Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Synthesis and Structure of Biomimetic Porphyrins Brian Morgan and David Dolphin Department of Chemistry, University of British Columbia, Vancouver, B.C., Canada V6T 1Y6 1. Introduction ................................................................................................................................ 2. 116 Porphyrins with Appended Peptides ........................................................................................... 121 3. 3. A. 3.B. 3.C. 3. D. CheIatedHemes ......................................................................................................................... Porphyrins HavingCovalently Attached Imidazole or Pyridine Ligands ......................................... Porphyrins Having Covalently Attached Sulfur Ligands................................................................ Porphyrins with Covalently Attached Ouinonc Groups ................................................................. Porphvrins with Covalentlv Attached Interactive Groups .............................................................. 127 127 137 142 146 4. 4. A. 4. B. "Picket-Fence" Porphyrins and Related Species ........................................................................ "Picket-Fence" Porphyrins............................................................................................................ "Tailed Picket-Fence" Porphyrins ................................................................................................ 148 148 156 5. 5. A. 5.B. 5. C "Capped" Porphyrins and Related Species.................................................................................. "Capped" Porohvrins ..................................................................................................................... "Pocket" and "Tailed Pocket" Porphyrins ...................................................................................... "Bis-Pocket" Porphyrins ................................................................................................................ 160 160 166 167 6. 6.A. 6.B. 6.C. 6. D. Strapped Porphyrins.................................................................................................................... Non-Functionalized Alkyl Straps.................................................................................................... Straps Containing Bulky Blocking Groups ..................................................................................... Straps Containing Interactive Groups............................................................................................ Doubly-StrappedPorphyrins .......................................................................................................... 169 169 175 184 192 7. List of Abbreviations.................................................................................................................... 198 8. References ................................................................................................................................. 199 1. Introduction Because have ing of an ubiquitousness investigated iron storage idases on porphyrin (hemoglobin reduction in heir been as 3 catalases) ', and contains porphyrin ring occupying their diversity of an variety group, four hydrogen porphyrin must protoporphyrin coordination by the sites number 2 oxygen destruction (perox- The the of active nitrogens the and and c) , P450)5. IX), contain- transport b, and proteins all oxygen (cytochromes utilization heme proteins, for (cytochrome (usually dictated functions, These responsible peroxide planar be natural levels. transport oxidation essentially function their are electron hydrocarbon iron of interdisciplinary prosthetic oxidase) , case the and myoglobin)l 4 each fore the and (cytochrome and and multi- metal. nature of site of the There- the axial ligands, the spin and oxidation state of the iron and the nature of he polypeptide chain. A basic tenet biomolecules sites. iron may Obviously porphyrins oxidation of bioinorganic be to mimicked fully understand must be and coordination state chemistry using the undertaken is that simpler mechanisms in which number) the inorganic of the and structure and complexes to heme protein characteristics the steric of and function model function, the a metal electronic of large the active study (spin effects of state, of the porphyrin and other ligands are systematically varied. Historically, ism of much reversible five of the research oxygen binding coordinate high proteins are become six-coordinate low spin on to metalloporphyrins myoglobin and spin (S = iron(II) = 0). The (S 2) has focussed hemoglobin. difficulty species, in on Oxygen which reproducing the mechan- binding upon his heme oxygenation behaviour is dominated by two problems: (i) (ii) the irreversible oxidation of iron(II) porphyrins on exposure to oxygen, and the difficulty in obtaining well-defined five-coordinate iron porphyrins. Simple iron(II) porphyrins cannot reversibly bind oxygen, except at low temperature. At room temperature, and in the absence of a large excess of a sixth ligand, formation of the six-coordinate iron(II) five-coordinate iron(II) breaks presumably down, dioxygen complex via to a species is immediately give the μ-peroxo ferryl intermediate to give followed by bisiron(III) a which the iron has been irreversibly oxidized to the ferric form (Scheme I)8-11. u.-oxo attack of complex. bisiron(III) a second This rapidly complex in 117 Therefore, the a oxygen irreversible porphyrins must major binding oxidation is role site, via possible provide an the enzyme to incapable of oxygen exists the body pathway formation is superoxide13'. chromes occurs inhibited, Similar P45014 and close transport) in in the complex. to occur the form acid believed cytochrome is to with oxidase3. of of That the the The by (the about of chain to so, of hemo- alternative complex protonated for stabilizes body hemoglobin μ-peroxo superoxide, iron(II) the This formation also of that Even 3%. sheath consequent iron(III) where assisted production fact form12. of is and oxidation oxidized conditions proton peptide rings the iron(II) extent under involve proteins heme irreversible functional to or heme two demonstrated methemoglobin ferric aqueous is backbone approach mechanism reduce oxidations and polypeptide the [μ-peroxo ano her being oxidation the by globin in for preventing the the cytoFe11-O2 species by enclosing the porphyrin in a hydrophobic pocket to which access In addition, recent neutron15 and X-ray diffractionl6 studies have indicated that stabili- by protons is inhibited. 