low-spin Co(Por)(B) structurally similar bases (substituted pyridines and imidazoles) complexes undergo dramatic ~hange~.~~.~~*~~~~-~~g~~*~~~~~~~-~~~ there was a linear correlation between pKa and log KB. The signal at g- 2.3 disappears, with a new symmetrical signal replacing it at g - 2. The original superhyperfine (shf) splitting 1. EPR of -80 G are replaced (Figure 14) with a much smaller shf Analyses of the EPR spectra of five-coordinate cobalt(l1) Schiff splitting due to 59C0of 10-12 G (values are in Table VII). This base, porphyrin, and macrocyclic comple~es~~~'~~show that change can be reversed by removing the oxygen. The small shf the complexes are low-spin d7, with the unpaired electron in the splittings have been interpreted as meaning that the unpaired dZz orbital. This is inferred from the presence of superhyperfine spin density no longer resides on the cobalt metal center, but splittings from the axial nitrogen. Certain five-coordinate Co(ll) instead resides on the dioxygen moiety. The re~ults~~,'~~of using Schiff base and macrocyclic complexes remain high spin. The 170and magnetic data indicate that in the Co(L4)(B)(02)com- complexes92,114.130d,13 1 [C~~~(cycIam)(Br)]+, CoIl(SalMeDPT), plexes there is present only one unpaired electron, and that and Co"(salHDPT) are high spin as evidenced by magnetic mo- greater than 90% of the residual electron spin resides on the ments of w,ff = 3.3 BM and the analysis of their EPR spectra. dioxygen. Upon coordination the symmetry of the oxygen mol- Four-coordinate cobalt(l1) chelates are very poor oxygen ecule is sufficiently reduced to split the otherwise degenerate binders,' l5 whereas their corresponding mono(base adducts) antibonding 'IIg orbitals of the oxygen and constrains the two and five-coordinate chelates readily bind dioxygen at ambient antibonding electrons to be paired in the more stable of the two pressures of oxygen. The binding of an axial fifth ligand leads orbitals. Because of this loss of this symmetry restriction, the 152 Chemical Reviews, 1979, Vol. 79, No. 2 Jones, Summervllle, and Basolo
TABLE VI. EPR Parameters for Five-Coordinate Cobalt(l1) Complexesa
compound solvent gx 9Y gz Ax, gauss A,, gauss A,, gauss ref
Co(salen)(THF) THF 2.409 2.013 50.7 126.7 130c Co(salen)(NCS) NCS-, DMA 2.54 2.31 2.011 1596 1376 104.4 130c Co(salen)(DMSO) DMSO 2.50 2.30 2.013 1536 128b 126.6 130c Co(salen)(py) C 2.380 2.180 2.014 101.0 115 Co(salenXpy) PY 2.354 2.27 2.028 1 186 5 196 81.3 130c Co(3-MeOsalen)(py) d 2.406 2.23 2.015 50 10 95.0 e Co(acacen)(py) 1 % py/toluene 2.449 2.739 2.013 47.3 100 115, 132 Co(acacen)(py) toluene 2.44b 2.225 2.01 1 43.5 11.6b 97.5 35, 130c Co(acacen)(4-CNpy) toluene 2.45 2.23 2.013 5.2 11 101.2 e, 35 Co(acacen)(4-Mepy) toluene 2.445 2.22 2.012 51.3 11 98.7 e, 35 Co(acacen)(4-t-Bupy) toluene 2.452 2.23 2.013 49 11 99.9 e Co(acacen)(PPha) toluene-CHpClp 2.4 2.26 1.958 91.8 e Co(acacen)(DMF) toluene 2.461 2.23 2.01 1 57.2 15 100.4 e Co(Meacacen)(py) PY 2.470 2.230 2.009 59 13 104.6 e, 115, 132 Co(Meacacen)(PPh~) toluene 2.4 2.26 1.961 90.0 e Co(Phacacen)(py) 1 % pyltoluene 2.446 2.237 2.014 52.5 103.0 115, 132 Co(sacacen)(py) 1 % py/toluene 2.443 2.169 2.003 77.6 115, 132 Co(benacen)(py) C 2.428 2.22 2.012 48.7 13 98.0 e Co(benacen)(py) 1 % py/toluene 2.444 2.231 2.014 45.0 98.0 115, 132 Co(benacen)(n-BuNHp) f 2.428 2.237 2.009 40 96.3 132 Co(benacen)(CBuNH2) f 2.441 2.244 2.012 45 96.0 132 Co(benacen)(sec-BuNH2) f 2.456 2.249 2.007 55 96.0 132 Co(benacen)(Melm) f 2.442 2.257 2.013 44 98 115, 132 Co(benacen)(5-CIMelm) f 2.451 2.267 2.013 50 101 115, 132 Co(benacen)(pip) f 2.442 2.244 2.013 44 93.5 115, 132 Co(benacen)(3,4-Me2py) f 2.441 2.248 2.009 45 98 115, 132 Co(benacen)(CMepy) f 2.442 2.251 2.012 47.5 99 115, 132 Co(benacen)(4-CNpy) f 2.470 2.267 2.013 47 103 115, 132 Co(benacen)(PPh3) f 2.319 2.250 1.958 89 115, 132 Co(NO2amben)(py) 50% py/DMF 2.295 2.216 2.003 107 115 Co(saW 20 % DMF/toluene 2.45 1 2.226 2.011 43.3 105.4 115 Co(saloph)(PPh3) CHpC12 2.4 2.26 1.998 87.8 e Co(saloph)(P(+Bu)3) toluene 2.4 2.26 1.950 78.0 e Co(ptsmXpy) PY 2.37 2.21 2.001 37 17 76.5 e Co(tetane)(py) 10% py/MeOH 2.626 2.364 2.019 34 116 115 Co(diene)(py) 10 % py/MeOH 2.360 2.290 2.010 110 115 Co(tetene)(py) 10% py/MeOH 2.354 2.354 2.023 91.7 115 Co(T(pMeO)PP)(py) 1% py/tol 2.312 2.312 2.022 83.3 115, 132 Co(T(pMeO)PP)(py) toluene 2.327 2.327 3.025
TABLE VII. EPR Parameters for Reversible Cobalt-Dloxygen Complexesa
compound solvent 91 SI1 Siso AI", G AllCo, G A,,,, G ref
Co(salen) CHzCl2 1.998 2.089 2.025 18.1 25.1 130c Co(salen)(DMA) DMA 1.998 2.086 20.0 130c Co(salen)(THF) THF 1.996 2.082 2.024 19.5 26.0 130c Co(salen)(DMSO) DMSO 1.998 2.091 2.024 17.8 23.8 130c Co(salen)(py) PY 1.999 2.079 2.028 14.0 17.5 130c Co(salen)(py) PY 1.997 2.079 2.024c 10.4b 18.0 12.9 d Co(salen)(py) toluene 1.999 2.072 2.023e 14.3 16.8 13 115 Co(salenXpy) 50% py/50% CHCl3 2.007 2.08 12.7 16.8 139 Co(salen)(py)'rg pyridine 2.022 13 179 Co(salen)(py) 50% ~~150%CH2C12 1.995 2.082 2.024h 10.5b 17.4 12.3 133 Co(3-MeOsalen)(py) toluene 1.998 2.079 2.024' 14.6 16.8 12.6 115 Co(3-MeOsalen)(py) PY 1.997 2.079 2.024' 10.2 17.3 12.6 d Co(3-MeOsalen)(py) PY 2.023 12.8 179 Co(3-MeOsalen)(4-Mepy) 4-Mepy 2.022 13 179 C0(3-MeOsalen)(4-Etpy)~ 4-Etpy 2.022 12.8 179 Co(3-MeOsalen)(DMF) DMF 2.028 17.0 179 Co(3-MeOsalen)(DMSO) ' DMSO 2.028 17.3 179 Co(4,6-Me2salen)(py) 50% ~~150%CH2C12 1.996 2.074 2.022h 9.2 17.0 11.9 133 Co(Fsalen)(py) toluene 1.999 2.078 2.028"' 13.0 17.0 14 115 Co(napsalen)(py) 50% ~~150%CHzClp 2.078 16.8 133 Co(acacen)(py) toluene 1.998 2.080 2.027" 16 19.3 13.7 115, 132 Co(acacen)(py) toluene 1.999 2.082 2.027" 10.7 19.7 13.7 d, 35, 130c Co(acacen)(py) 50% ~~150%CHC13 2.006 2.08 15.1 18.7 139 Co(acacen)(H20) toluene 1.997 2.088 2.027" 13.7 28.9 18.8 d, 35 Co(acacen)(DMF) toluene 1.9962 2.0859 2.026O 10.0 20.2 d, 35, 130c Co(acacen)(rl-CNpy) toluene 1.997 2.080 2.024O 10.3 20.1 13.6 d, 35 Co(acacen)(.Q-Mepy) toluene 1.997 2.082 2.026O 10.0 19.6 13.2 d, 35 Co(acacen)(4-t-Bupy) toluene 2.084 19.9 d Co(Meacacen)(py) PY 1.996 2.091 2.0270 11.0 21.7 14.5 d Co(Meacacen)(py) toluene 2.007 2.082 2.0199 17.0 20.3 14 115, 132 Co(Phacacen)(py) toluene 1.999 2.084 2.0239 15.7 19.3 12.8 115, 132 Co(sacacen)(py) toluene 1.997 2.085 2.023' 13.3 21.3 14 115, 132 Co(benacen)(Melm) s 2.000 2.008 2.024h 15 18.6 13.1 115, 132 Co(benacen)(5-CIMelm) s 2.000 2.089 2.025h 15.5 19.4 13.6 115, 132 Co(benacen)(pip) s 2.000 2.088 2.025 17.5 19 13.0 115, 132 Co(benacen)(3,4-Me2py) s 1.999 2.085 2.024 14 19 13.0 115, 132 Co(benacen)(4-Mepy) s 1.999 2.085 2.024h 18 19 13.1 115, 132 Co(benacen)(py) s 2.000 2.085 2.024h 18 19.2 13.2 115, 132 Co( benzcen)(py) PY 1.999 2.084 2.026' 10.3 19.4 13.3 d Co(benacen)(2,4,6-Me3py) s 1.999 2.084 2.023h 17.5 19.2 13.0 115 Co(benacen)(4-CNpy) s 1.999 2.085 2.022h 16 19.2 13.8 115, 132 Co(benacen)(wBuNH2) s 1.999 2.089 2.021 4 10.7 17.7 13 132 Co(benacen)(CBuNH2) s 1.992 2.087 2.0264 10.7 18.6 13.3 132 Co(benacen)(secSuNH2) s 2.000 2.088 2.025" 10.2 19.4 13.3 132 Co(benacen)(DMF) s 1.999 2.093 2.025" 14.4 29.4 14.8 132 Co(benacen)(PPhs) s 1.996 2.082 2.024" 14 15.5 13.5 115, 132 Co(benacen)(EtSMe) s 1.999 2.096 2.022" 13 25.8 15.5 115, 132 Co(benacen) s 1.999 2.093 2.025" 14.5 29.4 14.8 115 Co(amben)(py) toluene 2.007 2.083 2.018' 16.5 20.0 15 115 Co(amben)(py) 50% py/CHzClz 1.995 2.079 2.023' 10.2 18.2 12.9 133 Co(NO2amben)(py) 10% py1toluene 2.000 2.082 2.027 13.0 17.6 14.5 115 Co(MeOamben)(py) toluene 1.996 2.083 2.005' 15.5 20.0 115 Co(cyen)(py) 50% py/DMF 1.996 2.082 2.015' 15.5 18.3 15.5 115 Co(salpy) 20% DMF/toluene 1.998 2.078 2.025 15.5 19.0 14 115 Co(saloph)(py) 50% pylCHCl3 2.007 2.08 13.2 16.9 139 Co(saloph)(py) 50% py/CHzCln 1.994 2.081 2.023h 9.6 16.8 12.2 133 Co(salophXpy) w 1.995 2.082 2.0241 10.0 17.6 12.5 d Co(ptamXpy) PY 2.076 18.2 d Co(tetane)(py) 10 % py/MeOH 1.992 2.102 2.029' 17.5 21.6 15.5 115 Co(diene)(py) 10 % py/MeOH 1.987 2.075 2.0349 18.7 27.3 15 115 Co(tetene)(py) 10 % py/MeOH 1.995 2.054 2.0084 10.0 12.4 115 Co(Mes[ 14]4,1 ldieneN4)(lm)2+ DMF 2.007, 2.0843 13.3, 13.3 20.8 92 1.999 Co(T(pMeO)PP)(py) toluene 2.002 2.077 2.0139 12.0 16.3 10.4 115 Co(T(PMeO)PP)(py) toluene 2.002 2.077 10.7 16.6 130c Co(T(pMe0)PPNpy) toluene 2.002 2.077 11.4 17.1 128 Co(T(p-MeO)PP)(2-Mepy) toluene 2.000 2.076 11.5 16.8 128 Synthetic Oxygen Carriers In Blologlcal Systems Chemical Reviews, 1979, Vol. 79, No. 2 155
Table VII. (Continued)
~
compound solvent 81 911 QISO AI-, G Ailco, G A,,,, G ref
Co(T( pMeO)PP)(S-Mepy) toluene 2.000 2.073 10.6 16.6 128 Co(T( pMeO)PP)(CMepy) toluene 2.001 2.024 11.0 16.9 128 Co(T(pMeO)PP)(3,4-Mezpy) toluene 2.001 2.074 10.3 16.4 128 Co(T(pMeO)PP)(3,5-Me2py) toluene 2.001 2.073 10.5 16.3 128 Co(T(pMeO)PP)(2.4,6-Me3py) toluene 1.998 2.076 10.6 16.8 128 Co(T(pMeO)PP)(quin) toluene 2.002 2.074 11.0 16.8 128 Co(T(pMe0)PPXMelm) toluene 2.002 2.086 10.5 16.7 128, 130c Co(T(pMe0)PPMpyrrole) toluene 2.004 2.081 11.4 18.9 128 Co(T(pMe0)PPXpip) toluene 2.002 2.076 11.1 16.9 128 Co(T(pMe0)PPXquine) toluene 1.998 2.074 13.0 16.7 128 Co(T(pMe0)PPXrrhexylamine) toluene 2.002 2.077 10.7 16.4 128 toluene -1.998. 1.993 -2.05 -29.1, 30.1 -12.5 140 Co(TPP)(CH&N) toluene 2.004, 1.995 2.076 17.7, 17.8 15.6 140 Co(TPP)(CO) toluene -2.014 -2.07 -9.6 -12.4 140 Co(PPIXDME)(DMF) DMF 2.0197 11.47 168b Co(PPIXDME)(py) CH3CN 2.0207 11.88 168b Co(PPIXDME)(py)" toluene 2.02 11.8 168b Co(PPIXDME)(lm) toluene 1.99 2.08 16.4 122 Co(PPIXDME)(Melm) toluene 1.99 2.083 16.7 122 Co(PPIXDME)(Bzlm) toluene 1.99 2.08 122 Co(TpivPP)(Melm) toluene 2.01 2.09 -20 164 Co(MPHDME)(py) 50% py/CHCI3 2.003 2.08 11.1 17.4 139 Co(saldpt) U 2.007, IY 2.000 "2.085 2.O3Ov 13.3, 13.5 22.7 13.6v 130d Co(3-MeOsaldpt) U 2.007, 2.000 "2.091 2.030 13.1,w 13.6w 20.7 13.7v 130d Co(5-MeOsaldpt) U 2.008, 2.003 "2.089 2.031 13.3, 13.5 22.7 13.6" 130d Co(5-N02saldpt) U 2.002, 1.999 v2.082 2.028 12.9, 14.2 21.6w 13.3" 130d Co( 0-Mesaldpt) U 2.006, 2.001 "2.091v 2.003 12.7, 14.7 21.3w 13.gV 130d Co(sa1Medpt) U 2.005, 1.999 "2.086 2.030 12.OW,13.6w 18.7 12.4" 130d Co( 3-MeOsal Medpt) U 2.009, 1.988 "2.09ow 2.033 12.1 w, 14.3 18.6 12.4 " 130d Co( 5-MeOsalMedpt) U 2.01 1, 2.003 "2.091 2.035 12.3, 14.1 19.6 12.6" 130d Co(cu-MesalMedpt) U 2.004, 1.998 "2.089 2.024 13.0, 14.9 19.7 13.4" 130d Co(sal-n-Prdpt) U 2.006, 1.997 "2.084v 2.022" 12.1, 13.9 19.ow 13.5" 130d Co(saf-i-Budpt) U 2.004, 1.997 "2.087 2.025 12.1, 14.3 19.3 13.4" 130d Co( sal8zdpt) U 2.004, 1.998 "2.086 2.022 13.1,w 14.6w 19.6w 13.9" 130d Co(sa1Phdpt) U 2.004. 1.997 "2.088 16.0, 17.0 22.6 130d Co(salMe0Phdpt) U 2.002, 1.995 "2.084 14.6, 16.9 22.1 130d Co(5-Brsaldape) U 2.004, 1.996 "2.091 17.6, 18.7 28.EW 130d Co( 5-Clsaldape) U 2.003, 1.995 "2.090 16.4, 19.1 27.6 130d Co(5-BrsalMedapp) U 2.010, 2.000 2.009 14.3, 18.6 23.7 130d Co( 3-MeOsal Medapp) U 2.009, 2.000 "2.097 2.034v 14.3, 19.1 23.6 14.3v 130d
a Measured at 77 K, unless otherwise noted. gl and AICO calculated from 91 = l/2(3~, - g) and Al = 1/2(3aiso- A). Measured at -48 OC. D. L. Diemente, Ph.D. Thesis, Northwestern University, Evanston. Ill., 1971. Measured at -66 OC. ' Measured at 20 OC. Spectrum not well resolved. Measured at -70 OC. Measured at -44 OC. Measured at -35 'C. Measured at -10 OC. I Measured at -15 OC. Measured at -77 OC. " Measured at -74 OC. O Measured at -61 OC. p Measured at -25 OC. Q Measured at -52 OC. Measured at -80 OC. Solvent was 70% toluene-20% DMF-10% base (-1 M). ' Measured at -95 OC. Measured in toluene/dichloromethne. Measured at 24 OC. Measured at --150 OC. indeed function as oxygen-carrying proteins. Studies involving TABLE VIII. Values of YO-0for Cobalt-Dloxygen Complexes EPR showed that the cobalt atom in deoxy-CoMb and CoHb is five-coordinate and, as is true for the iron in natural proteins, is compound YO,, cm-' a ref coordinated to the imine nitrogen of the proximal histidine res- id~e.'~~Further, Co(PPIX) has the same orientation within the Co(3-Me0salen)(py)(O2) 1140 34 Co(acacen)(B)(03 -1 130 110 protein as does the heme. 153,154 Comparison with the spectrum Co(benacenXpyXO2) 1128 C of the monoimidazole complex of Co(PPIXDME) in organic sol- Co(cyenXpYX0ddfe 1137, 1078' 9 vents shows that the five-coordinate Co(ll) of CoHb exhibits no Co(cyen)(Melm)(02)e,h 1137 9 significant perturbations which are caused by its incorporation [WCN)S(O~)I3- 1138' 147 into the protein en~ir0nment.I~~Exposing CoHb (CoMb) to Co(TpivPP)(NTrlm)(02) 1153,) 1077,' 1125k 145 oxygen gives oxy-CoHb (oxy-CoMb).15*-15* EPR studies again Co(TpivPP)(Melm)(02) 1150. 1077' 145 show that the Co-02 linkage within the protein is not significantly Hb(Co(deut))(Oz) ' 1105,1065' m different from that of an oxygenated cobalt porphyrin in solution a Spectra obtained as a Nujol mull unless otherwise noted. Values for (gl = 2.08, giso= 202, ag = 118 G, A? = 9 G). VO-0for B equal to py, CHs-py, NHp-py, and 4-CN-py. J. D. Landels and Comparisons of the properties of the naturally occurring heme G. A. Rodley, Synth. /mg.MetUfg. Chem., 2,55 (1972). Spectrum taken in 10% py in DMF. e Resonance Raman used to obtain Value is for group both in and out of a protein environment were previously uia~~8 T. Szymanski. T. W. Cape, F. Basolo, and R. P. Van Duyne, J. Chem. impossible, since heme cannot ordinarily be prepared in a &7c., Chem. COmmUn., 5 (1979). Spectrum taken in 10% Melm in DMF. five-coordinate state and heme in solution is oxidized to hemin Spectrum taken in benzene. Doublet, with ~1%~= 1155, 1150 cm-l, due upon exposure to oxygen. Hoffman and co-w~rkersl~~reported perhaps to two different conformers of 02and NTrlm. Value is for YI~I.~~O. the first such comparison when Mossbauer parameters of the I Spectrum taken in buffered aqueous solution. J. C. Maxwell and W. S. daughter compound of 57Co(PPIX)(py)(02)agree well with the Caughey, Biochem. Biopbys. Res. Commun., 80, 1309 (1974). values for oxymyoglobin,lsO suggesting that the electronic structure of the heme iron in oxy-Hb is not measurably influenced Of OXY-COH~.'~~Thus, the stabilization of the heme group in by the protein. This parallels the conclusions from EPR studies hemoglobin is probably not ascribable to protein-induced 156 Chemical Reviews, 1979, Vol. 79, No. 2 Jones, Summervilie, and Basolo
-1.0
c ?Lt - -2.0 (u 0 Y
0 0 -3.0
I
- 4.0 1 I I I I -.30 -.40 -.50 - 60 -.70
E 1/2 (volts)