118 zation to of the hydrogen iron-oxygen bonding bond between in oxyhemoglobin the terminal and oxygen oxymyoglobin atom and may the in part imidazole be of due the distal histidine (His-E7). The influence barrier to believed to Similarly, provide the of the oxidation. be the an protein Conformational responsible arrangement avenue protein's of along role in tor backbone is changes upon the residues electron maintaining the than binding cooperativity on transfer pervasive oxygen remarkable certain which more the may coordination simply at the exhibited protein occur in sphere of has the providing active been iron are hemoglobin17. by postulated cytochromes. the a site But to it porphyrin is which determines the functions of the various heme proteins. The metal second for N-donor ria in major problem six-coordination. ligands, Eq. 9, in studying For six-coordination > K2 K1 (K2/K1 simple example, is = iron in favoured 10-30 in porphyrins solution over is the containing five-coordination, aprotic solvent 25°C)18. at preference strongly of the coordinating i.e., for In benzene the equilib- at 0 25 C the binding constants of 4 and K2 ~1.9 x IO the iron. Addition second field The of pyridine ligand ligand to stabilization have been estimated at K1 ~ 1.5 IO3 x M-1 M '. The size of K1 and K2 is obviously controlled by the spin state of four-coordinate one Fe11(TPP) to - form iron gives the energy19-20. the porphyrin high low spin In is spin (S (S = contrast, 0) for in an = 2) intermediate six-coordinate Co", spin five-coordinate no species (S = 1) complex which with gain stabilization a is gained state. adds a in crystal on going from five- to six-coordinate since Co" is low spin in both cases, and K1 > K221). A nate fur her iron which greater the iron ligating bis(imidazole) difficult. consequence porphyrins. is A this power of by an imidazole makes which is example coordinated complexes Strategies of typical self control the is difficulty the imidazole (His-18) coupled with assembly of coordination of preparation are its the preparing of mixed-ligand models and a essential to ligand for six-coordi- cytochrome thioether tendency mixed for form in The six-coordinate system, preparing c (Met-80). a Im-Fe-SR2, range of heme protein model porphyrins. Numerous approaches have been used to control oxidation and coordination in model oornhvrin svstems. (i) Excess Ligand: The presence of excess base (imidazole, concentration of five-coordinate heme and reduce u-peroxo complex formation. pyridine) will minimize the 119 (ii) Temperatures22-'25. Low atures one (~-60°C), is Iron(II)-O2 where reduced to the porphyrin irreversible studying competitive complexes oxidation oxygen are reactions binding stable are K2/K1 as at low slowed temper- down. increases as Again temperature decreases. (iii) Kinetic ible oxygen Ior has of subjected then binding even exploited solution Fast Measurements: the to a short of equilibrated laser preferentially pulse wi h me hods conditions stability Im-Hm-CO, reacts spectroscopic under where may imidazole-heme-CO with a which oxygen mixture dissociates at a fast be irreversible complexes of oxygen the but used to oxida ion carbon observe will towards and A monoxide, is The (kBO2 rate > Tray- oxidation26. carbon monoxide. measurable revers- occur. deoxy IO7 heme M-'s-1). In IO3 — 10s, the Im-Hm-O2 complex dissociates and returns to the Im-Hm-CO complex. Since kBCO determined is in the the rate of experiment return and kB before 2 O2 02 and k^ is may added, be kB CO calculated may from a be accurately plot of l/krelurn vs O2 (pressure). (iv) Metal proper ies. Co and Replacement Substitution: metalloporphyrins which Such Ru are an more approach porphyrins. In is the of iron inert to applicable case of cobalt28 with oxidation since Co, and apoproteins reconstituted ruthenium29 or possess Co different may be leads to coordination recons ituted hemoglobin exhibits with coopera- tive oxygen binding although to a diminished extent. (v) This Immobilization: anchoring diethyl The the ester matrix porphyrin or have contained a the Fe (TPP)(B)2 axial base attempts ligand may the a be latter (pyridine observe tion of oxygen by the silica support. Wang's of approach uptake covalently attached approach attached and piperidine) reversible to oxygen and two to in the binding rigid a also support. silica flowing Basolo gel obscured and support removed iron(II) by the a either Reaction helium five-coordinate was by heme provided Alternatively, surface31. the heating give a a l-(2-phenylethyl)imidazole. but observed. prepared oxidation experiment30 and hemes was to irreversible classic polystyrene of oxygen porphyrin or prevent In matrix groups the to support. close Reversible undertaken to in prevented coordinated attempts solid embedded only 3-imidazolylpropyl 11 However, approach to environment. colleagues sixth was not hydrophobic the porphyrin his which with the porphyrin. physisorp- 120 (vi) Steric approach vented. rin two The ring in prepare approach a sterically porphyrin rings most polymer compounds temperature. By encumbrance: of closely chain. capable However, doubts the approach has reversible about one or therefore mimicking This of blocking and the both bridge natural system been oxygen number faces u-oxo and is vigorously binding the to porphyrin, aqueous of the may enfold pursued in nature of formation in the an pre- porphy- attempt solution active close be at sites to room and the reversibility of oxygenation have made this approach less fruitful. In are contrast, obstructed porphyrins by have some been group(s) synthesized covalently in which bonded to one the or ring. both The faces function of of the ring the steric bases which hindrance is two-fold: (i) to direct base binding to the open face, ensuring five-coordination, and to allow O2 to bind on the hindered face, steric hindrance preventing u-oxo bridge (ii) formation. Five-coordination may also be ensured in these systems by using bulky axial cannot bind on the protected face. This ally approach different has been model used by many porphyrins, groups e.g. to produce picket-fence, a wide variety capped, of architectur- cyclophane, crowned, strapped, basket-handle, etc., which are discussed below. (vii) Chelated allows one thioether, of (Eq. Covalent Hemes: control phenoxide, likelihood ligand to the etc., coordination 15). As attachment extent of covalent to the long as of attachment metal the coordination. increases without displacement ligand For the does the necessity not to poor local of occur, the porphyrin ligands such periphery as thiolate, concentration a large addition excess of a and of the external second ligand allows formation of six-coordinate mixed ligand systems. On built-in six- he other 1:1 and hand, for base/porphyrin strong ligands stoichiometry. four-coordinate (Eq. 16), As is e.g. imidazole, long as prevented pyridine, chelation dimerization, this to approach form produces provides mixtures a of five-coordinate complexes. In the following brance and chelation porphyrins fixed sections as we models hat have been distances from the for examine those heme proteins. synthesized porphyrin in ring. order transfer between various components gained. Several excellent reviews exist these models and their congruency wi h the also create these of which We to Using energy porphyrins the discuss natural which review employ a series complexes models, photosyn hetic the with important ligand of encum- biomime ic quinones information apparatus binding systems20,32-37. concentrate here on the strategy and synthetic details of model porphyrin preparations. steric can properties Instead, we at on be of will 121 To this end, the compounds have been grouped toge her more in terms of structure than of function. The reader is directed to reference 56 for a discussion on porphyrin dimers and strati bisporphyrins which are not reviewed here. 2. Porphyrins with Appended Peptides Perhaps duce the the tide most local fragments acids (e.g. obvious approach environment to a histidine, of to the suitable the porphyrin. methionine), synthesis heme active If the reproduction of site heme by peptide of the protein covalently models attaching is to repro- various pep- fragments contain suitable amino coordination sphere of heme the protein may be possible. An early example histidine-containing (Scheme histidyl 2). imidazole via sulfide his tripeptides After histidine-containing of metal was to to give the insertion possible pep ides linkages approach were was propionic into depending attached 2(b-d), that the on to of Lautsch acid the al.38', side-chains porphyrin, the et length ethyl a situation similar of intramolecular of side to that the Miiller39' coupled L-histidine methylester and protohemin 3 with dicyclohexylcar- coupled coordination peptide chains in who mesoporphyrin of chain. various IX by Similarly, mesoporphyrin cytochrome c. la the Losse IX and 122 bodiimide in histidine for N,N-dimethylformamide. bound to coordination various the of di- the time Warme imidazole tripeptide to protohemin chlorocarbonate to yield groups. The mesohemin sulfuric anhydride, been converted histidine or (Scheme 4). methionine paration A and intramolecular min 8 with L-histidine mixture of ester bis(histidine the ester three 9c) methyl to was ester) 9b, and was tedious and have more The obtained in yields too histidine and the side chains had acids and and pre- low. also It a and as a (Scheme 5). The reduced iron(II) species was capable of binding oxygen reversibly at low unstrained five-coordinate of triethylamine, deuterohemin was allow Treatment deuterohemin as 7a-e histidine to gave, such hemins Unfortunately syn hesized yield same yielded both were and the 5 amino short triethylamine 16% At disubstituted properties. desired unreacted acid prepared. and L-Ala-L-His; 3). containing short coupled triethylamine complex with single too al.40', appended or also were al.42), of propionic reaction a was et (Scheme mono- ethylchloroformate 9a-c. from the with chain Gly-L-His; SO3/DMF 7e, coordinating of Heijden 4a-d was arms et the dihydrochloride separated ei her quite der presence a of model side Momenteau compounds both porphyrin was side containing with Subsequent c the products quantities or yielded cytochrome characterized equimolar porphyrins one peptide-containing and methyl which the derivatives 6 that, the P-Ala-His; in mesohemin anhydride. coordination. porphyrin bispeptidyl of Van (e.g. DMF ester of the in indicated length centre. fragments sulfonic attached the iron methyl potential isolation that iron methyl a covalently recognized a into the 3 of in models acid, prepared reaction methionine to the Hager41 and methionine However, propionic and Gly-L-His-Gly-OEt) ethyl porphyrin after deuterohefollowed by purification, 6(7)-mono-(histidine deuterohemin mixture of 6,7- isomers 123 124 temperature but dimerization oxidized of the irreversibly 5-coordinate at room species temperature. occurred at low Furthermore, temperature extensive (-60°C), com- plicating oxygen binding studies. A similar dimerization was observed for the iron(III) species at room systems which temperature in 6-coordinate, or concentrated solutions. To his mixtures of prepared after the all 5- porphyrin deuterohemin solvent stage for 8 or the and syntheses 6-coordinate having mesohemin la purification. The Controlled yielded species, derivatives hours43). three have two with bis-chelated hydrolysis with model separation of covalently excess M 10 are could be attached imidazoles, in in histamine product 2 which was hydrochloric vacuo obtained acid in gave tedious. Castro by heating the absence up to 50% a 20% yield of yield of the monochelated hemin 11, again as a mixture of isomers (Scheme 6). More recently, (obtained prepare and from a hemin triethylamine. protohemin series was The Molokoedov of dibenzyl al.44, have ester 12 histidine-containing completed yields et of by the product mixed used in peptide 61% from yield derivatives anhydride decreased protohemin method 47% to by monobenzyl partial 14a-e. using 25% Coupling ethyl as peptide chain increased, the products being obtained as a mixture of the 6- and 7-isomers ester hydrolysis), of length to peptide chloroformate the 13, of and the 125 (Scheme 7; tide heme 14e only the 6-isomers derivatives are were shown). reported