Flgure 15. Comparison of oxygen uptake (log KO*,-21 “C) with E1,2 values for Co(ll) -+ Co(lll) of Co(benacen)(B): (1) PPh3; (2) 4-CNpy; (3) py; (4) 3,4-Me2py; (5) pip; (6)sec-BuNH2; (10) n-BuNH2 (data from refs 132 and 165. changes at the electronic state of the iron in oxyheme. an oxygen carrier in a natural environment, the question arises A chief source of the ongoing interest in ligand binding to as to what properties of a metal are necessary to create an hemoglobin rests in the following allosteric properties which oxygen carrier. It had been suggested by Vogt et aL2 in a review result from its tetrameric nature.60aThe dioxygen binding curve that in order to synthesize reversible oxygen carriers it was is “cooperative” (autocatalytic), not hyperbolic (Figure 7). The necessary to have metal ions that have oxidation potentials lying degree of cooperative binding can be expressed by the Hill’s in a certain range so that there is some donation of electrons to constant, n, which has the value n FZ 2.8.161 For comparison, the oxygen molecules but not enough to cause irreversible ox- independent O2 binding by the four hemes of Hb would require idation of the metal. This implies that metals that are readily n = 1.O, whereas all-or-none binding to the four hemes would oxidized (e.g., Cr(ll)) react with oxygen irreversibly, and metals require n = 4. The degree of cooperativity, as measured by the difficult to oxidize (e.g., Ni(ll))do not react with oxygen. However, n value, appears to reflect the details of the ligation process and metals between the two limiting redox potentials (e.g., Co(ll)) thus the nature and type of intermediates which occur as the four should react reversibly with oxygen. They further stated that the hemes of Hb react. oxidation potentials of the metal ions could be modified to fall It was found that, for CoHb, the binding of oxygen is cooper- within the range of reversible carriers by chelation with the ati~e.~~~,~~~Hill’s constant n (a measure of cooperativity) is at proper ligands. Such qualitative suggestions have recently been least 2.3 and probably as large as 2.5 when the prosthetic group given quantitative significance.132 is CO(PPIX).~~~When the prosthetic group is Co(MesP) or Co- Equilibrium constants, Ko2, have been determined for the (DePP), values155for n are 1.2 and 1.5, respectively, compared reaction of dioxygen with cobalt(l1) in many different ligand en- with the Hb values of 2.8.161 Thus in accord with Perutz’sBBa vironments (eq 18). arguments, CoHb undergoes a quaternary structural change upon oxygenation, implying that the stereochemical changes that KO2 occur as the five-coordinate, low-spin CO~~(PPIX)moiety of CoHb Co(L4XB) -t 02 F+ Co(L4)(B)(02) (18) binds dioxygen are compatible with the mechanism that triggers For a given cobalt(l1)-Schiff base chelate Co(SB4) and different the quaternary structural transition in Hb. axial base B, a linear correlation was found to show that as the This cooperativity in CoHb has been used either to question ease of oxidation (€112 for Co(ll) - Co(lll)) of the complex in- or support Perutz’s mechanism of cooperativity. Two different creases, the dioxygen affinity (Ko2)of the complex increases approaches have been used in attempts to mimic the T state of (Figure 15).115,13211651‘66There are enough data to show that the Hb. In one the cobalt has been restrained by the coordination to protonic base strength of the axial base does not correlate with an axial base which is covalently attached to the porphyrin and oxygen uptake. For example, the values of Ko2for changes in the other uses the sterically hindered axial base 1,2-Me21m. By axial base decrease in the order +butylamine > l-methylim- varying the length of the chainlB2on which the axial base is at- idazole > piperidine, although the pKa’s of these protonated tached, it was possible to enforce various amounts of steric bases are 10.6, 7.25, and 11.3, respectively. That l-methylim- constraint on the metal center. The greater strain resulted in a idazole is much more effective in promoting complex formation weaker cobalt-ligand bond destabilizing the dioxygen adduct. than is expected from its protonic basicity may arise from its The use of a sterically hindered basels3.1s4also destabilizes the good 7r-electrondonating property. This same type of behavior dioxygen adduct. Both methods cause the cobalt metal center has been observed122~129~167for cobalt porphyrins. Figure 16 to be drawn out of the porphyrin plane toward the axial base, thus shows a plot of log Ko2vs. pKa for different axial bases on Co- weakening the metal dioxygen bond. (PPIXDME) in toluene solution. Neither for these equilibrium constants nor for the derived thermodynamic quantities, AH, 4. Equilibria AG, or AS, is there a simple, general relationship that is related to Since it has been found that cobalt is capable of serving as the pKa’s. Synthetic Oxygen Carriers In Biological Systems Chemical Reviews, 1979, Vol. 79. No. 2 157
However, direct correlations between the pKa of structurally related axial bases and O2 uptake have been observed. As the dashed line indicates (Figure 16) there is a reasonably linear correlation of the equilibrium constants with the pKa's of the -I 0 substituted pyridine pKa's of the substituted pyridines. Tetra- phenylporphyrin and other synthetic porphyrins yield approxi- mately the same results. Also for the series of P-donor ligands Me Im P(C6H5)3, P(OC6H5)3,and P(C4H& with Co(MPIXDME), Takay- 0" -20- anagilZ5et al. noted a correlation between pKa and log KB,and Y DMF 0, PIP log Ko2.For uptake of an axial ligand, the p (slope of the line for 1 pKa vs. log Kand a measurement of the sensitivity of the equi- librium to u donation) is much greater (0.4 vs. 0.1) for the -30- phosphorus ligands than for nitrogen ligands. However, the p values for the oxygenation equilibria (eq 18) is very similar for both the phosphorus and the axial amine systems. The fact that -40- a linear relationship is observed between the proton acidities / of a series of ligands containing the same donor atom, Le., N or Ill1 I P, and the equilibrium constants observed for the bonding to the -2-1 0 12 3 4 5 6 7 8 9 1011 12 cobalt(l1) metal center implies either that the ligand metal r-b- PK, onding plays a relatively constant role or that there exists an Figure 16. Comparison of log KO* (toluene, -45 'C) for Co(PPIXDMEXB) intimate balance between u- and a-bonding effects. Both u- and as a function of the pKa of the axial base (6)(data from ref 129). r-bonding have been implicated in the bonding of pyridine and P-donor ligands to metals. The variation in bonding of the neutral nance of ir effects (resonance interactions) over effects (in- ligand to the cobalt observed for the N- and Pdonor series may ductive contributions). Also solvent effects may contribute to therefore reflect differences in r-bonding between the cobalt(l1) this anomalous behavior. Furthermore, it has been noted168bthat center and the nitrogen- and phosphorusdonor ligands. a change from a nonpolar solvent such as toluene to the polar Such differences can be attributed to the donor properties r solvent DMF has a pronounced effect132on the equilibrium (eq of the ligands. In the Pauling3l model the bonding of an oxygen 18). In toluene (t = 2.4) at -23 OC Co(PPIXDME)(l-Melm)has atom to a metal complex may be explained in terms of the a a log Kopof -2.62, while in DMF (c = 36.1) at the same tem- donation from a nonbonding sp2 lone pair on oxygen to the dz2 perature log K is - 1.10. This large solvent effect can be ascribed orbital on the metal, accompanied presumably by synergistic to the stabilization of the polar Co(lll)-(O2-) species in the more r-back-bonding from the filled d, (or d,) orbitals into the empty polar solvents. r* orbitals of oxygen. Since9 ligands coordinated trans to oxygen For changes in the equatorial ligand,115s132keeping the same will compete for r-electron density on the metal, the binding of axial base, there is a linear correlation between log Ko2 and the 02 to Co(Por)(B) will be sensitive to the r-donating ability or E1/2value for the various cobalt(l1) complexes. Basoloi3* et al. r-accepting ability of the axial ligand 6.Good a-acceptors will suggested that this correlation exists because the redox potential decrease r-electron density on the metal, resulting in a poorer of the cobalt chelate provides a measure of the electron density oxygen carrier, whereas good r donors will promote oxygenation on the cobalt metal center, which appears to be the major factor by increasing the electron density available for back-bonding. in determining O2 affinity. Increasing electron donor properties Imidazoles are much better A donors than pyridines; the strong of the equatorial tetradentate ligand or the axial base results in r-donor properties of DMF have also been demonstrated. On an increase in the equilibrium constant Ko2.The lower oxygen the other hand, the log Kopfor piperidine is much less than that affinity117exhibited by Co"(benacen)(py)(log K = -0.28 at 31 expected from basicity arguments. It is possible here that steric "C) results from the electron-withdrawing effect of the aromatic effects play a role through the interactions of the ring protons rings in the former. with parts of the porphyrin core, preventing close approach of It also follows that the fact that cobalt(l1)-porphyrin complexes the base to the metal. have a smaller tendency to form dioxygen complexes than do The observed correlation between ElI2 values and log Ko2 cobalt(l1) Schiff base complexes may result from the porphyrin for base variation also holds for the variation of the equatorial ligand having a greater tendency to delocalize electron density ligand.109~132The greater the amount of electron density on the r away from the cobalt atom than do the less aromatic Schiff base cobalt metal center, the greater the oxygen affinity. In varying ligands. the para substituents of the phenyl groups of Co(T(pX)PP)(py), In addition to electronic effects, steric factors can greatly Walker et al.124found a Hammett relationship between 4a and influence oxygen affinity. Ugo and others167have shown that the log Ko2;again this is related to the amount of electron density ethylene-bridge-substituted compounds of Co(salen) exhibit at the cobalt center. Recently Cummingsl l3 and co-workers using Co(sacsacen)(Melm) found that the N2S2type ligands show differing behavior toward oxygen in adonor solvents, mainly due less oxygen affinity than those of the ketoiminato counterparts to the effects of the substituent on the coordination sphere around the cobalt center. For example, in the complex Co- (N202 type). This is due to the poorer a donor properties of the sulfur donor atoms. In addition the sulfur donors can drain (salpn)(py)the coordination of Co(salpn(+)) can be viewed as electron density from the cobalt ion via a a-back-bonding in- a distorted square pyramid, where Co(salpn(meso))is interme- teraction between filled d, and d, orbitals on the metal and diate between a square pyramid and a trigonal bipyramid. These empty d orbitals on the sulfurs. In addition the para substituents differences in the coordination polyhedra are thought to account of Co(pXbensacen) and Co(pXbenacen) were varied and their for the differences in oxygen affinity with Co(salpn(+)) being effects on log KO?were studied. It was found that the variation much more reactive. of para substituents resulted in a non-Hammett behavior of log Ko2. The trends observed, log Kop for pCI greater than log Ko2 5. Thermodynamics for pOCH3, cannot be explained simply on the basis of inductive Thermodynamic data for ligand and dioxygen uptake by co- effects and Hammett-Taft parameters. Since the rings of these balt(ll) complexes of Schiff bases and of porphyrins are given systems are expected to be coplanar with the Co-N202 and in Tables IX and X. A comparison of log Ke, AH, and AS for li- CO-N~S~,the author explains their results in part to the domi- gand uptake demonstrates that no simple correlation exists 158 Chemical Reviews, 1979, Vol. 79, No. 2 Jones, Summervllle, and Basolo
TABLE IX. Thermodynamic Values for the Bindlng of Axial Bases * to CoMb. Although producing no major effect on the electronic Cobalt(l1) Complexes structure of the oxygen adduct, the globin does produce a large Co(L4) + B + Co(L4XB) effect on its oxygen affinity. At 25 OC, the incorporation of ~ Co(PPIX) into globins of whale or horse myoglobins increases AH, AS the value of Ko2by a factor of ~300.129~156It is found for horse compound base kcal/mol (eu/mol) ref myoglobins that the protein provides a significantly favorables3 (positive) entropic contribution to binding whereas the en- CO(T(P-OCH~)PP) PY -8.5 -16 127 02 4-Mepy -7.3 -1 1 127 thalpic term is experimentally the same as that for the free 3,4-Lut -9.0 -16 127 metalloporphyrin in toluene solution. For whale CoMb there is Quin -0 -6 127 a balance between a more favorable entropic (positive) and Melm -11.4 -23 127 enthalpic (negative) contributions to O2 binding. Kaclm -10.1 -20 127 The basis of the more favorable entropy of dioxygen binding PiP -6.8 -7 127 in the protein environment is related at least in part to the sol- Co(PPIXDME) DMF -7.9 -21 129 vation effects on the binding of dioxygen. Formation of the 4-CNpy -10.0 -19 129 strongly dipolar Co(lll)-02- linkage from a neutral cobalt(l1) -6.9 -6 129 PY porphyrin and a neutral oxygen molecule causes solvent reor- PY -9.7 -18 171 Im -7.9 -10 129 ganization which accommodates the charge separation and thus Melm -10.7 -19 129 stabilizes the metal-dioxygen bond. This reorganization would ~-NH~PY -a. 1 -9 129 appear thermodynamically as a negative contribution to the PiP -10.4 -17 129 entropy of oxygen binding to the complex in solution. If the hy- 4-t-Bupy -9.0 -13 129 drophobic protein crevice is already organized to accommodate Co(MPIXDME) PY -9.2 -17 125 a polar metal-oxygen group, the negative entropy associated P(*Bu)s -13.3 -27 171 with the formation of the crevice would appear as part of the P(OCH3)3 -6.9 -15 125 entropy of formation of the metalloprotein itself, not as a con- PPh3 -7.0 -17 125 tribution to the entropy change upon oxygen binding. AsPhs -5.2 -15 125 Anomalous oxygen affinity has been noted by Coll- S(CH3)2 -4.5 -9 125 Co(salen) PY -7.8 -21 e man1s3,164,172for his cobalt “picket-fence’’ porphyrin. Although Co(sal(f )dpen) PY -8.8 -28.0 e Co(T(gOCH3)PPX1-Melm)has P11202of 15 500 Torr’64 (25 OC, Co(sal(m)dpen)d PY -8.6 -27.0 e toluene), Co(PFP)(l-Melm) has a PlI2O* of 140 Torr163(25 OC, Co(sal(f )chpn) PY -6.5 -17.0 e toluene). The value for PlI2O2of Co(PFP)(l-MeLm) is similar to Co(sal(m)chpn) PY -7.4 -21.0 e that of CoHb and CoMb (P11202at 25 OC -55 T~rr).’~~.’~~The a Solvent is toluene, unless otherwise noted. Quinoline. N-Acety- anomalous behavior of Co(PFP)( I-Melm) when compared to limidazole. Values obtained with CHC13 as the solvent. *E. Cesarotti, M. other model systems, and similarity to CoHb and CoMb, is ap- Gullotti, A. Pasini, and R. Ugo, J. Chem. SOC., Dalton Trans., 757 (1977). parently due to a control of solvation factors which otherwise between any of these parameters and the pKa of the protonated disfavor oxygenation. ligands. If one examines the data for a structurally similar series of bases, e.g., substituted pyridines, there does exist a corre- 6. Reactions lation’ 15.127,1299132 between the thermodynamic data and pKa For the nonaqueous solvent system of Co(PPIXDME) in toluene of the protonated ligand. A similar correlation also exists be- qualitative EPR and visible spectroscopy observations are tween the uptake of dioxygen and the pKa of the axial ligand. The consistent with a rapid formation of the 1:l complex followed values of AS for oxygenation are in the neighborhood of -60 by a slow reaction to yield the 1:2 species. James122et al. found eu. The main contribution to this value comes from the loss of that the rate-determining step appeared to be the formation of degrees of freedom of dissolved dioxygen on coordination. the dioxygen adduct. Since this is in direct contradiction with the In the series of cobalt(l1) chelates with the same axial base bulk of qualitative measurements, they invoked a rate-deter- the following order is noted for AH and AS of oxygenation, with mining step in which there is some slow rearrangement or dis- Co(SB4) being the most exothermic: tortion of the 1:l oxygen complex. In addition, they found that when the axial base was imidazole or benzimidazole 1: 1 oxygen Co(TPP) > Co(PPIXDME) > Co(SB4) (19) complexes were formed, but upon warming to room temperature It is also interesting to note that the more negative AH values these complexes rapidly dimerized to the p-peroxo compounds. are associated with the more negative values of AS. This behavior is contrary to that observed when the base is 1- The thermodynamic values for oxygen uptake by Co”- Melm or pyridine. This is believed due to the ability of imidazole (PPIXDMEXB) complexes reported by lbers and co-worker~~~~~~~~to hydrogen bond, thus lowering the activation energy of di- were reanalyzed by Guidry and Drago.ls9 They were unable to merization. use the published data to obtain reliable values for thermody- This observation of possible hydrogen bonding agrees with namic properties of the system. Reanalyzing their own data, lbers O~hiai’s~~O~proposed mechanism of dimerization. The co- and co-w~rkersl~~reaffirmed their method of analysis and val- balt-dioxygen complex has its odd electron in one of the rg* ues. They concluded again that there was no direct relationship orbitals of the oxygen. This unpaired electron may then pair with between pKa of the axial base and log Ko2. Drago et aI.l7O re- an unpaired electron in the d,z orbital of another cobalt complex. peating the work of lbers and co-workers found a AHof -7.80 This interaction is similar to the interaction between Co(ll) and kcal mol-’ for the addition of O2to Co1I(PPIXDME)(py)in toluene O2 in forming the 1:l oxygen adduct. The transition state is as compared to lbers and co-worker~~~~~~~~of -9.2 kcal mol-’. represented in Figure 17 and it can be seen that in the presence Recently Yamamoto17’ et al. investigating the same system of bulky equatorial ligands (e.g., porphyrins) there would be reported AHfor the same reaction as -10.3 kcal mol-‘. These considerable steric interactions. This barrier could be overcome discrepancies may be largely due to the difficulties in obtaining by raising the temperature or.,by deforTing or rotating the rg* good thermodynamic values on such systems. orbital in some way. The fact that dimerization is accelerated Also shown in Table IX for comparison are the corresponding by imidazole and not by I-Melm in the case of Co”(PPIXDME) data for CoMb and Mb. The influence of the globin (apoprotein) may be understood in terms of its hydrogen bond forming ca- can be directly observed by comparing the oxygen binding of pacity. The hydrogen bond may force rotation of the rs*orbital, the five-coordinate Co(PPIXDME)(Melm) complex with that of enhancing dimerization. Synthetic Oxygen Carriers In Biologlcal Systems Chemical Reviews, 1979, Vol. 79, No. 2 159