to The reduced be stable series of pentapeptide for 35-40 14d and hexapep- at room tempera- minutes ture in chloroform solution in the presence of air. This work was appended peptide derivatives (a ments, bisaminoacyl the of protohemin histidine more the prepare 6- IX 8). and hydrophobic previously were mixed anhydride derivatives in the 15a-i as spectra peptide environment protohemin prepared 7-isomers) or Absorption residues a The pentafluoroester (Scheme tuted to fragments45. mixture using (30-60%) extended of the condensed a mixture bulky pep ide the of chain with peptide the 6- frag- unsymmetric and 7-isomers having unsubsti- pentacoordination. was two monoaminoacyl give complexes capable 15 IX various to of that were derivatives with methods, indicated chain IX protohemin believed Further- to enhance the stability of the 5-coordinate iron(II) derivatives. There peptide have be invariant, the polypeptide imidazole teau been of structure via His-18 then metal by are covalently synthetic one IX strategy (16) optical centre mimic thioethers bonds to of of the poor the of to that the that a sphere for two ligands the obtain Binding ligands to indicated coordina ion attaching porphyrin, to spectra 17. the active c The methyl observed attempt thioether to the (TPP) cytochrome residues for iron the of Lautsch ethyl side in porphyrin. was natural to In this to and 17, while the the heme. attached were condensed with the TPP derivative 18 bearing a propenoate ester side chain at a (b- 9). could the cytochrome a protected 2,4-a,a'-dib- (Scheme to Momen- a of overcome Various to bound histidine case heme- 14-18 is methionine, made used. 17 using site chains the c segment of al.38, et of e.g. the was 14 atom porphyrin imidazole the active cysteine thioether An of reveals heme appended the iron. tetraphenylporphyrin site cytochromes he the similar (Cys-Gly-Gly-Cys-His) insertion, model various 14-Cys-X-X-Cys-His-18. sulfide a to of provides with romomesoporphyrin the attempts Sequencing with Loock46, and pentapeptide iron two compounds. After bind iron c. this cysteine However, poor deriva ive to would binding of the dipeptides 126 127 pyrrole position residue with atropisomers, on the the 1 Reaction cis-endo peptide 19 chain porphyrin. H-NMR of a dipeptide containing cis-meso-tetraphenylporphyrin-3-propenoic are When and cysteine residue the substituted Zn cis-exo disposed the magnetic the and circular might in dipeptide be porphyrin, 20 (Scheme a favourable chain 10). In the suggested However, that a recent interaction mixture cis-endo case, for binding (R metal EXAFS could S-alkvl a Gly-(SR)Cys-OEt dichroism Zn-sulfur terminal gave conformation was occurring. the a acid, only to a Me, metal bond weak in trityl), involving indicated be two substituents = sulfur data cysteine of that and for long range, if it occurred at all50. 3. Chelated Hemes 3. A. Porphyrins Having Covalently Attached Imidazole or Pyridine Ligands Chang and imidazole bond51. imidazole would Traylor had On the 21 wi h give argued either a too other the acid strain-free that few hand in or heme-pep ide too it chloride many was of models atoms argued pyrroporphyrin five-coordinate-system 23 to that XV the side chains achieve a strain-free condensation 22 (Scheme followed 11). was capable of binding dioxygen in a reversible manner in the solid state or when of by This containing the iron-imidazole l-(3-aminopropyl) insertion "chelated" of iron heme 128 dissolved -450C, in a only tives of polystyrene irreversible pyrro-, the porphyrin and mesoheme, and 1356. purified In or protohemin 3 base-containing methanol. pared. The of 25 was having amide or hemes binding pyridine were easily dimethyl then coupled to using with 30% 26, yield. 28 The 24 were as was amine followed was then isolated dichelated in solution series of covalently shown in partially or Alternatively chloride A investigated26,53-55. prepared primary mixture reversibly imidazole was ester chloride. pivaloyl reaction products to a pivaloyl excess The or linkages porphyrin oxygen temperature52. room the amine. up of at mesoheme monochelated in capable occurred ester base treated primary isomers While monochelated approach pyridine was and through the one monoacid imidazole mixture protoring film. oxidation by one containing were an of the water or chromatography compounds 12 The available equivalent with to proto- Schemes commercially quenched by bound For hydrolyzed. alcohol at deriva- as similarly a pre- 129 The versatility kinetics side of the chains, of O2 the the chelated and CO chelated heme binding base, and approach to has these the leng h allowed compounds. and nature the systematic Changes of the in study solvent, chelation arm of the porphyrin have been correlated with changes in the association and dissociation rates of O2 and CO57-58. Unlike tion the "chelated-histidine" at low temperatures, (Scheme 14) at Ior exploited iron(lll) he such dimerization IX binding the addition of titration of side-chain the titration gave a straight to greatly system 29, the side of (Scheme 30. A slope n = While 2.1, too and cyanide Tray- For short he to allow binds very vice versa. Therefore clean conversion leads to vs. log Y/l-Y indicating forms Indeed, cooperativity59. pyridine (log dimeriza- polymeric studies26. is affinity with plot any his chain 15). 29 in underwent of exhibiting pyridine Hill which presence used a protohemin dimer the concentrations increases pyridine line against design pyridine cyanide pyridine-hemin-CN_ the and Momenteau42 of argued derivative of hemin, to Traylor temperatures protoporphyrin intramolecular system poorly [CN]) cooperativity between symmetric diheme60. for to this the metal centres. Axial base chelation was di-(3-pyridyl)ethylenediamine ester 32 through (Scheme 16). the The similarly (31) pivaloyl used was anhydride, reaction with to prepare coupled CO followed by exhibits two a with iron insertion rate Meso-1,2- mesoporphyrin to give constants, monomethyl the diheme indicating either 33 two environments or a sequential change of environment due to cooperativity. The protohemins orientation shifts 1 paramagnetic for published 34 of and the H-NMR 35 base the methyl for various spectra with and of studied61. were respect vinyl heme to protons. proteins the imidazole-cyanide Chelation the of the