TABLE X. Thermodynamic Values for the Binding of Dioxygen a to Cobalt(l1) Complexes: Co(L4)(B) + O2 * Co(L4)(B)(02)
AH,b ASb AH,b compound base kcal/mol eu/mol ref compound base kcal/mol eu/mol ref
Co(acacen)c PY -15.03 -42.2 d 5-CIMelm -8.6 -54 121 Co(acacen) PY -17.3 -72.7 132 Melm -8.9 - 49 121 Co(Phacacen) PY -16.3 -72.5 132 PiP -8.2 -49 121 Co(Meacacen) PY -15.6 -69.5 132 3,4-Luth -8.5 -51 121 Co( benacen) ~I-BuNH~ -17.4 -72.3 132 PY -9.0 -53 121 i-BuNHp -18.0 -80.0 132 Co(T(pCH3)PP) PY -9.30 -55 124 Melm -17.5 -73.5 132 Co(TPP) ' PY -9.54 -57 124 5-CIMelm -17.5 -74.5 132 CO(T(~F)PP) PY -9.34 -56 124 sec-BuNH2 -17.8 -76.1 132 Co(T(pC1)PP)' PY -9.22 -56 124 PiP -16.7 -71.9 132 Co(T(pCN)PP) PY -8.39 -52 124 3,4-Lut -16.8 -73.9 132 Co(TPP) 3-Mepy -8.1 -46 162 4-CNpy -16.9 -77.2 132 Co(2)i-k -7.2 -40 162 PY -13.3 -64.5 132 Co(2)k -5.0 -34 162 PY -16.2 -69.6 113 Co(3)i, -8.5 -49 162 Co(CH3Obenacen) PY - 16.5 -70.6 113 Co(PPIXDME) t-BUpy - 10.0 -57 122 Co(CH3benacen) PY -16.3 -69.6 113 Melm -11.5 -58 122 Co(Brbenacen) PY -17.1 -72.4 113 Im -11.2 -58 122 Co(Clbenacen) PY -17.3 -72.8 113 Bzlm -9.6 -56 122 Co(bensacen) PY -8.05 -46.5 113 PY -9.2 -53 122 Co(CH3Obensacen) PY -10.8 -57.6 113 PY -7.80 -48.7 170 Co(CH3bensacen) PY -11.2 -57.8 113 PY -10.3 -57 171 Co(Brbensacen) PY -12.1 -61.1 113 PY a -14.5 -66 171 Co(C1bensacen) PY -13.3 -66.3 113 2-Melme -14.6 -66 171 Co(sacacen) PY -16.6 -75.1 132 Co(MPIXDME) P(OCH3)3 -10.3 -57 125 PY - 12.0 -61.5 113 P( ~-BU)~ -11.8 -59 125 DMF -14.1 -71.3 113 S(CH3)2 -8.1 -52 125 Melm -15.4 -75.0 113 PY -9.01 -50 171 Melm e -16.1 -75.6 113 PY e -12.0 -57 171 Melm' -18.5 -80.9 113 2-Melma -12.9 -59 171 Co(sal(f)dpen) PY -10.3 -42.1 9 Co(DPIXDME) PY -9.9 -55 171 Co(sal(m)dpen) PY -17.2 -58.1 9 PY -13.7 171 Co(sal(f)chxm) PY -12.9 -46.2 9 2-Melm -13.1 -60 171 Co(sal(m)chxm) PY -14.1 -53.3 9 Co(TpivPP) Melm' -13.3 -53.2 163, 164 Co(T(gOCH3)PP PY -9.3 -55 121 Melm -12.2 -51.2 163, 164 4-Pic -8.8 -52 121 1,P-Meplm -11.8 -53.2 163, 164 3,4-Lut -9.2 -54 121 CoMb -11.9 -47.6 197b 4-Me2Npy -8.5 -48 121 CoHb -7.5 -35.1 197b y-Col -9.5 -58 121 a Solvent used is toluene unless otherwise noted. Standard state 1 Torr unless otherwise noted. Values obtained with piperdine as the solvent. Standard state 1 atm. G. Amiconi, M. Brunori, E. Antonini, G. Taugher and G. Costa, Nature (London), 228, 549 (1970). e Values obtained with DMF as the solvent. 'Values obtained with CH3CN as the solvent. 9 E. Cesarotti, M. Gullotti, A. Pasini and R. Ugo, J. Chem. SOC., Dalton Trans., 757 (1977). Values obtained with CS2 as the solvent. ' Values calculated from data in ref 124. / Values obtained with CHpC12 as the solvent. Number in parentheses represents porphyrin: (2) 5-[2-(4-(3-pyridylcarbamide)-rrbutoxy)phenyl]-lO, 15,20-tritoylporphyrin; (3) 5-[2-(3-pyridyl)propoxyl] phenyl-lO,l5,20-tritoylporphyrin. ' Values are for solid state.
Co(L4)B + O2 Co(L4)(B)(02)
Whether the 1:l or 1:2 complex is observed depends on Keq (eq 20) and k (eq 21). Kinetically the 1: 1 adducts can be stabilized by use of low temperatures. At these temperatures the reaction to form the dimeric p-peroxo complex is virtually stopped. For example C~(salen)(py)~~reacts at room temperature with oxygen to form p-peroxo dimer,2 whereas at -70 OC, only the formation of the 1:l complex is 0b~erved.l~'The presence of bulky equatorial ligands, such as porphyrins, also hinder dimeriza- tion. James et a1.lZ2 noted in their studies on Co"(PP1XDME) \I complexes that if Keq(eq 20) is small, only the reaction to give the 1:l complexes is detected. If Keqis large the rapid reaction u to give the 1:l oxygen complex and the subsequent reactions Figure 17. Arrangement in the transition state of ngb(CO~~~O~-) and d22 (Co(l1)) in the formation of the 2:l complex. can be observed. The equilibria between 1:l and 1:2 are very solvent dependent. Since a charge separation is present in the greater stability to the dimer over the monomer. Thus the choice 1: 1 oxygen complexes, the use of polar solvent stabilizes the of solvent greatly influences the system as to whether the 1:l 1:l adducts, as mentioned earlier. The less polar solvents afford or 1:2 adducts will be observed. 160 Chemical Reviews, 1979, Vol. 79, No. 2 Jones, Summerville, and Basolo
It is interesting to note that the “stoichiometry switch” from metal-metal interactions as evidenced from EPR and visible binuclear to mononuclear complexation occurs with relatively spectra. No attempt was made to study the interaction of the little change in electronic structure. The EPR spectra of the system with oxygen. However, Chang,177 using a similar parent compounds of the 1: 1 and 1:2 dioxygen complexes show “cofacial” system, found that his system rapidly formed a type very little differences. McLendon and Mason1l4 studied the Ilb complex when it reacted with oxygen in a toluene-dichloro- binding of O2 by cobalt(l1) complexes of 14-member macrocy- methane mixture at room temperature. cles. With increased oxidation of the macrocycle ligand, they Earlier less elaborate experiments involved the attachment found that the oxygen affinity of the complex drops dramatically, of the porphinatocobalt(l1)complex either covalently or coor- and a change to 1: 1 stoichiometry occurs. This behavior cor- dinately to a support. Misono and c~-workers~~~-~~~showed that relates well with the observed behavior of cobalt-Schiff base when cobalt-Schiff base complexes were coordinately attached and -porphyrin complexes. The more oxidized cobalt-porphyrin to poly(4-vinylpyridine)they reversibly bound dioxygen from 40 complexes are poorer oxygen binders and are less likely to form to 140 OC. This behavior was also noted for some cobalt por- 1:2 complexes. phyrins coordinately bound to copolymer^^^^*^^^ derived from Theoretical calculations on the nature and geometry of the styrene and 1-vinylimidazoles. coordinated dioxygen in Co(acacen)(B)(02)have been performed Numerous cobalt porphyrin and phthalocyanine systems have by Veillard et al.37Using ab initio SCF calculations with a minimal been used as catalysts for the oxidation of organic substrates. basis set, the calculated configuration is a Co(lll)-(O2-) with an Hara and c~-workers’~~-~~~have used phthalocyanatocobalt end-on bent structure. Furthermore the calculations showed a as a catalyst for the oxidation of organic substrates such as direct relationship between the ease of oxygenation, the udonor cumene and acrolein. In these systems a metal-dioxygen ability of the fifth ligand, and the ease of oxidation of cobalt(l1) complex is formed which in turn initiates the oxidation process to cobalt(ll1). The calculations support a formal description of by abstracting a hydrogen atom from the substrate. This is fol- Co(lll)-(02-), where a bond is formed between the unpaired lowed by a series of radical reactions leading to the insertion of electron in the cobalt dZ2 orbital and an electron in a 7rg* orbital oxygen in the substrate. Similar to this is the oxidation of al- of the dioxygen. This leaves one unpaired electron in an orbital dehydes by the same systems,Ia5the initial step again being the of most oxygen rg*character. Though formally Co(lll)-(Oz-), formation of a radical by the abstracting of a hydrogen atom by population analysis indicates that a negative charge of 0.44 to a cobalt4ioxygen complex. Ohkats~~~~~’~~and TezukaIa6noted 0.64 is present on the dioxygen moiety, concomitantly there is the same behavior of Co(T(pCH3)PP)and Co(TPP). a decrease of 0.48 of an electron from the dZz orbital. The A better model for natural systems is the insertion of dioxygen variation in electron population on the oxygen is due to the in the catalytic oxidation of indoles (eq 22).1893190The catalyst variation of the axial base. If the coordinated dioxygen is superoxide-like it should be 0 possible to add superoxide to cobalt(ll1) and obtain the same complex as if one had added O2to a cobalt(l1) complex. This was done by Ellis and co-~orkersl~~when they added electro- chemically generated free superoxide in DMF to the cobalt(ll1) complex aquocobalamin (vitamin B12,). Since aquocobalamin can be either Co(~alen)~~~*~~~or Co(TPP).IgoThe oxidation undergoes rapid ligand substitution in the axial positions, it was products are the same as those observed for the oxidation of possible to coordinate the free superoxide. The EPR spectra at tryptophan by 2,3-dioxygenase. In the natural systemlgl it has - 170 OC (g = 1.999, Aco = 11.8 G) were identical with those been demonstrated that the reaction intermediate is a transient of the cobalt(l1) aquocobalamin complex (reduced by NaBH4) superoxo complex. product when reacted with oxygen (g = 1.998Ac0 = 11.7 G), Electrogenerated superoxide ion reacts with hydrocarbons providing support for the formalism of Co(lll)-(O2-). having labile hydrogens. It was found that the addition of co- Simic and Hoffman174reacted 02- with Co(l), Co(ll), and Co(lll) balt-phthalocyanine complexes to these system^'^^^^^^ ac- chelate complexes in aqueous systems. They found that su- celerated the reactions. The acceleration was believed due to peroxide did not bind to their Co(lll) chelate, [C0~~’(1,3,8,10- the complexation of the generated superoxide ion to the metal tetraeneN4)13+.They did note that superoxide did bind to the center. The coordinated peroxo group would then facilitate the cobalt(l1) species, [Coli( 1,3,8,1 O-tetraeneN4)I2+ and oxidation of the substrate. [C0“(4,1 1dieneN4)12+.The resulting spectra of the adducts were not those of the corresponding Co(l) or Co(ll) complexes, ruling C. Cobalt-Dioxygen Complexes in Aqueous out Oz-as a simple electron transfer agent. It was believed that the 02- added to the metal center at a labile axial site. The re- Solutions sulting complexes display intense charge-transfer bands. Much of the research on synthetic oxygen carriers has been Since the addition of 02- to Co(lll) complexes generates the done with metal complexes in aprotic solvents. Such solvents dioxygen adduct, the logical extension would be the generation are believed to create an environment at the metal site similar of Oz- from the dioxygen complex. This has indeed been done, to that provided by the hydrophobic pocket of the natural oxygen with the generation of Li02 from a cobalt(l1) complex and 02.175 carriers. The use of protonic solvents often results in the irre- Costa et al. using Co(salen) in pyridine solution, with added versible dioxygen oxidation of the metal complex. However, it lithium perchlorate and oxygen present, electrocatalytically has long been known that certain cobalt(l1) complexes reversibly generated Li02. A coordinated superoxide ion is postulated as react with dioxygen in aqueous solution. In fact the first dioxygen the intermediate which transfers the superoxide moiety to a complex, [(NH3)5Co-0z-Co(NH3)5]4+, was isolated from lithium ion forming Li02. aqueous solution in 1898 by Werner and M~1iu.s.~~The complex is readily prepared by the air oxidation of an ammoniacal solution of a cobalt salt. The complex has been extensively investigated 7. Catalysis with a variety of modern physical techniques, and it is known to There is currently interest in the development of metal por- be correctly formulated as a p-peroxo low-spin cobalt(ll1) phyrin catalysts. Approaches to the problem include the syn- complex (see type Ilb, Table 11). The complex reacts with oxi- thesis of “face to face” 178 or “cofacial” 177 diporphyrins, and dizing agents such as cerric ion to yield the corresponding p- also attachment of a metalloporphyrin to a rigid support. The superoxo cobalt(ll1) complex (type Ib, Table 11). cobalt “face to face” systems of C~llman’~~show some Similar pperoxo cobalt(ll1) complexes are formed by the Synthetic Oxygen Carriers in Biological Systems Chemical Reviews, 1979,Vol. 79, No. 2 161
reaction of dioxygen with a variety of cobalt(l1) chelates. These TABLE XI. Water-Solubte Dloxygen Complexes of Cobalt include amino acids, polyamines, and saturated macrocyclics as ligands. The dioxygen adducts of these cobalt complexes are complex ref listed and referenced in Table XI. Reviews which devote con- siderable attention to the aqueous solution chemistry of cobalt A. Mononuclear Complexes [CO(CN)~(~Z)~~- 147, 194, 195 oxygen carriers include the excellent articles by Fallab,5 Wilk- [Co(s-Me2en)2(02)X] "+ 196 ins,7 and McLendon and Martell.i6 vitamin B12(02) 130j Most of the water-soluble dioxygen cobalt complexes given Co(HBX02) and Co(Mb)(02) 152, 154, 157, 197 in Table XI are binuclear. One of the exceptions reportedlg6 B. Dinuclear Monobridged Complexes recently is the mononuclear compound ci~-[Co(s-Me~en)~- [(NH~)~C~(OZ)C~(NH~)~~4+ 6, 7, 57, 198 (C1)(02)]CI which was prepared by the room temperature re- [ (tetraen)Co(02)Co(tetraen)14+ 199 action of an ethanol solution of [Co(.~-Me~en)~Cl~]with dioxygen. [ NH~(~~)zCO(O~)CO(~~)~NH~]~+ 200 The optical and EPR spectra of the dioxygen complex are in [ (en)(dien)Co(02)Co(dien)(en)]4+ 199,201 accord with its being a monomeric species of the quperoxo type, [(tn)(dien)C0(02)Co(dien)(tn)]~+ 202 [ (pn)(dien)Co(02)(dien)(pn)14+ 202 CO'~~(O~-).That this system yields the monomer, instead of the [ (NH3)(trien)Co(02)Co(trien)NH3]4+ 199 usual bridged dimer, is believed to be due to the steric hindrance [(NH3)(tren)C0(02)Co(tren)(NH3)]4+ 203 afforded by the N,N'dimethyl substitution on ethylenediamine. [ ~(cyc1am)Co(02)Co(cyclam)X]"+ 204 However, models show that it should still be possible to form the [(phen)(ter~y)Co(0~)(ter~~)(phen)l~+ 205 p-peroxo complex. Whatever the reason, this does show that [(b~~)(ter~~)Co(O~)Co(ter~~)(bi~~)l~+205 there is a delicate energy and/or kinetic balance between the [(hist)Co(02)Co(hist)] 206, 207 formation of the mononuclear and binuclear oxygen com- ~~~~Y~~Y~~~~~2~~~~~~Y~~Y~l208,209 plexes. [(di~ep)Co(O2)Co(dipe~)l 209,210 Also worthy of note (Table XI) is the fact that although many [ (diapr)Co(O~)Co(diapr)] 21 1 of the complexes are of the monobridged (p)type Co-02-C0, [(CN)~C~(OZ)CO(CN)~~ 212,213 [(dgenta)Co(02)Co(dgenta)] 214 several of the complexes are reinforced by forming dibridged C. Dinuclear Dibridged Complexes [(en)~Co(02)(oH)Co(en)~I~+ 200,201,215,216 [(trien)Co(02)(0H)Co(trien)]3+ 21 7-219 [ (tren)Co(02)(OH)Co(tren)]3+ 200, 217, 220 [(~hen)~Co(0~)(0H)Co(~hen)l~+ 221 [(~PY)ZC~(OZ)(OH)C~(~PY)Z]3+ 221,222 [(hista)Co(02)(0H)Co(hista)13+ 201,210,215 H H2 [(sedda)Co(02)(0H)Co(sedda)]- 223 species. It appears that dibridging tends to occur whenever two [(uedda)Co(O2$(OH)Co( uedda)] - 223 cis coordination sites are available on the metal center. For [(sdtma)Co(02)(OH)Co(sdtma)]+ 224 example, the tetraethylenepentamine complex [Co(tetraen)- [(udtma)Co(02)(0H)Co(udtma)]+ 224 (glyhist)Co(O2)(OH)Co(glyhist)]- H20]2+ forms the p-peroxo complex, whereas the triethyl- [ 209,210 enetetramine complex [C~(trien)(H~O)~]~+with two available [ (amacs)Co(02)(0H)Co(amocs)]- 209 [(NH~)~C~(~Z)(NH,)C~(NH~)~] (two water ligands) coordination sites forms the p-peroxo-p- 3+ 57,225 [(~~)ZCO(OZ)(NH~)C~(~~)Z~~+ 200, 226-228 hydroxo complex. The effect of dibridging is said16 to "lock in" [(trien)Co(02)(NH2)Co(trien)] 200 more tightly the dioxygen bridge. This explains why the oxy- [(tren)Co(02)(NH2)Co(tren)I3+ 203 genation of some cobalt complexes is reversible within the buffer [(phen)Co(O~)(NH~)Co(phen)l3+ 229, 230 region where significant amounts of the monobridged complex [(~PY)CO(O,)(NHZ)CO(~PY)~'+ 229,230 exists at equilibrium (eq 23). However, at higher pH where the [H~O]LCO-O~-COL(OH~)]~' oxygenation of several different cobalt chelates and have ex- plained their results in terms of the mechanism represented by eq 24 and 25.
ki COL + 02 CoL(O2) (24) k- 1 kz CoL(O*) + COL e LCO-02-COL (25) dibridged species is largely present, the dioxygen moiety may k- 2 be locked in go firmly as to make the oxygenation irrevers- This mechanism agrees with the recent studies by Martell and ible. co-workersi6 on other cobalt complexes of polyamines, amino acids, and polypeptides. The kinetic data reported are collected 1. Kinetics and Mechanism of Reversible Oxygenation in Table XII. Reactions Assuming a steady state of CoL(O2), and using the initial rate The original dioxygen-cobalt complex, [(NH&CO-O~- data where the term ~-~[LCO-O~-COL]is small, the mechanism CO(NH~)~]",was for many years not regarded as an oxygen proposed is consistent with the experimental rate expression carrier. The first synthetic oxygen carrier in water solution was given by discovered in 1946 by Burk and co-workers.206They observed d [ LCO-O~-COL]- klk2[ COLI * [02] that an aqueous solution of bis(histaminato)cobaIt(ll) reacts - (26) dt k-1 k2[CoL] readily at room temperature with dioxygen to yield an amber- + colored species, which in turn releases dioxygen upon the ad- If k2rCoL] >> k-1, then eq 26 reduces to dition of acid or by flushing the solution with nitrogen. Early d [LCO-O~-COL]/d t = kj [COLI[ 021 studies206 characterized the amber compound as (hist)Co- (27) Ol-Co(hist). Some years later Simplicio and WilkinsZo7em- which is what is generally found. However, Huchital and Mar- ployed a stopped-flow apparatus to investigate the formation have reported that the reaction of [Co(terpy)(bpy)(H20)] 2+ and decomposition of the dioxygen-cobalt complex. Wilkins and and of [Co(terpy)(phen)(H20)]*+ with dioxygen is second order co-workers7 have investigated the kinetics of the reversible in CoL. This implies that for these systems k-l >> k2[CoL], 162 Chemical Reviews, 1979, Vol. 79, No. 2 Jones, Summervllle, and Basolo
TABLE XII. Kinetic Data for the Reactions of Cobait(l1) Complexes TABLE XIII. Equlllbrium Constants lor the Oxygenation of Cobait(li) with Dioxygen in Water Solution at 25 OC Complexes In Water Solution at 25 OC
ki, k--2, AH,*, AS,*, complex ZPK, log KO* ref complexes M-’s-I s-l kcal/mol eu ref Monobridged Speciesa 2.5 X lo4 56 4 -25 231 [Co(tetraenXH2O)]2+ 34.6 15 235 -105 18 +9 218 [Co(dgenta)]2- 44 14.5 214 4.7 X lo5 0.015 15 4-19 201 [Co(hist)2] 30.4 6.6 215, 234 1.2 X IO3 0.016 10 -12 201 [ Co(terpyXphen)HzO]2+ -13 6.3 205 2.5 X lo4 0.45 7 -15 218 [C~(~~~PYX~PY)HZOI’+ -12 5.4 205 2.8 X lo5 0.46 218 Dibridged (fi-Hydroxo) Species 2.8 X lo3 0.4 220 [Co(en)~(H~0)~12+ 35 10.8 215, 235 7.2 X lo2 6 -25 201 [Co(dien)(HzO)3] 2+ 23.3 1.1 201 1.8 x 104 20 1 [Co(trienXH20)212+ 28.7 6.1 219 3.5 x 103 0.47 5 -25 207 [Co(tren)(H20)2]2+ 30.5 4.4 236 2.6 X lo3 0.043 6 -23 207 [Co(hedien)2(H20)2]2+ 22.5 1.5 236 2.6 x 104 207 [Co(hi~ta)~(H~O)~]2+ 32 8.5 201, 215 1.0 x 104 232 [ Co(~dtma)(H~O)~]+ 25.3 2.3 224 2.0 x 105 7 [Co(~dtma)(H~O)~]+ 24.6 2.4 224 3 x 103 0.6 224 [Co(~edda)(H~O)~] 16.2 -4.1 223 1.4 X lo4 0.3 224 [Co(uedda)(H~O)~l 16.7 -5.3 223 25 223 a Monobridged: Kop = [LMOzL]/[ML]2[02]. Dibridged: Kop = 22 223 [LM(02)(0H)ML][Hf]/[ML]2[Oz1. 2Co(hist)2 + 02 (hist)Co-02-Co(hist) (29) Other investigators have obtained such equilibria data by using was investigated in considerable detail. The initial rapid oxy- spectros~opic,~~~polarographic,201 and potentiometric meth- genation to give the monobridged complex [(HpO)(trien)Co- od~.*~~The recently reported data were largely obtained by O2-Co(trien)OHI3+ is followed by the slower formation of the Martell and co-workers,16 using the potentiometric equilibrium dibridged complex. Kinetic studies at different pH values suggest method. The available data are collected in Table XIII. that the p-hydroxo bridge is formed by the usual olation process, It should be noted that except for three ligands (bpy, phen, e.g., terpy), all of the ligands used are saturated. This is important because it restricts these ligands to 0-bonding, and avoids any c1 effect due to a-bonding. With this restriction, it is important that McLendon and Marte11236find a good linear free energy relation between the dioxygen uptake constants of the complexes and 2M the protonic basicity of the ligands. The stronger the base ‘OH, strength of the ligand, the more stable the dioxygen complex. H This is in accord with the concept that these systems involve a charge transfer of electron flow from cobalt to coordinated represented by eq 28. Thus, for such systems k-2 is no longer dioxygen. Thus the stronger the base strength of the ligand, the simply the rate constant for the deoxygenation of a monobridged greater the electron density on cobalt, the greater the electron species, LCo-02-CoL, but it must also include the breakup of the hydroxo bridge. transfer from cobalt to dioxygen, the more stable the dioxygen complex. This result suggests that the KO* values should in- crease with increasing ease of oxidation (€112 for Co(ll) - Co(lll)) 2. Thermodynamics of Reversible Oxygenation of the cobalt complexes, as is true for corresponding systems Reactions in aprotic solvents.132Also these results show that it is the total There has been a continued interest in collecting thermody- basicities of the ligands that are important in determining whether namic data on the dioxygen uptake by oxygen carriers, in order a cobalt complex will form a dioxygen adduct. However, the Synthetic Oxygen Carriers In Blologlcal Systems Chemical Reviews, 1979, Vol. 79, No. 2 163 previous suggestion that for cobalt complexes containing only [NH,(en),Co- -Cr(H20)d4+ + H+ N and 0 ligand atoms, at least three N's are required to stabilize a dioxygen adduct, is not valid. For example, the symmetrical and unsymmetrical ethylenediamineacetato complexes (con- %H H taining 2 N's and 4 0's)form stable dioxygen complexes in an - [NH,)(~~I)~CO-O-C~(H,O)~+ + OH (36) appropriate pH range. analogues. Also there is precedence240for the structure of the 3. Reactions of Dioxygen-Cobalt Complexes protonated species shown in eq 34. However, it should be noted that a recent suggests that such protonated species are Numerous studies have been made of reactions of dioxy- not necessarily involved in the redox process. gen-cobalt complexes in aqueous solution, but there remains Little work has been done on ligand substitution reactions of a need for the discovery of catalytic dioxygen activation reactions dioxygen cobalt complexes. One such involves the which more closely mimic biological reactions. Using the replacement of NH3 in [NH3(en)2Co-0z-Co(en)2NH3]4+ by either classical complex [(NH~)~CO-O~-CO(NH~)~]~+as an example, NOz- or NCS-. This reaction takes place with ease at room it has long been known that the complex is stable in ammoniacal temperature, without cleavage of the 1.-peroxo bonds. That solution but that it readily decomposes with the stoichiometry substitution at Co(lll)-NH3 takes place this readily is most unusual given in eq 30. when compared with the very firmly coordinated NH3's in other [(NH~)&O-O~-CO(NH~)~]~++ 10H' Co(lll) complexes such as [Co(NH3)5Cll2+. At present it is a curious fact that the peroxo ligand has a marked labilizing in- - 2C02+ + 10NH4+ + O2 (30) fluence on the Co-NH3 bond, and speculation on why this is the Also, as stated earlier, the y-peroxo complex is readily oxidized case is premature. Another example204of a substitution reaction to the p-superoxo complex. Complexes of both types can be of a p-peroxo complex is given by eq 37 reduced to give, for example, the overall reaction represented trans-[Hz0(cyclam)Co-02-Co(cyclam)HzO] 4+ 2X- by the equation + - trans-[X(cyclam)Co-Oz-Co(cyclam)X] 2+ + 2H20 (37) [(NH3)5Co-O2-Co(NH3)5I5+ + MZf + 10H+ where X- = CI-, NOz-, NCS-, and N3-. The ready replacement -P M3+ 2Co2+ 10NH4' 02 (31) + + of the aquo group qualitatively corresponds with the behavior Sykes and co-w~rkers~~~,~~~and others,238f239 have investigated of other aquoamminecobalt(l1l)complexes. There is a need for the kinetics and mechanism of this redox reaction using M2+ = quantative kinetic studies of substitution reactions of dioxy- Cr2+, V2+, Fe2+, and Eu2+. The results show that there is an gen-cobalt complexes. initial rapid reaction of the psuperoxo complex, followed by a Some studies have been reported on the photochemistry of slower much more complicated reduction of the y-peroxo p-superoxo complexes, but little has been done on the p-peroxo complex. The rapid reaction compounds. Valentine242reports the photochemical reaction represented by [(NH3)5Co-02-Co(NH3)515+ + M2+ [(NH~)~CO-OZ-CO(NH~)~]~++ H20 + 5H+ + [(NH~)~CO-~~-CO(NH~)~]~++ M3+ (32) proceeds by an outer-sphere mechanism. % [CO(NH~)~H~O]~++ Co2+ + 5NH4+ + O2 (38) Hyde and Sykes228*237investigated in detail the Cr2+ reduction of the p-peroxo-p-amido complex The reaction goes in good yield with irradiation at 365 and 313 nm, and similar reactions were observed for two other corre- sponding dioxygen compounds. In the presence of anions the product is [CO(NH~)~X]~+,in accord with other experiments243 designed to trap the intermediate [CO(NH~)~]~+.The photo- chemical reaction was also tested for the formation of singlet and they conclude that the mechanism is of the inner-sphere type state dioxygen by adding 1,3-~yclohexadieneto the reaction and that it involves four steps (eq 33-36). The OH radical (eq 36) mixture. Some endo peroxide was formed, indicating singlet then rapidly reacts with Cr2+ to yield OH- + Cr3+. It is suggested dioxygen, but other products also formed and the results remain that the inner-sphere process occurs with peroxo complexes, inconclusive. because peroxo groups are better donors than are superoxo Other types of water-soluble cobalt oxygen carriers include the sulfonated porphyrin and phthalocyanine complexes. Less work has been done with these systems, but in general they behave similar to the polyamine and amino acid cobalt com- plexes discussed in this section. For example, a kinetic of the reaction of a water solution of tetrasulfophthalocyanina- tocobalt(ll), with dioxygen shows that the same mechanism (eq ---f lNH,(en)2Co-Oz-Cr(HzO)5]4+ + Co2+ + PenH+ (33) 39) is involved in the reversible formation of (TSPc)Co-02- Co(TSPc). The complex Co(TSPc) also behaves as a catalyst for t'NH,(en)zCo-0,-Co(HzO)5]4+ + H+ the dioxygen oxidation of hydrazine and of hydroxylamine in aqueous solution.244Kinetic studies support a process shown [NH,(en),Co- -Cr(H20),I5+ (34) - by eq 39. N2H4 IH CO(TSPC)* (N~H~)CO(TSPC) W,(enhCo- -Cr(&Ok]5+ + Cr2+ 02 8, -+ (N~H&O(TSPC)(O~)-+ CO(TSPC)+ N2 + 2H20 (39) - lNH3(en)2Co-O-Cr(HzO)5]4++ C$+ (35) In contrast to this, the Co(TSPc) catalyzed dioxygen oxidation of cysteine to cystine is believed245to involve the intermediate d, formation of Co(l) and RS. The free radical then dimerizes to give 164 Chemical Reviews, 1979, Vol. 79, No. 2 Jones, Summervllls, and Basolo TABLE XIV. Structural Parameters of Cobalt-02 Complexes complexa 0-0,A deg deg co-0, (A) commentsc ref la monomeric, 1.26(4) 126 1.86 reversibled 144 superoxo 1.95(5) reversiblee 167b 1.240(17) 153.4 1.904(14) irreversible ' 195, 251 1.273(10) 117.5 1.974(8) reversible 252 1.257(10) 118.5 1.974(8) 1.302(3) 117.4 1.881(2) reversible 253 1.277(3) 120.0 1.889(2) reversible 254 1.1 136 irreversible ' 195,251 1 .l-1.302 Ib dimeric, 1.243(13)8 121.2 166 1.944, 265 superoxo 1.289(20) 120.7 180 1.919 1.317(20) 117.3 180 1.895 257 1.312(20) 117.7 175.3 1.894 258 1.353 119.2 23.4 1.878 240,261 1.320(5) 120.9 0.0 1.867 262 1.243-1.353 Ila monomeric 1.420(10) 1.87l(7) irreversible) 246 1.902(7) 1.441(11) 1.888(9) 247 1.91 O(9) Ilb dimeric, 1.447(4) 118.8 180 1.985 irreversible 260 Deroxo 1.473(10) 113 145.8 1.883 irreversible 198 1.469(6) 110.8 180 1.879 irreversible 259 1.488(6) 110.0 180 1.896 irreversible 263 1.53 110 180 1.89 irreversible 264 1.42 115 1.92 irreversible 240,261 1.308(28) 118 122 1.931 reversible 265 2.000 1.339(6) 120.3 110.1 1.910 reversiblep 266 1.45(2) 118.5 149.3 1.93 irreversible 267 1.383(7) 120.0 121.9 1.911 reversible 268 1.308-1.488 a For abbreviations see section XI. Torsion angle. Reversible implies that some reversibility has been noted for these compounds insolution. Reference 132. e Reference 110. Reference 147. Two crystallographically independent molecules occupy a unit cell. *This structure replaces an earlier study255 that showed the 0-0 bond lying perpendicular to the Co-Co axis. This compound contains a bridging NH2- group as well as a bridging 02-.) Reference 270. The dioxygen is bound to only one of the Co centers. This structure determination replaces an earlier that indicated a longer 0-0 bond length (1.65 A). Reference 241. 'This compound has a bridging NH2- group, and a bridging hydroperoxo, OzH-, group. Only one of the oxygen atoms is bound to both cobalt atoms. Reference 272. p Reference 34. the product RSSR, and Co(ll) is restored by the reaction of Co(l) complex. This behavior is similar to that observed by Bosnich with dioxygen. Clearly more effort is needed in the direction of et al.249for the oxygenation of complexes of cobalt(1) containing catalytic dioxygen activation by metal complexes. a quadridentate arsine ligand, and it is also characteristic of the oxidative addition of molecular oxygen to low-valent complexes D. Solid-state Structures of second- and thirbrow group 8 transition metals. This generally occurs when the metal can readily increase its oxidation state 1. Monomeric Cobalt-Dioxygen Complexes by two. A unique exception is CO~(CN)~(PM~~P~)~(O~),formed The structures of several 1: 1 cobalt-dioxygen adducts have by the oxygenation of a benzene solution of the five-coordinate now been reported (Table XIV). With the exception of the com- cobalt(l1) complex CO"(CN)~(PM~~P~)~.~~~The resulting dioxygen plexes [C0(2=phos)~(O~)]BF4246 and CO~(CN)~(PM~~P~)~-complex is a cyano-bridged dimer of the form (Me2PhP)3(NC)2- (02),247the adducts reported have all been type la complexes CO"'-(NC)CO'~'(CN)(PM~~P~)~(O~~-).The dimer is apparently (see Table XIV). Both [Co(2=ph0~)~(02)]BF~and CO~(CN)~- formed because the CN bridge allows electron transfer between (PMe2PhM02) are type Ila complexes. Although the latter the two cobalts, such that a total of two electrons are available complex contains two metal centers, the compound is still to generate a peroxo group. It is not understood why peroxo is considered a type Ila since the dioxygen moiety is bound to-only not the bridging group, as it is in all other known bridged reaction one of the cobalt metal centers. Thus, it is a very special kind products of the reactions of Co(ll) complexes with 02 (including of "monomeric" cobalt-dioxygen complex. [ Co(CN)5]3-).248 Thus, the complex CO~(CN)~(PM~~P~)~O~ap- The compound [Co(2=phos)AO2)]BF4 was formed by ex- pears to be the only example of a 7r-bonded dioxygen complex posing either crystals or a solution of the cobalt(1) chelate [Co- formed from the reaction of a Co(ll) complex with molecular (2=phos)2]BF4 to atmospheric oxygen. Oxidative addition of the oxygen. dioxygen to the cobalt(1) complex produced the cobalt(ll1)-peroxo The 0-0 bond lengths and Co-0 bond lengths are similar for Synthetic Oxygen Carders in Blologlcal Systems Chemical Reviews, 1979, Vol. 79, No. 2 165 both [C0(2=phos)~(O~)]BF4 and CO~(CN)~(PM~~P~),(O~)(Table benacen derivative with the exception that the dioxygen atom XIV). These values (and also values of the 0-0 stretching shows a twofold disorder. Thus the 0-0 vector bisects both the frequencies) are comparable with 0-0 and M-0 distances found 0-Co-0 and N-Co-N angles of the chelate ring. The large un- for complexes of second- and third-row group 8 transition ele- certainty in the structure determination (R = 0.19)resulted in ment~.’~,~~~ neither an 0-0 bond length nor a Co-0-0 bond angle being Despite difficulties in obtaining single crystals of adequate reported. quality for X-ray analysis, including problems of disorder and Brown and Raym~nd~~~?