porphyrin Comparison provided ring, of complexes imidazole causing these for dichelated a different shifts confirmation of maintains with the fixed chemical the values heme-imidazole orientations proposed in the natural systems. Tabushi heme et groups densation (22%) of (Scheme al., in have gable the chelated 62-64 c3 . The heme approach "gable-porphyrin" (m-formylphenyl)triphenylporphyrin 17). metal insertion, 38 and g,g'_pyridylmethane porphyrins the binding of I-MeIm and CO. wi h bridging the 36 After N,N'-diimidazolylmethane stable used cytochrome ligands use which with of 39 to 37 mimic was the pyrrole dimeric resulted displayed orientation prepared and bridging in by of the the con- benzaldehyde ligands such as the formation of cooperative behaviour to 130 131 1 The dimers H-NMR or chlorophyll-a mate. analysis higher and converted Reaction chlorophyll "chelated with derivative magnesium of chlorophyll aggregates. chlorophyll" mixed he complicated Sanders65 to (Scheme 18). aggregation 42 often and was and used by with 40 Intramolecular by its tendency to he phytyl group removed anhydride l-(3-hydroxypropyl)imidazole 41 prevented it is Denniss triethylamine/ethyl resulted binding gave well resolved Boxer and Wright in of 1 the to he spectra. model the of chloroforchelated imidazole H-NMR form to the A similar complex formed when apomyoglobin is reconstituted with chlorophyll derivatives66. Momenteau et al. this series the base ring, via amide or have is synthesized attached ester to linkages afforded the monoformyl derivative to the acrylate as tion yield and saponification sponding pyridine 45 acid 49 gave chloride resulted in 47 he a a 44, cis chelated of Vilsmeier was and acid of position 19). which of propionic with series (3-pyrrole (Scheme mixture the similar the chelated elaborated by trans isomers. derivative 46. porphyrin heme a of Cu(TPP) Wittig Demetallation, Treatment 48 50 compounds67. tetraphenylporphyrin formylation l-(3-aminopropyl)imidazole appropriate a or of In (TPP) (43)68 condensation hydrogenathe corre- or 3-(3-hydroxypropyl) 51 (70% respectively) (Scheme 19). These models were used to study the kinetics of base binding and 60% 132 to 4- and 5-coordinated TPP69), iron(II) and also to study the by Eaton et transient oxygenation of iron(II) carbonmonoxy TPP after photolytic displacement of CO70. The acid chloride labelled was same of TPP-acrylic acid Cu-TPP acrylic Cu-TPP investigated derivatives using EPR system acid 52b-f by was 52a wi h (Scheme varying used the a 20). nature nitroxyl The of al.71,72 resulted extent the of nitroxyl, in the Treatment metal-nitroxyl the of appropriate linkage the spin- interaction (amide or ester), and the geometry of the complex (cis or trans). A similar study was carried out on a vanadyl porphyrin73, 133 Collman to the al.74), et benzaldehyde (54) chromatography, with have position ortho and of stannous chloride various imidazole pounds 58a-c as chains prepared of a pyrrole chelated meso-phenyl (55) the in compounds where Condensation of glacial acetic acid the chain he (Scheme 21). for the mono-o-amino-TPP Collman less and readily his gave (57) which colleages accessible a attached 2% was merely (53), yield 56. "tailed-picket rins which are discussed in Sect. 4B. Mashiko et al.75 used the same chelated TPP is o-nitrobenzaldehyde meso-mono-(o-nitrophenyl)triphenylporphyrin produced substitutes hot TPP ring. after Reduction coupled used the fence" with com- porphy- 134 compounds els for to frustrated by covalently ligand tem. control cytochrome the coordination c, which in greater affinity the imidazole attaching a contain was provided; addition These authors prepared of of mixed histidine heme to the thioether several ligand and iron for porphyrin then complexes system. methionine imidazole ring furnished with Attempts as a the different to the rather axial than stoichiometric mixed tail prepare mod- ligands, are thioether. By amount six-coordinate lengths and of sys- various thioethers. For the Cs tail with tetrahydrothiophene as the thioether, a crystalline iron(II) complex structure determined (59) (Scheme 22) was obtained and its crystal (Fig. 1). Efforts to obtain the corresponding were defeated by "head-to-tail" dimerization. Fig. 1. Computer produced perspective of Fe11(C5Im)(TPP)(THT) 59. Adapted from Ref. 75 iron(III) complex 135 A similar chelated TPP compound 60 was used by Walker to study the effect of axial ligand plane orientation of axial complexes . ligand In bond a pyridine ligand bound (57) to H-NMR this strain. (o-aminophenyl)triphenylporphyrin ing 1 the 76 (TPP)bis(imidazole) effect on a In shifts case of the addition, to prepare zinc TPP77). pyrrole was Walker a 1 the tail and series H-NMR made and protons shorter Benson of iron(III) study have derivatives visible in to used 61a-e spectroscopy the monocontain- were used to study the displacement of the 3-pyridyl ligand by free 3-picoline (Scheme 23). Condensation porphyrin 6378). common N-I deprotonation of In this position addition 57 with case to of the allow trans-urocanic imidazole deprotonation Cu(acac)2 acid was yielded to chloride attached the the at (62) the imidazolate. furnished C-4 rather After [μ-imidazolato (Scheme 24), a poten ial model for he [Cuu2+/Cyta33+] center of cytochrome oxidase. iron binuclear the than chelated the more insertion and complex 64 136 However magnetic essentially and EPR studies non-interacting, unlike al.79 used of the 64 indicated strongly that FeII the 2+ coupled CuII and 3+ [Cuu /Cyta3 ] pair centers in the were natural system. Molinaro attach a et series of pyridine 0-hydroxyphenyl-TTP chelated (68) the (Scheme (- 500C Goff The to 80°C) Reaction of - used K2CO3 the of or length or 40% but 72, the ester the which, elongation of the of to (65) with allowed axial a to react TTP may iron-imidazole was prepare chelated "tension" via be bond. an (65) ether of 65 elaborated with base did not dibromoalkane derivative 73 into This was the splitting and shift of the pyrrole resonances in the 1H-NMR spectrum. in 27% overall at low temperatures oxygen to have affinity. the corre- solvent 26). molecule yield imidazoles80. forms DMF (Scheme the found of the in appended (71) imidazole introduced furnished enhance with covalently Reaction methyl-4-bromobutyrate 70 oxygen porphyrins with (66) and to to