~~’have reported the crystal structure those due to large anisotropic thermal vibration, the structures of [Et4N]3[Co(CN)5(02)]-5H20. This 1:l cobalt-dioxygen of several type la cobalt-dioxygen complexes have been re- complex, which has been postulated as being an intermediate ported. The first structurally characterized 1: 1 Co-02 type adduct in the formation of the [(CN)5Co-02-Co(CN)5]6- anion,248was was the six-coordinate Schiff base complex Co(benacenXpyX02) formed by exposing a DMF solution of [Et4N]3[C~(CN)5]to at- (XI).144The 0-0 bond length (1.26A) is in reasonable agreement mospheric oxygen. The 0-0 distance of 1.240(17) A is some- what less than that expected for an ideal superoxide anion. The most unusual aspect of the structure, however, is the large Co-0-0 bond angle of 153’ as compared with the bond angle observed for the Schiff base adducts. This may arise from the repulsive interaction of the negative charge on the terminal oxygen atom of the dioxygen species with the four adjacent cyanide anions in the [CO(CN)~(OZ)]3- complex. The terminal oxygen atom in the Schiff base adducts have adjacent ligand atoms which are essentially neutral. Recently, Schaefer and co-~orkers~~~-~~~have published structures for three 1: 1 dioxygen-cobalt Schiff base complexes of the form XIII. It is interesting to note that the workers were able XI with that expected for a coordinated superoxide moiety. As in- dicated in XI, the cobalt lies essentially in the plane defined by the Schiff base ligand. The plane containing the cobalt center and the two dioxygen atom bisects the N-Co-N angle of the Schiff base while the orientation of the plane of the pyridine ring is approximately normal to the Co-0-0 plane. The two phenyl kt substituents are approximately coplanar with the plane of the Xlll Schiff base. The orientation of the Co-O2 unit permits maximum overlap to isolate a 1:l adduct of the sterically unhindered Co(saltmen) of the xxorbitals of the O2 with a drr orbital of the cobalt. It has complex. Similar complexes generally yield only the 2:1 adducts. been suggested144that the coplanarity of the phenyl substituents These complexes have proven particularly suitable for X-ray may facilitate delocalization of the electron within the cobalt analysis for two reasons: (1) the ligand apparently stabilizes the Schiff base, thus enhancing the rr interaction of the cobalt with formation of the 1:l adducts relative to the 2:l adducts suffi- the O2 moiety. It is interesting to note that although the orientation ciently to allow the isolation of good quality single crystals, and of the pyridine ring apparently minimizes interaction with adja- (2) the dioxygen adducts exhibit neither the solid-state disorder cent atoms on the Schiff base, the rr orbitals of the pyridine are nor the large anisotropic thermal vibration observed for other not available for interaction with a delocalized x system of the 1:l adducts. Co-O2 group. The gross structural features of the three dioxygen adducts Structure XI1 of a similar Schiff base, Co(acacen)(py)(02),has are similar. In all cases the plane defined by the cobalt center and the dioxygen atoms essentially bisects the inplane 0-Co-N also been determined.167b The overall gross structural features of the molecule are quite similar to those of the corresponding bond angle. In all cases the Co-O2 group lies almost in the plane of the substituted imidazole group. In this orientation, the sub- h stituted imidazole group, which has been shown to be capable of rr-donation, is able to delocalize electron density by back- bonding to the cobalt dx-dioxygen rr* system. It must be pointed out, however, that the orientation of both the substituted imid- azole groups and the dioxygen moiety in these complexes is 0 C largely dominated by steric effects. The 0-0 bond lengths and 0 N the Co-0-0 bond angles observed for the three complexes @ 0 (Table XIV) are all consistent with a formal representation of these cobalt-dioxygen adducts as superoxide-cobalt(ll1) com- co plexes. The variation in the bond angles are within the range 0 attributable to packing forces. 2. Dimeric Cobalt-Dioxygen Complexes The single-crystal X-ray structure has been determined for a number of 2:l cobalt-dioxygen complexes of the types Ib and Ilb. The structural parameters obtained for these complexes are 166 Chemical Reviews, 1979, Vol. 79, No. 2 Jones, Summervllle, and Basolo summarized in Table XIV. dency of the iron(l1) porphyrin complexes, in the absence of large The classic example of these 2: 1 cobalt-dioxygen adducts excesses of a strongly coordinating neutral ligand such as pyr- is the diamagnetic complex [(NH~)~CO~~'-O~-CO~~'(NH~)~]~+idine, to undergo rapid irreversible oxidation without detectable originally observed by Fremylo0 and later characterized by formation of an iron-dioxygen complex.272(In the presence of Werner and Myliu~.~~Oxidation of this complex gives the large excesses of a strongly coordinating neutral ligand it has paramagnetic specles [(H3N)5C002Co(NH3)5]5+indicating that long been realized273-274that the porphyrinatoiron(l1) complexes the O2was a-bonded to the two cobalt orbitals with the 0-0 are inert both toward irreversible oxidation and formation of bond axis lying perpendicular to the Co-Co axis. This was in dioxygen complexes.) agreement with a suggestion made by on the basis of In contrast to the oxygen-carrying ability of hemoglobin and theoretical considerations. However, a recent reinvestigatlon myoglobin, in the absence of special precautions, simple ferrous of the structure for this complex,257as well as for the similar porphyrins are rapidly and irreversibly oxidized by molecular compound [(NH3)5(Co-02-Co)(NH3)5](S04)(HS04)3,258has oxygen. Although it had been previously thought that the irre- shown this initial structure to be incorrect. The 02on the de- versible oxidation product was the hemin hydroxide complex,275 caamine structure adopts a skewed configuration (XIV). Feil'(PorXOH), it is now kno~n~~~-~~~that the autoxidation product is the p-oxo dimer: 2Feii(Por)(B)2 i- 1/202- (Por)Feiii-O-Feii'(Por) + 48 (41) Prior to confirmation that the presumed hemin hydroxides were in reality pox0 dimers, the dimeric nature of the autoxidation XIV product had been postulated by one group of workers279on the The structural parameters for the Co2O2 unit obtained from basis of elemental analysis of the solid product obtained when [(NH3)5C002C~(NH3)51(N03)5257and [(NH~)~CO~~CO(NH~)~I-benzene solutions of the dimethyl ester of dipyridine 2,4di- (S04)(HS04)3258are quite similar. The 0-0 bond lengths, 1.317 acetyldeuteroporphyrinatoiron(II) were exposed to 02,and by (20) and 1.312 (IO)A, agree within experimental error and are analogy with the phthalocyanatomanganese(ll1) pox0 dimer280 in accord with the value expected for superoxide groups. The (py)(Pc)Mnill-O-Mnlil(Pc)(py), obtained when pyridine solutions Co-0-0 bond angles (117.3 and 117.7') and the Co-0-0-Co of Mnii(Pc) were exposed to 02.281,282 torsion angles (180 and 175.3') are close to what would be On the basis of kinetic data283v284on the autoxidation of six- anticipated for an sp2-hybridized superoxide bridge. Comparing coordinate bis(base)iron(ll)porphyrin complexes, Fei1(PorXB)2, these values with those obtained from the type Ilb, peroxo- and on the basis of recent studies285of oxygen binding to these bridged species [(NH3)5C002Co(NH3)5](S04)2*4H20and complexes at low temperatures, it is now generally believed that [(NH3)5C002Co(NH3)5](SCN)4259shows that the 0-0 bond length the autoxidation proceeds via formation of the monomeric in the peroxo-bridged species (1.473 (IO) and 1.468 (6) A) are iron-dioxygen adduct, Fe(Por)(B)(O,), to a dioxygen-bridged diiron significantly different for the S042- and SCN- salts. This dif- ~omple~~~~,~~~of the form (BXPor)Fe-02-Fe(Por)(B). This ference has been attributed to248,259hydrogen-bonding ef- bridged species then rapidly decomposes via the formation of fects. a presumably ferryl, Fe(lV)-02-, intermediate, as first proposed The p-peroxo- and p-superoxo-decacyanobiscobalt(l1i) by Ca~ghey~~~and Hammond,286 to give the p-uxo dimer: complexes have also been studied by X-ray analysi~.~~~,~~~The Fell(P~r)(B)~+ Fe"(Por)(B) B dimeric, type Ib, p-superoxo complex K~[CO~(CN)IO(O~)]~~~ + (42) contains two structural independent molecules. A comparison Feii(PorXB) + O2+ Fe(Por)(B)(O2) (43) of the two 0-0 bond lengths shows a difference between the two conformational types of 0.046 A. Upon considering the Fe(Por)(BX02)+ Feii(PorXB) differences involved in the structure determination, it is felt that (BXPor)Feiii-02-Feiii(PorXB) (44) while this difference may be real, it is of marginal significance. rapid it was pointed out259that a single MO approach would predict (B)(Por)Fe-O2-Fe(Por)(B) --t 2FeiV(PorXBX02-) (45) a-bonding character and a planar conformation for the Co- 0-0-co linkage, allowing maximum overlap of the co da or- Feiv(Por)(BX02-) -I-Fe"(Por)(B) bitals. The presence of both a planar (Co-0-0-Co = 180') and rapid a nonplanar (Co-0-0-Co = 166') complex in the same crystal -+ (Por)Fe"'-O-Feiti(Por) + 28 (46) indicates that packing forces may play a dominant role in de- termining the 0-0 torsion angle. The p-peroxo complex That the autoxidation reaction involves the formation of a K~[CO~(CN)~O(O~)](NO~)~-~H~O~~~shows a significant increase dioxygen-bridged diiron intermediate is supported by a recent in the 0-0 bond length compared with the p-peroxo criteria. The report53that exposure of toluene solutions of Feii(T(pCH3)PP) planar configuration of Co-0-0-Co has been explained as at -50 ' to O2 results in the formation of the p-peroxo dimer arising from the Coulombic repulsion between the two highly [Feiii(T(pCH3)PP]2022-, which upon warming gives the ex- charged Co(lll) centers. pected p-oxo dimer. The p-peroxo diiron(ll1) complex is analo- gous with the p-peroxo dicobalt(ll1) complexes formed by the Vlll. Iron- Dioxygen Carriers reaction of O2with the cobalt(l1) Schiff base complexes. That the 0-0 bond in p-peroxo diiron(ll1) complex should cleave more Research on synthetic iron-containing oxygen carriers as rapidly than the 0-0 bond in the corresponding cobalt(ll1) models for the natural occurring heme containing oxygen- complexes has been explained287on the basis of the relative carrying proteins hemoglobin and myoglobin has undergone stabilities of the Co-0 and Fe-0 species formed from direct significant theoretical and experimental developments with the cleavage of the 0-0 bond. It should be noted that a kinetic study recent observation that, under the proper conditions, iron(l1) on the autoxidation of the ferrous hemes, suggesting the for- porphyrin complexes react reversibly with molecular oxygen mation of free superoxide, has been reported.288These data to form 1: 1 dioxygen adducts: have been reir~terpreted~~~,~~~in terms of the formation of a Feii(Por)(B) 02 e Fe(Por)(B)(02) Fe-02-Fe intermediate. + (40) Three recent synthetic approaches13have led to the formation Historically, the major difficulty that has been encountered of 1: 1 iron-dioxygen complexes by suppressing the formation in obtaining porphyrinatoiron-dioxygen complexes is the ten- of the p-peroxo diiron complex. These are (1) steric-in such Synthetlc Oxygen Carriers In Blologlcal Systems Chemical Reviews, 1979, Vol. 79, No. 2 167 a fashion that dimerization is inhibited, (2) low temperature-in 0 0 order that reactions leading to dimerization are very slow, and (3) rigid surfaces-attachment of the iron complex on the sur- face in a manner that dimerization is prevented. In addition to suppressing the irreversible oxidation of the iron(l1)-heme complexes, two additional features are desirable in constructing a model for the natural heme oxygen carriers, These are (1) a five-coordinate geometry, Fe"(Por)(B),for the deoxyheme; and (2) a nonpolar, hydrophobic environment for the heme. In the natural oxygen-carrying heme proteins, the protopor- phyrinatoiron(l1)active site lies within a "cleft" in the protein principally through noncovalent apolar interactions. The only covalent linkage between the iron(l1) porphyrin and the protein Figure 18. Structure of the ferrous "capped" porphyrin. Double bonds arises from a coordinate bond between the iron(l1) center and are deleted for clarity. the imidazole portion of the proximal histidine residue. Thus in the deoxy form, the iron(l1) center is five-coordinate with the high-spin (S = 2) Fe(ll) projecting out of the mean plane of the in preventing autoxidation of the heme-dioxygen complex by four porphyrin nitrogen atoms toward the coordinated imidazole a reaction path that does not involve a second iron(l1) center.304 moiety. Even in the presence of the protein matrix, HbOp and MbOp are The problem encountered when attempting to model the known to undergo a slow oxidation to the met species. In the natural heme oxygen carrier, using simple ferrous porphyrins normal human erythrocyte, HbA undergoes autoxidation at a rate in solution in the presence of strongly coordinating N-donor li- large enough to necessitate the presence of enzyme systems gands, is the strong preference of the iron for six-coordina- to effect reconversion to functional Hb. Thus, a steady state tion: concentration of Fe(lll) of about 1 % of the total Hb present is Ki Kz maintained.305 Fe"(Por) + B +Fe"(Por)(B) + B +Fell(Por)(B)p (47) The mechanistic pathways for this autoxidation reaction are not well understood. The formation of superoxide ion (or the The difficulty in forming the five-coordinate complexes, Fell- hydroperoxyl radical, Hop)has been implicated in this oxidation (Por)(B), in solution results from the fact that, unlike the situation reacti~n,~~~,~~~suggesting that the autoxidation proceeds via found for normal consecutive equilibria, K, K,- 1 ,289 for the < either of two pathways: consecutive equilibria K2 and K1,"O Kp > K1, making the dominant species in solution Fe"(Por)(B)p. For example, in Feil(Op) + H20 - Fe"'(OH2)+ 02- (48) benzene at 25 'C, the bonding constants of pyridine to Fe"(TPP) H+ have been estimated as K1 - 1.5 X lo3 and Kp - 1.9 x lo4 Fe"(0p) + H20 -+ Fe1I'(OH2)+ HOz (49) M-'. The relative magnitudes of K1 and Kp undoubtedly result from a spin-state change in going from five- to six-coordination. Such steps have also been suggested for the autoxidation of The five-coordinate hemes have been shown to exist in the simple ferrous complexes in aqueous sol~tions.~~~-~~~On the high-spin, S = 2, form,292~293whereas the six-coordinate hemes basis of the redox potentials involved in the above processes, are well known to be diamagnetic low-spin complexes,294the the production of a hydroperoxyl radical seems a more likely simple four-coordinate ferrous hemes assume an intermediate, mechanism.312 This is consistent with the recent report by s = 1, spin stafe,292,293,295,296 Caughey and coworkers42 that human Hb in the presence of Several of the synthetic strategies used to prevent autox- excess nucleophile cleanly undergoes an acid-catalyzed oxi- idation of the ferrous heme complexes have also led to the dation which apparently involves the nucleophilic displacement synthesis of five-coordinate heme containing oxygen carriers. of a superoxide ion (or hydroperoxyl radical) from a protonated These include (1) the use of sterically hindered systems, such intermediate. Although the precise mechanism by which ferrous as the Baldwin "capped" porphyrin (Figure 18),297in which steric hemes are oxidized in an aqueous environment has not been hindrance inhibits not only irreversible oxidation but also the worked out, experiments with model systems of heme oxygen bonding of an axial ligand to one side of the porphyrin ring; and carriers are generally conducted in nonaqueous media.313 (2) the attachment of the heme to a rigid or semirigid support Although the investigation of iron-containing oxygen carriers containing covalently attached donor ligands. In this case, the has burgeoned in the past few years, a number of early claims juxtaposition of heme and donor ligands attached to the surface of iron(l1) oxygen carriers should be noted. In 1927, Kunz and can be such that formation of a six-coordinate adduct is not Kress314reported the reversible absorption of O2 in pyridine by possible. In addition to these two approaches, five-coordination a ferrous indigo complex. More careful investigation^,^^^^^^^ of the deoxy heme has been achieved by covalently attaching however, have shown that O2 does not bind reversibly in this a donor ligand to the porphyrin moiety in such a way that it is system. Later report^^'^^^^^ that bis(dimethylg1yoximato)iron- capable of axial coordination with the iron(l1) enter,^^^,^^^,^^^ (II), Fe"(DMG)p, in aqueous dioxane solution in the presence of and by the use of sterically hindered ligands such as P-methyl- ligands such as pyridine, ammonia, histidine, or imidazole re- imidazole and 1,2dimethylimidazole, in which case it has been versibly formed the dioxygen adducts, Fe(DMG)2(B)(Op),have shown that these sterically hindered bases form only the five- not been confirmed by a more recent Other reports of coordinate adducts with ferrous hemes at room tempera- iron(l1) oxygen-carrying complexes that have appeared include t~re.~~~~~~~It should be noted that at low temperatures, evidence the reversible combination with oxygen in the solid state by of six-coordination with the hindered ligands has been ob- bis(imidazo1e) and bis(pyridine) complexes of proto- and tait~ed.~"That the five-coordinate hemes containing a sterically mesop~rphyrin.~~~~~~~ hindered axial N-donor ligand are capable of bonding dioxygen The synthesis of iron(l1)-containing molecules having ap- to form the six-coordinate complexes Fe(Por)(B)(Op), has re- pended bulky substituents which prevent formation of a pperoxo cently been observed.163 diiron(ll1) intermediate have led to a number of Fe(ll) reversible In addition to preventing irreversible oxidation of the heme oxygen carriers. The first oxygen carrier that utilized steric en- centers by keeping them spacially apart, the heme proteins Hb cumbrance to inhibit irreversible oxidation was reported by and Mb provide a hydrophobic environment for the heme centers. Baldwin and Huff321in 1973. At -85 OC, a pyridine-toluene It is well re~ognized~O~-~O~that such an environment is important solution of an iron(ll) macrocycle containing 9,lO-bridged 168 Chemical Reviews, 1979, Vol. 79, No. 2 Jones, Summervllle, and Basolo CO Flgure 19. Structure oran iron(l1) macrocycle containing 9,lO-bridged 9,1O-dihydroanthracenes. L/ 9,lO-dihydroanthra~ene~~~(Figure 19) reacted reversibly with Figure 20. Structure of Fe(TpivPP)(L)(O,), the oxygen adduct of the 1 mol equiv of 02.Above -50 OC however, irreversible degra- "picket-fence" porphyrin. Double bonds are deleted for clarity. dation of the oxygenated complex to yield an uncharacterized substance was observed. That the suppression of the irreversible oxidation process was due to steric hindrance and not a function n = 2.4) for the bonding of O2 to a poly-L-lysine-protoporphy- of the low temperature, a similar unhindered ferrous macrocycle rinatoiron(l1) polymer. The origin of the cooperativity appears irreversibly absorbed 0.5 mol equiv of O2 at -78 OC. Shortly to have been demonstrated by the authors. In the absence of the after this report, Collman and co-worker~~~~published the first heme group, po1y-L-lysine adopts a regular a-helix conforrpation. example of the synthesis and room-temperature oxygen-carrying Upon formation of the polymer-heme complex, in which two of ability of an iron(ll) porphyrin, Fe"(TpivPP) (Figure 20). This the polylysine amine moieties are coordinated to the iron(l1) "picket-fence'' porphyrin has all four of the pivaloylamide groups center, the helical nature of the polymer is disturbed. When 02 above one face of the porphyrin ring.324A number of picket- (or CO) is bound to the iron(l1) center, the helix content of the fence porphyrins containing different pendant groups have now polymer increases. Thus, bonding a dioxygen molecule to a been reported.325Suppression of irreversible oxidation was so heme center, and thereby displacing one of the coordinated ly- successful with this complex that a benzene solution of Fe"(T- sine-NHZ groups from the iron center, increases the helical pivPP) in the presence of an excess of Melm was observed to nature of the polymer. This conformational change in the polymer reversibly add O2 at room temperature. results in a weakening of other (lysine-NH2)2-Fe(ll) interactions, Despite the steric bulk of the pivaloyl groups, they do not block making the lysine dissociation coordination of a sixth axial ligand, and solid complexes of the Fe"(polylysine-NH2)2 Fe"(polylysine-NH2) form F~"(T~~VPP)(B)~have been i~olated.~'~?~~~However, it is polylysine-NH2 (50) believed that the binding constant for 1-Melm on the "picket- + fence" side of the porphyrin is significantly less than on the more favorable, thus increasing the overall equilibrium constants unhindered side, and thus O2 binding occurs inside the protective of the remaining deoxy iron(l1) centers for 02.Since Tsuchida's enclosure of the pivalamido groups. Were this not the case, models involve cooperativity in the formation of the O2 complex significant amounts of the Fe(TpivPPXl-Melm)(02) complex with from a six-coordinate complex, it does not represent a model the O2 bound to the unhindered side would be found in solution, for the cooperativity observed in Hb. A brief account of coop- with subsequent formation of the p-oxo dimer complex having erative dioxygen bonding in a polymeric heme system has also the two unhindered sides of the porphyrin rings facing one an- been reported by Ba~er.~~~However, it has been pointed other. that the Bayer isotherm, when displayed as a Hill plot, is not well Although Fe"(TpivPP) is capable of binding two Melm ligands behaved, and that the visible spectrum of the oxy complex does in solution, the five-coordinate complex Fe"(TpivPP)(Melm)has not correspond to that of known dioxygen complexes. It appears been isolated326as a solid and as such has been shown to react that the cooperativity found in solids and in polymeric solutions reversibly with 02. Thermodynamic data obtained from this do not relate to that for Hb. solid-gas equilibrium gave values for the enthalpy and entropy The dioxygen adduct, Fe(TpivPP)(1-Melm)(02), has been of & binding similar to those obtained from natural myoglobin. isolated as a solid323and has been characterized by magnetic No cooperative binding of O2was noted for this complex. More susceptibility measurements325as well as by IMti~sbauer~~~and recently, Collman and co-~orkers~'~have examined the infrared spectroscopy.334In addition, a single-crystal X-ray solid-gas equilibria between dioxygen and the solid five-coor- structure determination has been made.30s335In general these dinate iron(ll) picket-fence complexes containing the sterically measurements indicate that the picket-fence dioxygen complex hindered imidazole, 2-methylimidazole and 1,2-dimethyIimida- bears a close resemblance to the natural systems. zole, in the axial position, and have shown the binding of O2 to Magnetic susceptibility measurements327on Fe(TpivPP)(1- be cooperative. The binding of 02to solid Fel1(TpivPP)(2-Melm) Melm)(02) show the complex to be diamagnetic, the same as is quantitatively similar to that found in human HbA; upon fitting was found for oxyhemoglobin by Pauling and Corye1Iz4in 1936. the data to the Hill equation one observed limiting values for In contrast to this behavior, however, Cerdonio and co-~orkers~~ P1/2O2 at low and h igh partial pressures of O2of 0.7 and 14 Torr have recently observed that human oxyhemoglobin shows a for the model complex which compares with 0.3 and 9 Torr for magnetic susceptibility consistent with a thermal equilibrium HbA.328*329In addition, Hill coefficients of 2.6 were observed between a ground-state singlet and an excited-state triplet, with for Fe(TpivPP)(1,2-Me21m),which is similar to the value of 2.5 the singlet-triplet energy separation, ,2J, being 146 cm-'. This observed for HbA. work has been recently challenged by Pa~ling.~~Mossbauer Two other reports of the cooperative binding of 02to synthetic measurements333of the axygenated picket-fence complexes iron(l1) porphyrin oxygen carriers have appeared. Tsu~hida~~~~~~~indicate a close similarity to oxyhemoglobin with respect to both and co-workers have observed sigmoidal behavior (Hill slope, isomer shift and quadrupole splitting. In addition, the 0-0 infrared Synthetic Oxygen Carrlers In Blologlcal Systems Chemical Reviews, 1979, Vol. 79, No. 2 169 stretching frequencies obtained for Fe(TpivPP)(MelmX02),11 59 ,CH H~\ cm-1,334 is similar to the values obtained for HbO2 (1107 ,CH2 NYC"O and Mb02(1 103 cm-1).28 GN\ \ k " CH2 In agreement with the structure predicted from the 0-0 CH- 1. stretching frequencies observed for the picket-fence iron- '2 dioxygen complexes,334 X-ray crystallographic results30 on Fe(TpivPPXl-MelmX02)show the dioxygen bonding in an endon, Pauling-type conformation with Fe-0-0 bond angles for the crystallographically independent 02groups present in the crystal being 133 (2) and 129 (2)'. Problems with disorder and high thermal motion in many parts of the structure resulted in dif- Figure 21. Structure of pyrroheme-N-(3-(14midazolyl)propyl)amide. ficulties in obtaining a precise structure analysis. Thus, the 0-0 bond lengths of 1.15 and 1.14 A, which are unrealistic when The synthesis of the capped porphyrins represents the first compared with the value of 1.21 A found in 02,336 may be un- model for the natural oxygen-carrying heme proteins in which derestimated by as much as 0.15 A. As expected, the iron center a five-coordinate iron(l1) porphyrin is observed to bind oxygen lies virtually within the plane of the porphyrin ring, being dis- reversibly in solution at room temperature. That such severe placed 0.015 (3) A from the porphyrinato ring toward the coor- steric hindrance as is found in the capped porphyrin is necessary dinated 02.The Fe-0-0 plane bisects an N-Fe-N right angle to prevent coordination of a sixth axial ligand is demonstrated of the equatorial porphyrin plane and is, consequently, fourfold both by the six-coordination of Fel1(TpivPP)(B)2in small excesses disordered. of a coordinating ligand and the recent synthesi~~~~,~~~of iron(l1) In addition to the complex Fe"(TpivPP)(Melm), other picket- porphyrins containing a single bridge constructed across the fence porphyrins have been shown to reversibly bind 02. Re- porphyrin macrocycle that irreversibly oxidizes in solution at duction of Fe"'(TpivPP)(Br)in THF yields of high-spin room temperature.346 Fe"(TpivPP)(THF)2, yeff= 4.9 BM at 25 OC, in which only one THF In contrast with the picket-fence and capped porphyrin^,^^^^^^^ is presumed to coordinate to the iron(l1) center. This assumption which are sterically hindered on only one face of the porphyrin, is in agreement with the behavior of simple ferrous complexes Vaska and coworker^^^^^^^^ have synthesized meso- in THF solution.290In the solid state, Fe(TpivPPXTHF)2reversibly tetrakis(2,4,6-trimethoxyphenyl)porphinatoiron(ll), Fe"(T- absorbs 1 mol equiv of O2 to form a reported paramagnetic (ye,, (OMe),PP), and the ethoxy analog, Fel'(T(OEt)3PP),351which have = 2.4 BM) dioxygen adduct. The complex was later shown by protecting groups above and below the porphyrin plane. Expo- Mossbauer spectroscopy to be diamagneti~.~~~.~~' sure of these complexes to dioxygen as solids or in benzene In addition to the picket-fence complex, Fe"(TpivPP),in which solution at 25 OC involves uptake of 02, which is at least partially the four pickets (pivalamido group) lie on one side of the por- reversible. phyrin ring, Collman and co-~orkers'~~have synthesized "tail-base" iron(l1) porphyrins, Fe"(triPiv(4C Im)PP) and Fe"(tri- 1. Low Temperature Piv(5C Im)PP), which have three pivalamido pickets lying on one side of the porphyrin and an appended imidazole moiety which One of the first synthetic iron(l1) oxygen carriers was reported is capable of coordinating to the iron(l1) center. Solutions of these by Chang and Trayl~r~~~in 1973. By reacting 1-(3-aminopro- tail-base porphyrins reversibly oxygenate at 25 OC,having PllZo2 py1)imidazole with the acid chloride of pyrroporphyrin XV these values (0.60 and 0.58 Torr, respectively) comparable both with workers were able to prepare a pyrroporphyrin complex that had the PllZo2 obtained from FelI(TpivPP)(l-Melm) (0.49 Torr) in the the imidazoyl propyl side chain covalently attached by an amide solid state and with those of Mb (0.7 Torr) and the isolated a (0.63 linkage to the porphyrin ring. After insertion of iron into the Torr) and p (0.25 Torr) chains of Hb. porphyrin, subsequent reduction gave the five-coordinate, iron(l1) In a synthetic tour d'force Baldwin and co-workers synthesized complex (Figure 21), which was observed to bind O2 reversibly the "capped" porphyrin-iron(l1) ~omple~~~~,~~~and have shown both in the solid state and when dissolved in a polystyrene film. it to be an oxygen carrier in pyridine solution at 25 OC. Reversible When the five-coordinate pyrroheme-N-[3-( 1-imidazoy1)pro- oxygen binding has also been observed in a benzene solution pyllamide was dissolved in CH2C12 at -45 OC, the complex was containing 5 % 1-methylimidazole; however, in this medium the observed353 to bind O2 reversibly. When the solution was stability of the oxygenated heme toward autoxidation has been warmed to room temperature, an irreversible oxidized product shown to be considerably less than in neat pyridine. In 5% was obtained. These workers attributed the reversible oxygen pyridine-benzene, autoxidation was rapid, consistent with the binding of the heme complex to two factors: (1) the neighboring observed339stronger affinity of iron(l1) heme for imidazole than group effect of the covalently attached imidazole group; and (2) for pyridine in benzene. The oxygen-carrying ability of the capped the fact that at low temperature the rate of irreversible oxidation heme is due to two effects: (1) the small "pocket" inside the cap was significantly inhibited. The fact that the pyrroheme complex preventing the coordination of a donor ligand inside the cap (this used by Chang and Traylor was sterically capable of forming a permits high concentrations of an N-donor ligand to be present y-oxo dimer led several groups354-358to examine the binding to prevent oxygen bonding to the open-side of the porphyrin with of dioxygen to six-coordinate iron(l1) complexes having the form subsequent autoxidation while maintaining the iron(l1) as five- Fe"(p~rphyrin)(B)~.These workers discovered that exposing coordinate); and (2) the steric influence of the cap preventing solutions of the six-coordinate heme to dioxygen at low tem- y-peroxo dimer formation. perature resulted in the reversible binding of O2 and were thus At this point it is interesting to note that although the iron(l1)- able to conclude that the oxygen-carrying ability of the Traylor capped porphyrin reversibly binds O2 in 5 YO l-methylimidaz- complex was due to the effect of reduced temperature on the ole-benzene, in 5 % pyridine-benzene instantaneous autox- rate of irreversible oxidation and was not a function of a idation was noted. The autoxidation of iron(l1) porphyrins coor- "neighboring group effect". That the effect of the pendant im- dinated by imidazole has been noted by other ~~rker~.~~~-~~~idazole leads to an increased oxygen affinity of the ferrous heme Although the nature of the reaction has not been investigated, when compared to the affinity of the heme in the presence of a recent has shown that in the presence of acids iron(l1) a free 1-alkyl-imidazole has been reported.355However, a recent hemes are oxidized by an apparent outer-sphere acid-catalyzed investigation162 using cobalt(l1)-porphinato complexes with process, and that the proton on imidazole is acidic enough to attached N-donor ligands has failed to see any enhancement of carry out the reaction. the oxygen affinity due to the attached axial base. 170 Chemical Reviews, 1979, Vol. 79, No. 2 Jones, Summervllle, and Basolo TABLE XV. Comparison of Kinetics of Oxygenation of Heme Proteins and Model Systemsa k’, k’lk, M-‘ s-’ X k, M-’ X heme 10-7 s-1 10-6 1 (H20, pH 7.3)b 6 35 1.7 1 (DMF)b 80 160 0.5 1 (CH&iz)* 100 800 0.15 isolated (Y chainsC 5.5 31 1.a Mb (sperm whale)c 1.9 10 1.9 xv Mb (Apiysia)d 1.5 70 0.22 Hbe 0.2 1080 0.009 heme sites oxygenated) may indicate that the tail-base heme Hb(Oz) 0.4 244 0.017 represents a reasonable model for the bonding of O2 to the R Hb ( 0z ) z 0.35 28 0.12 state of hemoglobin. Hb(Od3 4.0 48 0.8 In addition to having shown that for nonaqueous solvents, as a Kinetic data at 20 or 22 OC. Compound 1 refers to pyrroheme-K in water at approximately neutral pH, the addition reactions of [3-(l-imidazoiyi)propyl]amide.Data for this compound come from ref 361. M. Brunori and T. M. Schuster, J. Biol. Chem., 244,4046 (1969). B. A. CO and O2 to the tail-base hemes proceed via the simple as- Whittenberg, M. Brunori, E. Antonini, J. B. Wittenberg, and J. Wyman, Arch. sociation process in eq 51, Traylor and co-worker~~~~have Siochem. Biophys., 111, 576 (1965). e G. llgenfritz and T. M.Schuster, J. recently shown that at low pH a different mechanism for CO Siol. Chem., 249, 2959 (1974). addition is observed. At low pH, the equilibrium lies strongly to the right, and formation of the six-coordinate, carbon monoxide Despite the fact that the “tail-base’’ porphyrins do not inhibit complex, XVla-CO, proceeds via coordination of CO to the irreversible oxidation, they do provide five-coordination for the iron(l1) and a variety of tail-base porphyrins have now been prepared. A on a tail-base porphyrin containing a pendant pyridine coordinated to the iron(l1) center has shown that, compared with the analogous imidazole complex, the affinity of the five-coordinate heme for O2 is quite small. Comparative P1,202 values (at -45 O in CH2CI2)are 0.2 and >760 Torr for the imidazole and pyridine complexes, respectively. It has been XVlb XVlC proposed359that this large difference is due to the ability of the XVla Kalkylimidazole to donate n-electrons to the coordinated 02, four-coordinate porphyrins, XVlb, followed by coordination of thus stabilizing the Fe-02 bond. However, a systematic study the appended imidazole to the iron center. The data obtained for of the O2affinities of five-coordinated hemes with different axial CO addition to mesoheme dimethyl ester in aqueous solution in substituents has not been undertaken. the presence of 2-Melm, a ligand which, owing to steric inter- Several other studies on the kinetics and thermodynamics of ference forces only five-coordinate complexes with hemes, is O2 and CO binding to tail-base hemes have a~peared,~~O-~~~the also consistent with the reaction proceeding via the so-called results of which carry interesting implications both as to the “base-elimination” pathway. Although such a mechanism has nature of the environment about the heme prosthetic group in yet to be shown to occur for O2 bonding, it may represent a Hb and Mb, and as to possible modes for protein control of heme mechanism by which the heme proteins can regulate oxygen binding. Chang and Trayl~r~~’have measured the kinetics for affinity. the oxygenation of the tail-base heme complex, pyrroheme- With the introduction of proximal base strain in the tail-base N[3-(1-imidazolyl)propyl]amide (Figure 2 1). In nonpolar solvents heme complexes Trayl~r~~~has created models for the R and or in aqueous solution at approximately neutral pH, the tail-base T states of hemoglobin. The presence of strain decreases the heme exists almost entirely in the five-coordinate form and the oxygen affinity. This steric effect also changes the mechanism kinetics for O2 addition are consistent with the mechanism given of binding carbon monoxide (but not that of oxygen), implying by eq 51. that such mechanism changes also occur in natural systems. This behavior supports the proposal that such strain could flr ft contribute to the differences in affinity of R- and T-state hemo- globin. A detailed kinetic and thermodynamic study of oxygen and carbon monoxide binding to six-coordinate ferrous porphyrins, Fe”(TPP)(B)2,has been made.265s365These simple ferrous por- A comparison of the kinetic results obtained from the model phyrins, Fe(TPP)(B)2,in methylene chloride solution at -79 OC compound with those from natural heme systems (Table XV) are excellent oxygen carriers. The spectral changes show that shows (1) the effect of going from a relatively nonpolar solvent Fe(TPP)(py)2 is oxygenated in the presence of dioxygen, and to the polar solvent water is to significantly decrease the 02 deoxygenated when the solution is purged with dinitrogen. off-rate, k, while having a small effect on the 02on-rate, t.This Several oxygenation-deoxygenation cycles are possible at -79 effect is consistent with the aqueous environment stabilizing an OC with a minimum of irreversible oxidation occurring, and at iron-dioxygen dipole relative to the less polar solvents CH2C12 this temperature a solution of the complex in 1 atm of oxygen and DMF. However, the fact that the kinetics observed in water is stable for at least 1 day. The stoichiometry of the reaction more closely resemble those obtained from the natural mono- corresponds to 1 mole of dioxygen per mole of iron: meric heme protein systems than do those obtained in the less Fe(TPP)(B2) 4- O2 * Fe(TPP)(B)(O*)+ B (53) polar solvents is somewhat surprising and may imply the pres- ence of some polar interaction between the coordinate dioxygen Under 1 atm of oxygen, complete complex formation occurs in and the protein. (2) The similarity between the kinetic data ob- methylene chloride; only a small amount of complex is formed tained for the model system and the addition of 02to Hb(02)3, in toluene, whereas the degree of complex formation in ethyl (where Hb(O2)3 represents the Hb molecule with three of the four ether lies between these extremes. Similarly, dioxygen com- Synthetic Oxygen Carriers in Biological Systems Chemical Reviews, 1979, Vol. 79, No. 2 171 TABLE XVi. Comparlsons between Kinetic and Thermodynamic Parameters for Reactions of 02 and CO with a Slmple Ferrous Porphyrin and with Heme Proteins ferrous systema kdkz k-3lk-2 KcolKo, Fe(TPP)(Melm) 0.031 2. Solid The third successful method of obtaining an oxygen-carrying iron complex is to attach it to the surface of a solid or polymer 172 Chemical Reviews, 1979, Vol. 79, No. 2 Jones, Summervllle, and Basolo dinated iron(l1) porphyrin in hemoglobin and myoglobin. The open oxidation might proceed through a peroxy-bridged species. The coordination site can then reversibly bind dioxygen. possibility that this intermediate might be phthalocyanatosu- The reported chemisorption of oxygen is weak. It is irre- peroxomanganese(ll1) has recently been suggested.390 versible at -127 OC; it has a Pl1202 of 0.4 Torr at -78 OC and The first example of a synthetic reversible oxygen carrying a Pl1202 of 230 Torr at 0 OC. Data for human myoglobinsoaex- compound of manganese(l1) appears to be the report of the trapolated to 0 OC give Pl1202 of 0.14 Torr. Successful 02binding dioxygen adduct formed with meso-tetraphenylporphinatopyr- on the modified silica gel, however, confirms the utility of the idinemanganese(ll), Mn(TPP)(py), in toluene at -79 0C.3g1-3g3 rigid-surface approach. Recently it was suggested3" that the This reversible oxygenation was also observed independentlfg4 low affinity for 02found for the (Fe)(TPP)(IPG)system was due by using Mn(TPP) in a toluene-THF solution at -90 OC. As in the to physisorption of 02. The system is being reinvestigated and case of the synthetic iron(l1) oxygen-carrying chelates, the aprotic seems to show evidence of iron centers having different ac- solvent and low temperature inhibit the irreversible oxidation and ti~ities.