linkage. hydrobromide reversibly the strategy required chain, ring condensation which reacted presence when the alkane porphyrin The (69), derivatives synthetic gives the yield. butoxy cobalt to 3-(bromoalkyl)pyridine o-hydroxyphenyl-TTP Et3N), of with in same ether tilting 67 porphyrin 25). sponding the (65) porphyrin gave mono-(o-hydroxyphenyl)tritolylporphyrin ligands By in an (using varying the effect form on 137 3.B. Porphyrins Having Covalently Attached Sulfur Ligands Because of cytochrome large heme the poor affinity P450 have usually consisted of excess mercap ide concentrations approach available for to binding covalently to the of attach metal iron(II) porphyrins of ion. solutions However, mercaptide without for of the to the mercaptide porphyrins Traylor81 has porphyrin necessity of anion, models of the presence of in used periphery, excess (Scheme 27). Protohemin chloride monodimethylamide monoacid (74) was coupled to 1- the chelated making external it ligand 138 amino-3-mercaptopropane addition CO of anion in formation resulted pound he 79, benzoyl dimsyl containing analogous CO ester (77) and of the two masked complex 80. (75). After warming reduction removed the carbonmonoxy-mercaptide mercaptides Protection also the mercaptide sodium group, complex was of with benzoyl prepared as dithionite, and 78. addition A similar and deprotected the benzoylthio of com- to give derivative before reduction of FeIII was necessary because of the reducing ability of mercaptans. Alternatively resultant protohemin 82 disulfide was was coupled treated with with sodium bis(3-aminopropyl)-disulfide dithionite, the iron being (81). The reduced faster than the disulfide. Addition of CO then furnished the carbonmonoxy complex 80. 1 H-NMR of the CO complexes indicated that the sulfide underwent intramolecular binding without appreciable dimer formation. UV/visible band spectroscopy (384/460 or in DMSO 363/446 nm) solution which or was aqueous similar suspension to the hyper showed a split spectrum of carbonylated Soret cytochrome P450. A and series Groh of alkyl and 28)82. (Scheme aryl The (oaminophenyl)triphenylporphyrin (83). Since the chain introduced by detritylation (HgIIZH2S) indicated that spectra, in species. The was first he alkyl with gave chain was similar introduction of CO has acid derivatives were the porphyrin TrS-K+ thiol. flexible to does to to those hold of lead to more give after the by by Collman treating difficult 85 and to insertion, at planar formation the monochloride obtain, the Deacetylation iron mercaptan square the prepared directly S-tritylthiohexanoyl AcS-K+. or However, been prepared or to too be S-acetyl free were may wi h either the porphyrins chain pentanoic attached treatment toluene, alkyl (57) S-protected bromoalkyl "mercaptan-tail" C6 thio (MeOH/NH3) visible metal site; six-coordinate or spectra four-coordinate of the group the iron(II) low-spin FeII-CO complexes. To ensure CH3) or case the quen ly greater rigidity, tails (m-mercaptophenyl)acetic potential cleaved thiol with was sodium derived acid introduced 87 as borohydride from were o-mercaptobenzoic acid attached aminoporphyrin. the disulfide to give the to (see free the 86 or aryl 87) (86; which X was "mercaptan-tail" rins 90 and 91. As in the alkyl case, the aryl iron(II) species did not show five-coordina- = H In or this subseporphy- 139 140 tion. Furthermore, depending on addition the of nature of CO the gave mixtures mercaptan and of the five- and temperature, six-coordinate suggesting species, a tail-off/tail- on equilibrium. Deprotonation of the mercaptan to give the mercaptide was attempted. incomplete deprotonation The extent of mercaptide formation depended both on the nature of the base and of for the the was clean system tail. Indeed, for most tails only tail system (m-mercaptophenyl)-acetamide and gave complete a using six-coordinate acetanilide anion 92, as iron(II)-mercaptide-CO deprotonation base. In complex the 93 occurred. to presence whose However the mercaptide of CO visible this spectrum exhibited a split Soret absorp ion at 450 and 380 nm, typical of cytochrome P450. In for Sect. 3.A. we 75 cytochrome attaching the c . thioether (Scheme allowed 95a-c, 29). the displacement 57 After sulfide model for cytochrome c. ligand the iron by the the of pyridine FeII(C5Im)(TPP)(THT) of Rauchfuss and ligand or adopted porphyrin corresponding thioether, insertion ordering synthesis and to with containing following of to Buckingham phenyl)triphenylporphyrin porphyrins referred sulfoxide, reduction, affinities: imidazole the periphery83. anhydrides or Reaction 94 sulfone precluded > R2S this as a model strategy of afforded groups spectrophotometric R2SO (59) alternative titration > R2SO2. system as of (o-aminothe tailed in 60-90% with base The an easy effective 141 Smith and Bisset model84, P450 but octalkylporphyrin. placement A at the anediol the gave hydrolysis nately, of phyrins ether with with was 99 dithiols tetrahydrofuran no the yielded containing is leading sign with of by the only the excess a to give RS—FeII-CO melt 30). the disulfide spectrum of sodium of of suitably Conversion to salt he 98, 99. Unfortufrom the acetoxymethylpor- Treatment hydride an dis- 1,6-hex- 100 l-(3-aminopropyl)imidazole of of with thiouronium treatment potential nucleophilic (Scheme the a position introduction a meso-methylporphyrins. suspension meso to in formation Alternatively, with synthesize the ready 96 afforded oxidation characteristic to to susceptible to dimer thiourea unsuccessful. octaethylporphyrin approach attached substituent accompanied were heme were acetoxymethylporphyrin refluxing generate chelated atom the 97 by to complex the substituents carbon Heating which acetoxymethyl ing the followed attempts disulfide used case "benzylic" chains. bromide also this meso-acetoxymethyl functionalized the have in 21 provided of meso- in reflux- the meso-che- lated imidazole porphyrin 101 (Scheme 30), a potential model for T-state hemoglobin. The success of the chelated heme approach to model heme proteins is due to its ability to control captide, tion and strongly binding the coordination thioether, covalent enhances binding ability. binding ligands Addition e.g. of of a metalloporphyrin. attachment without the imidazole, one to the need of pyridine, equivalent of For porphyrin poorly binding increases excess external chelation can base mixture of four- and six-coordinate species, since K2 > K1 in Eq. 22. to an ligands the ligand. be iron e.g. local In used porphyrin the to mer- concentracase lower results of their in a 142 However covalent equivalent of attachment base which of the can base bind to the porphyrin intramolecularly to give provides the a stoichiometric desired five-coordinate species, provided dimerization is not significant. Such an model approach has porphyrins been e.g. followed by picket-fence, many capped, groups to produce cyclophane and an array crowned, of different strapped and basket-handle systems. 