~~~ stabilize the dioxygen adduct. At -79 OC, decomposition of the Protoporphyriniron(l1)has been attached via a coordinate oxygenated complex to give unidentified irreversibly oxidized linking to several poly(4-vinylpyridine) and poly-L-lysine poly- products is slow; 70% of the initial manganese(l1)-porphyrin mer~.~~~~~~~,~~~-~~~These polymers have been shown to re- complex can be regenerated by flushing the solution with dini- versibly add dioxygen in a ratio of 1Fe:102in the solid state and trogen after exposure of the system to 1 atm of 02 for 14 their behavior in solution has been studied. Bayer and Holz- h.391 ba~h~~~have covalently attached protoporphyrinatoiron(l1) to On the basis of the optical and EPR spe~tra,~~'.~~~charge water-soluble polymers which also contain appended imidazole transfer from the manganese(l1) to dioxygen appears to occur groups that are capable of bonding to the iron(l1) center. Polymer upon formation of the manganese-dioxygen complexes. Ex- complexes were prepared in which the heme had either one or posure of porphyrinatomanganese(l1)to oxygen in toluene at -79 two imidazole moieties bound to the heme. In aqueous solution OC results in dramatic changes in the visible spectrum. The at room temperature the complexes were shown to be oxygen optical densities of the visible, Q bands,395decrease markedly, carriers and the PT1202values observed are similar to those re- and the Soret band splits to give spectra similar to those ob- ported for myoglobin. In addition, cooperativity in 02 bonding served for Mniil(TPP) species. Despite the appearance of a between the heme sites was reported. Although it was previously Mn(lll)-type optical spectrum, a detailed analysis of the EPR reported379that iron(l1) porphyrins attached to a polyphospha- spectra of Mn(TPP)(02)at 77 and 4.2 K has been interpreted as zene polymer reversible bound oxygen in aqueous solution, later arising from a quartet ground state for a 4(t23)manganese ion. results380indicate that in aqueous solution or as solid films the These results and the absence of spin density on the dioxygen presence of the polymeric ligands did not prevent the irreversible as determined by 170-labeling experiments suggest a formal oxidation of heme on contact with oxygen. valence state for the complex as MniV(TPP)(022-).While the Several binuclear metal complexes have been prepared in authors391*392have tentatively favored a symmetric, Griff ith-type an attempt to model natural systems which have two metal ions structure similar to that observed for a titanium porphyrin per- in their active sites, such as hemerythrin or hemocyanin. There oxide complex,396it is not possible to rule out a Pauling-type exist several ligands with the capabilities, such as Kagan'~~~~structure similar to that found for cobalt-dioxygen complexes strati-bisporphyrins, the picket-fence-like porphyrin (P-N4) of with only one of the oxygen atoms of the dioxygen moiety bound Elliot382and Bu~kingham~~~where the pivalamido pickets are to the manganese. replaced by nicotinoyl groups allowing for the coordination of The reaction of molecular oxygen in toluene, with a series of a metal by four pyridines, or Chang'~~~~crowned porphyrin. It para-substituted meso-tetraphenylporphinatomanganese(l1) has been possible to insert only one Fe(ll) into the P-N4 por- complexes, Mnii(T(pX)PP)(B),containing an axial ligand, B, has phyrin, with the Fe(ll) coordinated to the porphyrin. Its reactivity recently been studied.397Spectrophotometric titrations of tol- to oxygen is very similar to Collman's iron picket-fence com- uene solutions of these complexes at -78 OC with molecular plexes. At present there is no reported incorporation of any oxygen confirm the previous interpretati~n~~~~~~~that at low metals in the strati-bisporphyrin systems. temperatures an equilibrium between the five-coordinate mo- Chang's crowned porphyrin384has a crown ether covalently noligated species, Mnii(T(pX)PP)(B),and the dioxygen complex, attached to the porphyrin and occupies a position directly above Mn(T( pX)PP)(02), is established the porphyrin plane. This crown porphyrin allows for the coor- K dination of a transition metal ion in the porphyrin plane with the Mn"(T(pX)PP)(B)+ O2 Mn(T(pX)PP)(02)+ B (58) simultaneous ligation of a metal ion in the crown ether portion. An interesting sidelight is that the crown can act in a similar which can also be written in terms of the two equilibria: manner as Baldwin's cap, with the addition of a bulky nitrogen K-B donor, such as 1-triphenylmethylimidazole;the iron(l1) complex MnIi(T(pX)PP)(B)+ Mnii(T(pX)PP) + B (59) is a stable (f1/2 > 1 h) room-temperature (25 "C) oxygen car- rier. Koz Mnii(T(pX)PP) + O2 Mn(T(pX)PP)(02) (60) Equilibrium constants for eq 58, where X = CI, F, H, CH3, and IX. Manganese-Dioxygen Carriers OCH3, and B = pyridine, have been determined and a fit of the The interaction between dioxygen and tetradentate chelates observed values for the equilibrium constants to the Hammett of manganese(l1) in solution usually results in the irreversible equation3g8(-log Kvs. 4a) gave a Hammett p value of -0.41 oxidation of the metal to a Mn(ll1) or Mn(lV) species.385The early f 0.08. By subtracting a calculated value for the Hammett p report281that manganese phthalocyanine, Mn(ll)(Pc),in pyridine value for eq 59, the authors397obtained an estimated399value solution at room temperature acts as a reversible oxygen carrier of -0.08 at -78 OC for the oxygenation of the four-coordinate has been shown to be in error, and the end product of the aut- base-free Mnii(T(pX)PP) complexes. Thus, at low temperatures, oxidation has been identified280$386as the pox0 dimer, (py)- para substitution of the peripheral phenyl rings of tetraphenyl- (Pc)MniiiO-Mniii(Pc)(py). Calvin and c~-workers~~~-~~~have porphinatomanganese(l1) has a relatively small effect on the determined that the formation of the pox0 dimer from MnPc oxygen affinity. A small Hammett p value was similarly ob- proceeds via a manganese(ll1) intermediate. They have sug- served124 for the O2 affinities of Coii(T(pX)PP)(py) com- gested that this intermediate is phthalocyanatohydroxomanga- plexes. nese(lll), while Elvidge and Lever281have speculated that the The equilibrium constant for the oxygenation of Mn"(TPP)- Synthetic Oxygen Carriers In Blologlcal Systems Chemical Reviews, 1979, Vol. 79, No. 2 173 (4CN-py) was determined, in toluene at -78 OC, as K = 10-5.57. TABLE XVII. Equilibrium Conslants for the Oxygenation of In addition, equilibrium constants for the reaction: Metalloporphyrin Complexes at -78 Oca K4-cN-p~ complex conditions log KoP €112, M""" Mn"(TPP) 4- 4-CN-py LMnIi(TPP)(4-CN-py) (6 1) Co"(TPP)(py) toluene soln -1.7c +0.13c were determined at several temperatures, and an extrapolated Co"(T(p0Me)PPXMelm) toluene soh -0.8d +0.11 value for K4-cN-p~at -78 OC of 107.63was obtained. From these Fe"(TpivPPXMe1m) solid 6.4e -0.11' values of K and K~N-~~an estimate of the equilibrium constant Mn"(TPP) toluene soh -2.1 Q -0.27h for the oxygenation of four-coordinate Mnii(TPP) of KO:,- 102.1 Cr"(TPP)(py) solid large -0.86' Torr-' was obtained. a The equilibrium constants reported in this table are for the addition of A comparison of the equilibrium constants for oxygenation 02to a vacant axial coordination site on the metal(l1) center. Values for log for a series of porphyrinatometal(l1)complexes at -78 OC with KO?at -78 OC are calculated from thermodynamic data given in references cited. Units of KoPare Torr. In DMSO. Values reported in volts vs. SCE. the M1li/llhalf-wave reduction potentials (Table XVII) shows that, For Co(TPP) and CoIl(T(pOMe)PP), ref 124. Reference 121. e TpivPP with the exceptions of Mn1I(TPP),there is a direct relationship represents the dianion of the "picket-fence'' porphyrin. ' K. M. Kadish, M. between the affinity of the complex for dioxygen and the ease M. Morrison, L. A. Constant, L. Dickens, and D. G. Davis, J. Am. Chem. Soc., of oxidation of the metal(l1) center. Thus, KO:, observed for 98, 6387 (1976). Reference 397. T. W.Cape, Ph.D. Thesis, North- Mn"(TPP) is several orders of magnitude less than would be western University, 1979. K. M. Kadish and M. M. Mison, Biodectrochem. predicted on the basis of the half-wave reduction potential. This Bioenerget., 3, 480 (1976). ' The dioxygen adduct forms irreversibly. apparent anomaly in the binding of O2 to Mn(TPP) compared with the porphyrinatometal(l1)complexes of cobalt, iron, and chro- figuration, it has been suggested392that the Griffith conformation mium may indicate that the nature of the bond between man- (XVII) is to be preferred, in agreement with the geometry favored ganese and dioxygen differs significantly from the M-02 bonding for other metal-peroxo systems. This structural assignment is with these other metals. also consistent with the observation that the porphyrinatoman- With the exception of manganese for which an 0-0 stretching ganese-dioxygen complexes do not bind an axial ligand. The frequency has not yet been reported, the porphyrinatometal- binding of an axial ligand on the dioxygen complex would tend dioxygen complexes of cobalt, iron, and chromium have been to draw the manganese center into the plane of the porphyrin. shown to be superoxide-like, having 0-0 stretching frequencies This would be expected to result in severe repulsive interaction at 1120 f 50 cm-l. If the bonding of O2 in manganese-dioxygen between the coordinated dioxygen ligand and the porphyrinato complexes were also superoxide-like, a KO:, larger than that ring. For the Pauling geometry (XVII), however, this repulsive observed would be expected. The anomalous value observed interaction would not occur, and the dioxygen complex of such for KO* of the manganese complex is an indication that the a structure would be expected to bind an axial ligand readily. bonding may differ from that of the cobalt, iron, and chromium The differences in affinities of Cr"'(TPP)(CI) and Mn(TPP)(02) systems. Thus this result supports the assignment MnIV(TPP)- toward binding a sixth axial ligand can also be interpreted as (022-).392There is, however, another interpretation for the arising from differences in the electronic ground-state config- anomalous manganese value for KO:,.Basolo and co-~orkers'~~ uration of the manganese(1V) and chromium(ll1) centers. For the have reported that although five-coordinate complexes of the porphyrinatochromium(ll1) complexes, the electrons adopt the cobalt(l1) Schiff base CoIl(benacen)(B) readily bind 02in toluene expected (dxy)'(dxz)l(dyz)l configuration. For the porphyrinato- solution at 0 OC, only a small amount of the four-coordinated manganese-dioxygen complexes, however, the ground-state Co"(benacen)complex is oxygenated under 1 atm of 02 in tol- electronic configuration has not yet been unambiguously de- uene at 0 OC. Thus if the dioxygen moiety in Mn(TPP)(02)adopts termined. If the electronic ground-state configuration of the d3 the Pauling conformation, the seemingly low value of KO? is manganese center has an unpaired electron in the dZz orbital, consistent with the absence of a sixth axial ligand. by analogy with the Co(ll) and Mn(lll) metalloporphyrincomplexes A comparison can be made of the properties observed for the which bind a sixth axial ligand only weakly,127the complexes O2 adducts of tetraphenylporphinatomanganese(II) complexes would not be expected to strongly bind an axial ligand regardless with those expected on the basis of an assigned d3-Mn(lV)ground of the geometry of the Mn02 bond. Although, in general, one state. A recent study400 on the chemical and spectroscopic would not predict an unpaired electron in a dZz orbital in a d3 properties of CriI1(TPP)(CI),which contains a d3 metal center, has complex, several configurations including dZz occupancy have shown that five-coordinate Cr"'(TPP)(CI) has an exceptionally been investigated401in some MO calculations. A recent rein- large affinity toward binding a sixth N-donor axial ligand. In vestigation402of the EPR spectra of some Mn(Por)(O2) com- contrast with this behavior, no tendency for the presumed d3- plexes are consistent with the previous interpretation that the Mn(lV) center in Mn(TPP)(02)to bind an axial ligand at -78 OC ground state electronic configurations of these manganese- has been observed.397This large difference in the affinities of dioxygen complexes do not include an unpaired electron in the the d3 metalloporphyrincomplexes Cr1ll(TPP)(CI)and Mn(TPP)(02) dZz orbital and are better represented in terms of the Mr1'~(02~-) for an axial ligand can be interpreted as arising from either of formal ism. two factors: (1) repulsive steric interaction between the coor- The O2 binding of simple manganous porphyrins397is con- dinated dioxygen and the porphyrinato ring in Mn(TPP)(02)that sistent with the observed403 inability of manganese(l1) hemo- results in the manganese center lying out of the plane of the globin to carry 02.The proximal histidine of the protein provides porphyrin toward the coordinated dioxygen, and (2) differences an adjacent imidazole which coordinates with the Mn(l1) in MnHb. in the ground-state electronic configurations of the chromium With this high effective local concentration of coordinating base, and manganese centers that favor the Mn(TPP)(02)structure. the equilibrium lies heavily toward the five-coordinate Two geometric conformations have been suggested for the MnIl(Por)(imidazole)complex rather than the dioxygen adduct. bonding of dioxygen to the manganese-porphyrins (XVII and Valentine404 has investigated the reaction between XVIII). On the basis of the formal Mn1V(022-)ground-state con- Mn1I1(TPP)CIand KO2 in DMSO solution. Addition of 1 equiv of superoxide to the complex in DMSO resulted in the rapid re- duction of the metalloporphyrin to Mnll(TPP). Further addition of 0-0 02-to the above solution or addition of 02- to a fresh Mn"(TPP) 7' 7' \/ solution resulted in changes in the visible spectrum; however, M'n Mn the product has not been characterized. It is interesting to note XVll XVlll that addition of 02- to a solution containing ZnIl(TPP) results405 174 Chemical Reviews, 1979, Vol. 79, No. 2 Jones, Summerville, and Basolo in the formation of the superoxo complex [Zn11(TPP)02]-. by purging with nitrogen. One mole of O2 is bound for two moles Recently, Lever and Wil~hire~~~have reported that in rigor- of Cu, suggesting the formation of a peroxo bridged species ously purified pyridine, phthalocyanatomanganese(l1)does not (Cu(ll)-O2-Cu(ll)). The complex does not bind CO, whereas a react with molecular oxygen. In the presence of a source of bimetallic complex of ~oppefl'~in the solid state reversibly binds protons, i.e., water or imidazole, they observed the formation oxygen and CO. Using the ligand, 1,4-bis( l-ox0-4,lOdithio-7- of a 1: 1 adduct between dioxygen and MnPc: azacyclododecan-7-ylmethyl)benzene, with two copper(1) atoms ligated the complex binds CO in the solid state or in nitromethane Mn"(Pc) + O2 -Mn111(Pc)(02-) (62) solution (YCO 2070 cm-'). Purging the solution with argon at N,NDMA - 80 OC removed the CO ligand. At 25 OC (slowly) or 80 OC the The adduct is reported to be stable to further reaction under solid complex reacts with oxygen to give a compound with an conditions of the experiment, and it was isolated as a solid. EPR spectrum having values of = 2.05, 911 = 2.22, and Ail Reconversion to MnPc and O2 was accomplished by flushing the 91 75 g. Heating in vacuo at 110 OC regenerates the starting solution with dinitrogen or by freeze-thaw degassing. The re- - complex. Reversibility was not observed in solution. Because action is reported to have a P1,202 of 1 Torr at 25 OC. It appears of the presumed structure of the complex it was referred to as that this is the first example of a synthetic manganese(l1) oxygen an "earmuff" compound. carrier at room temperature. On the basis of both the optical and infrared spectra, the authors tentatively suggest that the complex X1. Addendum should be formally considered as the superoxo complex Mn"l(Pc)(02-). A recent report406that exposure of a DMF solution Since the submission of this article two recent reports on the of Mn"(Pc)at room temperature results in a complex having an structural determinations of two oxy-heme proteins have ap- EPR spectrum that is consistent with the presence of a super- peared. Huber et al.41 have studied the oxy-erythrocruorin oxide moiety has appeared. No further characterization of the system. The oxygen molecule was found to be bound in an complex nor comments on the reversibility of complex formation end-on fashion (LFe-0-0 - 170') and hydrogen bonded to a were noted. water molecule. The large Fe-0-0 angle, as compared to other Although not of direct biological interest in terms of the bio- natural and model complexes, may be due to the bonded water. logical oxygen carriers, a recent report407on the reversible Upon oxygenation, unlike most other natural systems, it was bonding of O2 by an oxidation product of tris(3,5-di-terf-butyl- observed that the iron shifts only slightly toward the porphyrin catecholato)manganese(ll)in DMSO may prove of interest as plane with accompanying minimal changes in porphyrin con- formation. This behavior of the erythrocruorin system is con- a model for the manganese-catalyzed oxygen evolution reaction of green plant biosynthesis. Upon exposure of a DMSO solution sistent with the small changes observed for all of its other ligated of tris(3,5di-tert-butylcatecholato)manganese(lll)to 02,the first states. step appears to be oxidation of one of the bonded catechol li- Diffraction data were collected to a resolution of 2.0 A on the gands to the semiquinone resulting in a mixed catechol-semi- oxygen adduct of sperm whale myoglobin.412In the oxy form the quinone complex, which is then capable of reversibly binding oxygen is also bound in an end-on bent manner, with an Fe-0-0 angle of 121'. However, Phillips found that the iron moves from 02. 0.55 A (deoxy state) to a position 0.33 A (oxy state) above the mean porphyrin plane upon oxygenation. These results show X. Dioxygen Carriers of Other Metals the expected shift of iron toward the heme plane upon oxygen- The reversible binding of dioxygen at room temperature to ation, but the magnitude of this movement is smaller than that tetraphenylporphinato- and octaethylporphinatoruthenium(l1) reported earlier.60e-gIt now appears that current cooperativity complexes has been reported.408Solutions of Ru(OEP)(CH&N)~ theories may have to be somewhat modified. in DMA, DMF, or pyrrole, the exact nature of the axial ligation of the ruthenium(l1) center in these solutions being uncertain, are XI/. Abbreviations observed to absorb 1.O mol of oxygen for each ruthenium metal N-Aclm N-acetylimidazole center at room temperature and 1 atm of 02.At constant O2 acr acrldine pressures, the reactions follow pseudo-first-order behavior with amaco various amino acids the value for f1/2 being reported as -1 min (DMA), -7 min B various neutral donor ligands (pyrrole), and -30 min (DMF). However, solutions of Ru"(0EP)- BM Bohr magneton (&, where B = pyridine or 1-methylimidazolein the presence bPY 2,2'-bipyridine of oxygen, result only in irreversible oxidation of the ruthenium Bzlm benzimidazole center to a Ru(lll) species. 5-CIMelm 5-chloro- 1-methylimidazole The synthesis of the chromium-dioxygen adduct, Cr(TPP)- 3,5-C12PY 3,5-dichloropyridine (PY)(O,),~' from solid five-coordinate Cr"(TPP)(py) represents 4-CNpy 4-cyanopyridine a logical extension of metalloporphyrin complexes containing cyclam 1,4,8,1l-tetraazacyclotetradecane bivalent first-row transition metal ions. Previous to the prepa- DePP dianion of deuteroporphyrin IX ration of the complex, on the basis of the M1l/lil redox potentials, deut dianion of deuteroporphyrin IX it had been predicted that the chromous porphyrins should bind dgenta diglycylethylenediaminetetraaceticacid O2 more strongly than do the Fe, Mn, and Co metalloporphyrin diapr 2,3-diaminopropionic acid complexes. In agreement with this prediction Cr(TPP)(py)(OP) dien diethylenetriamine is observed to form the dioxygen complex irreversibly. On the dipep various dipeptides basis of the 1:l O&r uptake and an uo-o of 1142 cm-', DMA N,Kdimethylacetamide Cr(TPP)(py)(OZ) appears to be a normal monomeric type la DMF N,Ndimethylformamide complex. The coordinated oxygen can therefore be described DMSO dimethyl sulfoxide as superoxide-like. In solution, a stable dioxygen species does en ethylenediamine not appear to be formed. 4-EtCOOpy ethyl isonicotinate Interest in model systems of hemocyanins has resulted in the 4-EtaNCOpy nicotinic acid diethylamide appearance of two copper complexes capable of reversibly 4-Etpy 4-ethylpyridine binding dioxygen. The c~pper(l)~~~complex of the pentadentate !$Y glycine ligand derived from 2,6diacetylpyridine and histamine reversibly glYglY glycylglycine binds dioxygen at room temperature in DMSO or acetonitrile glyhist glycylhistidine solution. The reaction is readily reversed by gentle warming and Hb hemoglobin Synthetic Oxygen Carriers In Blologlcal Systems Chemical Reviews, 1979, Vol. 79, No. 2 175 HbA hemoglobin A of this work. The authors also thank the National Institutes of hedien K2-(hydroxyethy1)ethylenediamine Health and the National Science Foundation for their support. hist histidine XI//. References hista histamine (1) L. Vaska, Science, 140, 809 (1963). Im imidazole (2) L. H. Vogt, Jr., H. M. Faigenbaum. and S.E. Wiberly, Chem. Rev., 63, 269 IsoQ isoquinoline (1963). (3) J. A. O'Connor and E. A. V. Ebsworth. Adv. Inorg. Chem. Radiochem., 6, L coordination sphere of a metal 279 (1964). L4 quadridentate ligand (4)E. Bayer and P. Stretzmann, Struct. Bonding (Berlin), 2, 181 (1967). quinquedentate ligand (5) S. Fallab, Arigew. Chem., lnt. Ed. Engl., 6, 496 (1967). L5 (6) A. G. Sykes and J. A. Weil, Prog. Inorg. Chem., 13, 1 (1970). Mb myoglobin (7)R. G. Wilkins, Adv. Chem. Ser., No. 100, 111 (1971). s-Me2en N,N'4imethylethylenediamine (8) V. J. Choy and C. J. O'Connor, Coord. Chem. Rev., 9, 145 (1972/73). (9) L. Elevan. J. Peone, Jr., and S. K. Madan, J. Chem. Educ., 50, 670 Melm or Kmethylimidazole (1973). 1-Melm (10)J. S.Valentine, Chem. Rev., 73, 235 (1973). 2-Melm 2-methylimidazole (11) G. Heirrici-Olive and S. Olive, Aiigew. Chem., Int. Ed. Engl., 13, 29 (1974). 1,2-Me21m 1,2-dimethyIimidazole (12)F. Basolo, J. Indian Chem. SOC., 51, l(1974). 4-Mepy 4-methylpyridine (13) F. Basolo, B. Hoffman, and J. Ibers, Acc. Chem. Res., 8, 384 (1975). (14) E. Ochiai, J. Inorg. Nucl. Chem., 37, 1503 (1975). ~,~-M~zPY3,4-dimethylpyridine (15) L. Vaska, Acc. Chem. Res., 9, 175 (1976). 3,5-Me2py 3,54imethylpyridine (16)G. McLendon and A. E. Martell, Coord. Chem. Rev., 19, 1 (1976). 2,4,6-trimethylpyridine (17)R. W. Erskine and B. 0. Field, Struct. Bonding(BerIin), 28, l(1976). 2,4,6-Me3~~ (18) J. P. Collman, Acc. Chem. Res., 10, 265 (1977). MesP dianion of mesoporphyrin (19) W. M. Latimer, "The Oxidation States of the Elements and Their Potentials MOEP dianion of meso-phenyloctaethylporphyrin in Aqueous Solution", 2nd ed., Prentice-Hall Inc., Engiewood Cliffs, N.J., 1952,p 50. ~-WPY 4-aminopyridine (20) A. L. Lehninger, "Biochemistry", Worth Publishers, New York, 1970,p Ntrlm Ktriphenylmethylimidazole 46. OEP dianion of octaethylporphyrin (21)A. A. Frost, J. Am. Chem. SOC.,73, 2680 (1951). (22)P. George in "Oxidases and Related Redox Systems", Vol. 1, T. E. King, OEPH2 octaethylporphyrin H. S. Mason, and M. Morrison, Eds., Wiley, New York, 1965, Chapter p1/202 pressure of oxygen necessary to oxygenate '12 1. (23)G. Herzbera. "Molecular SDectra and Molecular Structure". 2nd ed.. Van of the available sites Nostrand, 6ew York. 1950. Pc phthalocyanine L. Pauling and C. D. Coryell, Proc. Natl. Acad. Sci. U.S.A., 22, 210 PFP dianion of "picket-fence porphyrin" (1936). A. Rossi Faneili, E. Antonini, C. DeMarco, and S.Beuerecetti, Biochem. phen 1,lO-phenanthroline Hum. Genet., Ciba Found. Symp., 144 (1958),cited in E. Antonini and M. 2 = phos 1,2-bis(diphenyIphosphino)ethylene Brunori, "Hemoglobin and Myoglobin in Their Reactions with Ligands", American Elsevier, New York, 1971,p 221. PiP piperidine The standard definition of oxidation states holds that the oxidation number Pn 1,2-propylenediamine represents the electric charge that a constituent atom in a molecule would Por dianion of a natural or synthetic porphyrin have were the bonding in the molecuie entirely ionic. Assignment of a numerical oxidation state to a specific electronic configuration of a PPDE dianion of protoporphyrin IX dimethyl ester molecule is accomplished by following a set of rules that can be found PPh3 triphenylphosphine in most freshman chemistry texts: in particular, in a covalent bond, a shared electron pair is assigned to the more electronegative of the two PPlX dianion of protoporphyrin IX atoms sharing it. When this is done for all the bonds in a molecule, the PPIXDME dianion of protoporphyrin IX dimethyl ester numerical oxidation state of an atom in the molecule is defined as being pyridine the net electric charge that resides in the atom. See, for example, L. PY Pauling, "General Chemistry", 2nd ed., W. H. Freeman, San Francisco, quin quinoline 1954. quinuc quinuclidine D. A. Summerville. R. D. Jones, B. M. Hoffman, and F. Basolo, J. Chem. any Schiff base Educ., in press. SB J. C. Maxwell, J. A. Volpe. C. H. Barlow, and W. S. Caughey, Biochem. SB4 quadridentate Schiff base Biophys. Res. Commun., 58, 166 (1974). quinquedentate Schiff base C. H. Barlow, J. C. Maxwell, W. J. Wallace, and W. S. Caughey, Biochem. SB5 Biophys. Res. Commun., 55, 91 (1973). sdtma N,Kbis(2-aminoethyl)glycine J. P. Collman, R. R. Gagne, C. A. Reed, W. T. Robinson, and G. A. Rodiey. sedda ethylenediamine-N,N'diacetic acid Proc. Natl. Acad. Sci. U.S.A., 71, 1326 (1974). Ktrimethylsilylimidazole L. Pauiing. Nature (London), 203, 182 (1964). l-SiMe31m J. J. Weiss, Nature(London), 202, 84 (1964);203, 183 (1964). terPY 2,2',2''-terpyridine (a) We note that this configuration is not easily representable in terms tetraen tetraethylenepentamine of a simple valence bond type picture and thus, using the conventional oxidation state definition, we cannot assign numerical oxidation states; THF tetrahydrofuran see ref 27.(b) See refs 44 and 45. tn trimethylenediamine C. Floriani and F. Calderazzo. J. Chem. SOC.A, 946 (1969). TpivPP dianion of "picket-fence porphyrin", meso- B. M. Hoffman, D. L. Diemente, and F. Basolo. J. Am. Chem. SOC.,92, 61 (1970). tetra(cu,a,cu,cu-o-pivalamidopheny1)por- D. Getz. E. Melemud, B. C. Silver, and 2. Dori, J. Am. Chem. SOC.,97, phyrin 3846 (1975). M.-M. Rolumer, A. Dedieu, and A. Veillard, Theor. Chim. Acta, 39, 189 dianion of meso-tetraphenylporphyrin (1975);A. Dedieu, M.-M. Rohmer, and A. Veillard, J. Am. Chem. Soc., meso-tetraphenylporphyrin 98, 5789 (1976). dianion of a para-substituted meso-tetraphen- J. B. Wittenberg. B. A. Wittenberg, J. Peisach, and W. E. Blumberg, Proc. Nati. Acad. Sci. U.S.A., 67, 1846 (1967). ylporphyrin T. Yamamoto, G. Palmer, D. Gill, i. T. Salmenn, and L. Rimai, J. Biol. tren tris(2-aminoethyl) amine Chem.. 248,5211 (1973). K. Spartalian and G. Lang, J. Chem. Phys., 63, 3375 (1975). trien triethylenetetramine D. L. Anderson, C. J. Weschler. and F. Basolo, J. Am. Chem. SOC.,96, triPiv(4C Im)PP meso-tri(a,a,cu-o-pivalamidophenyl)-~-o-3- 5599 (1974). (Nimidazolylpropylamidophenyl) porphyrin W. J. Wallace, J. C. Maxwell, and W. S.Caughey. Biochem. Biophys. Res. Commun., 57, 1104 (1974). triPiv(5C Im)PP meso-tri(c~,cu,cu-o-pivalamidophenyl)~-o-4- M. Cerdonio. A. Congiu-Casteiiano, F. Mogno, B. Pispisa, G. L. Romani. (Nimidazolylbutylamidophenyl)porphyrin and S. Vitale, Proc. NatI. Acad. Sci., U.S.A.. 74, 398 (1977). B. H. Huynh. D. A. Case, and M. Karplus. J. Am. Chem. Soc., 99, 6103 TSPc phthalocyaninetetrasulfonate ion (1977). udtma diethylenetriamine-Kacetic acid R. F. Kirchner and G. H. Loew, J. Am. Chem. Soc., 99, 4639 (1977). uedda ethylenediamine-N,Ndiacetic acid L. Pauling. Proc. Natl. Acad. Sci. U.S.A., 74, 2612 (1977). S.K. Cheung, C. J. Grimes, J. Wong, and C. A. Reed, J. Am. Chem. Soc., 98, 5028 (1976). A paper attempting to resolve this metal-dioxygen formalism controversy Acknowledgments. The authors thank Janice M. Summerville has appeared: C. A. Reed and C. E. Cheung, Proc. Natl. Acad. Sci. U.S.A., and Jan Goranson for the help and patience in the preparation 74, 1780 (1977).However, a MO scheme presented in the paper for the 176 Chemical Reviews, 1979,Vol. 79,No. 2 Jones, Summervllle, and Basolo M"'(O,-) species is shown with all electrons paired. Mogno, and R. L. Romani, J. Am. Chem. Soc., 98, 1029 (1976). (49) J. S. Griffith, Proc. R. SOC.London, Ser. A, 235, 23 (1956). (84) T. J. Thamann. J. S. Loehr. andT. M. Loehr, J. Am. Chem. SOC.,99,4187 (50) R. Guilard, J.-M. Latour, C. Lecomte, J.4. Marchon, J. Protas, and D. Ripoli, (1977). lnorg. Chem., 17, 1228 (1978). (85) J. E. Falk, "Porphyrins and Metalloporphyrins". American Elsevier, New (51) R. Guilard, M. Fontesse, P. Fournari, C. Lecomte, and J. Protas. J. Chem. York, 1964. SOC.,Chem. Commun., 161 (1975). (86) K. M. Smith, Ed., "Porphyrins and Metalloporphyrins," American Elsevier, (52) B. Chevrier, T. Diebold, and R. Weiss, lnorg. Chim. Acta, 19, L57 New York, 1975. 11'476\, . - . - , . (87) TPPH2 is universally prepared by the method of A. D. Adler, F. R. Longo, (53) D.4. Chen, J. Del budio, G. N. La Mar, and A. L. Balch, J. Am. Chem. R. D. Finarelli, J. Goldmacher, J. Assour, and L. Korsakoff, J. Org. Chem., SOC.,99, 5486 (1977). 32, 476 (1967). It should be noted that the product obtained by this mew (54) J. A. Weil and J. K. Kennaird. J. Phys. Chem., 71, 3341 (1967). always contains some meso-tetraphenylchlorin impurity. This can be (55) M. J. Bennett and P. B. Donaldson, J. Am. Chem. Soc., 93, 3307 easily removed by using the method of G. H. Barnett, M. F. Hudson, and 1197 1). K. M. Smith, Tetrahedron Left., 2887 (1973). (56) k.8tomberg, L. Trysberg. and J. Larking, Acta Chem. Scand., 24, 2678 (88) (a) H. W. Whitlock and R. Hanauer, J. Org. Chem., 33, 2169 (1968); (b) (1970). H. H. Inhoffen, J.-H. Fuhrhop, H. Voigt, and H. Brockmann. Jr., Justus (57) A. Werner and A. Mylius, Z.Anorg. Chem., 16, 745 (1898). Liebigs Ann. Chem., 695, 133 (1966). (58) J. M. Pratt in "Techniques and Topics in Bioinorganic Chemistry", Part (89) P. Hambright in ref 86, Chapter 6. 2, C. A. McAuliffe, Ed., Wiley, New York, 1975. (90) N. F. Curtis, Coord. Chem. Rev., 3, 3 (1968). (59) B. D. Carlisle, Proc. R. SOC.London, Ser. 6,171, 31 (1968). (91) D. H. Busch, Helv. Chem. Acta, Fasc. Extraordinarius, Alfred Werner (60) Recent reviews on Hb and Hb include: (a) E. Antonini and M. Brunori, ref Commem. VoI., 1967. 25; (b) J. M. Rifkind in "Bioinorganic Chemistry", G. L. Eichhorn, Ed., El- (92) V. L. Goedken, N, K. Kildahl, and D. H. Busch, J. Coord. Chem., 7, 89 sevier, New York, 1973; (c) N. W. Makinen in "Techniques and Topics (1977). in Bioinorganic Chemistry", Part 1, C. A. McAuliffe, Ed., Wiley, New York, (93) €.E. Fleischer and T. S. Srivastava. Inorg. Chim. Acta, 5, 151 (1971). 1975; (d) ref 58; (e) M. F. Perutz, Brit. Med. Bull., 32, 195 (1976); (f) J. M. (94) E. B. Fleischer and M. Krishnamurthy. J. Am. Chem. SOC., 93, 3784 Baldwin, ibid., 32, 213 (1976): (9) Prog. Biophys. Mol. Biol., 29, 225 (1971). (1975). (95) E. 8. Fleischer and M. Krishnamurthy, J. Coord. Chem., 2, 89 (1972). (61) M. F. Perutz and L. F. TenEyck, Cold Spring Harbor Symp. Ouant. Biol., (96) E. B. Fleischer, S. Jacobs, and L. Mestichelli, J. Am. Chem. Soc.,90, 2527 36, 295 (1971). ( 1968). (62) For deoxyhemoglobin displacement of the Fe(ll) from the mean plane of (97) P. F. Pasternack and M. A. Cobb, Biochem. Biophys. Res. Commun., 51, the porphyrin has been calculated to be as much as 0.75 A (ref 30); 507 (1973). however, it is likely that this distance has been overestimated (ref 63). (98) T. Tsumaki, Bull. Chem. SOC.Jpn., 13, 252 (1938). (63) J. L. Hoard in "Porphyrins and Metallophyrins", K. M. Smith, Ed., American (99) P. Pfeiffer, E. Brieth, E. Lubbe. and T. Tsumaki, Justus Liebigs Ann. Chem., Elsevier, New York, 1975, Chapter 8 (contains an excellent review of the 503, 84 (1933). relation between conformation and spin state for the iron porphyrins). 100) D. Fremy, Ann. Chim. Phys., 35, 271 (1852). (64) See ref 24. A weak temperature-dependent paramagnetism has been 101) R. F. Stewart, P. A. Estep, and J. J. S. Sebastian, U.S. Bur. Mines Inform., observed for frozen aqueous solution of HbOP. This has been attributed Circ. No. 7906 (1959). to a thermal equilibrium between a ground-state singlet and an excited 102) A. J. Adduci, presented at the 170th National Meeting of the American triplet state.43 Chemical Society, Chicago, Iil., Aug 1975. (65) Based on X-ray crystal data from the model compound, Fe(TpivPP)(l- 103) (a) M. Calvin, R. H. Bailes, and W. K. Wiimarth, J. Am. Chem. Soc., 68, Melm)(02),the Fe is only 0.03 A out of the mean plane of the porphyrin 2254 (1946); (b) A. E. Martell and M. Calvin, "Chemistry of the Metal toward the dioxygen (ref 30). 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