3.C. Porphyrins with Covalently Attached Quinone Groups An approach, many have similar researchers to to stimulated that interest photosynthesis, of prepare where as the chelated porphyrins possible heme with models photoinduced for charge model systems, appended the transfer has quinone primary occurs been groups. electron from adopted Such transfer excited by systems event singlet of state chlorophyll donors to nearby quinone acceptors. One of the earliest such models dime hoxybenzene 103 was (102)85. (p-carboxyphenyl)tritolylporphyrin followed by that of Kong and Condensation demethylation Loach with and who a prepared suitably oxidation a meso- substituted furnished he desired porphyrin-quinone pair 104 (Scheme 31). A et similar al.86-87*, linkage (ester compounds, transfer series who of varied or amide). especially occurred substituted both 105 from the EPR (a, tritolylporphyrins length of b; porphyrin and n to = 105 the chain (n laser flash 3), could quinone; have = 2, photolysis adopt subsequent a been 3, prepared 4) and the studies indicated conformation flipping of extended conformation could then prevent recombination and lead to a long-lived radical by Mcintosh nature of that the these in which electron the chain to an 143 ion pair. quinone Wang rings al.88', et attached lar porphyrins with of compound have prepared to an the a appended been series porphyrin of porphyrins periphery carotenoid incorporated by group into 106,107 amide were bilayer also lipid having linkages either one (Scheme prepared, membranes. and or 32). both two Simi- classes Photoconductivity in such membranes was enhanced relative to simple membranes89. The lead to Possible use of amide complications solutions or as to ester both the linkages the to join the separation and orientation problems of porphyrin of porphyrin-quinone and the quinone two orientation moieties centers and can of can vary. prolonging the change-separated species have included: (i) the use employing of more capped, rigid strapped spacers and to doubly separate the strapped quinones porphyrin are and quinone described later (models in the appropriate sections); (ii) attempts to the porphyrin. stabilize the transient radical ion pair by introducing other groups onto 144 Tabushi chloride in et (108), which the al. have which, after reacted selective porphyrin-quinone observed but no mechanism extended and the relative tion of TPPBQ the tively). (40%) 110 The constants fixed Illb 2-aldehyde with and distances charge oxida ion, fixed. Efficient The in benzaldehyde TPPNO photoinduced is were and Hlc prepared and at 10, (15% 10.5 and recombination for have been reported92. The condensation of a linear tetrapyrrole 112 and an aldehyde to has 33) was been 34)91. (Scheme yielded benzaldehyde (Scheme quenching distance llla-c benzoquinone were 2,5-diacetoxybenzoyl 109 fluorescence pyrrole with estimated separation with furnished porphyrin-quinone and TPPAO 57 compounds reaction pyrrole TPP and proposed. Diels-Alder porphyrin-quinone for was (25%). 111a. corresponding distance orientations 2-anthraldehyde, triphenylporphyrin mono-o-amino hydrolysis Reac- meso-(2-anthracenyl) gave by the product condensation and 11 18% A. these of respecThe rate compounds 145 form mesosubstituted 113-115 The (Scheme bicyclooctane Preliminary porphyrins 35) with units fluorescence was used increasing eliminate yields of to prepare porphyrin-quinone flexibility the free and base another series distance only and (6, rotational zinc of 10 compounds and freedom porphyrins )93. Å 14 is indicate allowed. an incre- mental effect of distance on photochemical electron transfer93'. A similar systems incremental shown substituted showed in which of 36 which were 116 (as the nickel reduction 118 an demonstrate effect Scheme porphyrin Deme hylation, porphyrins in and inverse a the the b. double The exponential multistep pair of 119a, of porphyrin-quinone electron quinone of dependence transfer separa ion by complex) bonds rate rings prepared and with then photoinduced on the provide the Wittig observed of of phosphorus furnished electron length redox the oxidation bis-quinone a was condensation transfer the porphyrin potential stabilize charge separation. Comparison with the mono-quinone etioporphyrin 119a 11794). free such chain95. In 120 was gradient and the meso- ylide the in with the base systems order to prepared96 may thus 146 showed the approximately decay is much for the time was longer than generation exponential much for of 120 charge group 121. recombination to A of for charge Similarly he prepare a inhibited by state of states. Moore system charge transfer photoinduced importance charge-separated photodriven was the 120. demonstrating long-lived aminophenyl)-bistolylporphyrin carotenoid decay longer the electron . . a quinone was the in quinone used both from cases, al.97, complex transfer both transfer second et incorporating separated in charge but 119b in 120 5,15-bis(4and observed carotenoid a since to the porphyrin cation radical, to give a long-lived (us scale) C+ -P-Q - species. 3.D. Porphyrins with Covalently Attached Interactive Groups A number than of o her potential Krishnan98 and variable tion have length between "tailed" ligands. prepared 122. the porphyrins Using Both porphyrin have a series of fluorescence ring been mono-(m- and which contain groups other p-hydroxyphenyl)triphenylporphyrin, derivatives and the prepared or EPR terminal containing data a phenoxyglycol indicated phenoxy group, chain intramolecular suggesting Maiya that of interacthe tail existed in a folded-over conformation. Similarly a While 123 (65) mono-(o-hydroxyphenyl)triphenylporphyrin cyclodextrin did unit, not in the display hope the of preparing desired a properties, was covalently water-soluble guest moiety appears to induce novel conforma ional changes in aqueous solutions. oxygen inclusion in attached carrying the to model99. cyclodextrin 147 Other cyclodextrin thylimidazoles capped included in hemes an have prepared101 been a-cyclodextrin which formed using a 1-substituted pentacoordinated 2-mecomplex with protoheme. The by ability several Fe11 of groups porphyrins to attachment of a suitable DNA the helical surface where DNA Lown and Joshua101 124a-c which series of and mimic in intercalator reactive prepared the properties which 125, a generate systems have compounds protohemin, to prepare a suitable to iron oxygen the of could might give deuterohemins glycopeptide from is radicals bound has antitumour porphyrin species derived intercalator oxygen potential an series of 126, reactive with with antibiotic been exploited properties. deliver rise an to Covalent the heme to DNA scission. attached acridine bleomycin. A similar mono-p-aminophenyl)-tritotyIporphyrin to the porphyrin chain, has also been prepared which exhibits oxygen-dependent DNA cleaving ability102. via a spermine 148 4. "Picket-Fence" Porphyrins and Related Species 4.A. "Picket-Fence" Porphyrins Perhaps the porphyrin of most successful Collman. of Steric the heme encumbrance protein about active the site metal models is the "picket-fence" site of these substituted conformation in which the TPP molecules depends on two factors: (i) due to steric phenyl repulsion, rings are the TPP essentially will adopt perpendicular a to the porphyrin ring; four meso- substituents at the orr/io-positions of the phenyl rings will lie above and below the porphyrin plane, and (ii) for TPP molecules depending on containing the bulk mono-ortho-substituted of the subs ituent, phenyl rings, interconversion of separation the four and, possible atropisomers may be achieved. Collman four "protected could of reasoned pivalamido pocket". not ligand. bered and a stable since syn hesis located Ligands penetrate excess that groups the The e.g. bulky of the pocket, a pivalamido the porphyrin ring would bind to the metal the open ensuring could five-coordination molecule form. groups tetraphenylporphyrin of dioxygen complex iron(II) side could thereby smaller substituted same imidazole, much six-coordinate the on would This should on even not oxygenated prevent be in face the sterically complex irreversible having give presence encum- should oxidation a but be through close approach of two porphyrins and formation of a u-peroxo complex. Condensation acetic acid chloride atropisomers of which of pyrrole gave to the (4a, was (55) and four equivalents meso-tetra(o-nitrophenyl)porphyrin 128 meso-tetra(o-aminophenyl)porphyrin 3ab the 2a2b) desired were aaaa separated isomer 129. by of which o-nitrobenzaldehyde was reduced 37)103,104. (Scheme chromatography, Interconversion of sufficiently slow at room temperature to afford clean separation. Refluxing the unwanted the the by (53) The slowest in stannous four moving atropisomers was 149 products further gave in toluene isolation the for of 20 he "picket-fence" frozen by the bulky zation of these min aacta effected isomer. porphyrin of the to 130, Several the have studies on made105-107'. been the amino a,a,a,a-H2(TpivPP) substituents. atropisomers reequilibration Reaction statistical groups with which the in physical Treatment mixture allowing pivaloyl chloride configuration properties with and FeBr2, is isomeri- followed by II reduction with Cr(acac)2 gave Fe (a,a,a,a,-TpivPP) 131. Although addi ion FeB2(a,a,a,a-TpivPP), "picket-fence" compounds pyridine, side was oxygen amounts of it strong was was less prepared piperidine, reversible of field suspected than (B that = ligands that on Im, behaviour decomposi ion. Indeed, in the l-Melm, low spin binding "open" benzene side. l-n-Bulm, the solution oxygen six-coordinate constant A of at All 25 complexes, the series l-trityllm, tetrahydrofuran)104. tetrahydrothiophene, binding gave the complexes, base of 4-t-BuIm, of °C, these without Fe(TpivPP) were stable for long periods (ty2 2-3 months) in solution provided 2-4 equivalents of axial on the six-coordinate l,2-Me2Im, showed appreciable (N-RIm)(O2) 150 base talline were present dioxygen to protect complexes Fen(TpivPP)(I-MeIm)(O2) 132a the unshielded could be (Fig. 2)104108, face. Furthermore, obtained104. The Fe"(TpivPP)(2-MeIm) analytically crystal • and its dioxygen adduct109 (Fig. 4) have been determined. Further structural information Fig. 2. Perspective view of Fen(TpivPP)(I-MeIm)O2 (132a). Adapted from Ref. 108 pure, structures EtOH (Fig. crysof 3) 151 Fig. 4. Perspective view of Fe(02)(TpivPP)(2-MeIm). The dioxygen and imidazole are disordered. The disorder has been idealized and only one concentration is shown in this figure, which is adapted from Ref. 109 152 was obtained I.R108,110,111 by measurements82'108*. also The studied112. been and reversible Reviews Mossbauer binding on of spectroscopy oxygen oxygen to binding to and cobalt magnetic complexes picket fence, susceptibility of and TpivPP related has systems have also appeared32-37 113-115). Binding of determination crystals a five-coordinate state tive binding (at Collman increasing as in be solu ion. deoxygenated under vacuum solid Hill Y/l - (log these two O2 a in terms of imidazole its bound of molecules in the induces solid sufficient which are strain the the towards of and Similar = that non-cooperacooperative molecules' dimensions the this (B of porphyrin ring. As change in molecular a conforma- crystallite to induce affinity of the oxygen the O2 concluded region the oxygenated in enhances move of was regions intermediate shrinking give cycles116. it two However, to Fe(TpivPP)B P0z) showed prevented between many of log an this and over vs. compounds and cycling samples Y pressures) of This oxidation by low solid in irreversible plot side re-oxygenated. iron the porphyrin heme be the presumably change the five-coordinate demonstrated for and rationalized numbers dimensions the "picket-fence" the could observable binding high the to could was From oxygen oxygenation tional no l,2-Me2Im). binding. on binding which oxygenation solid on species produced reversible 2-MeIm, base oxygen FeII(TpivPP)(I-MeIm)(O2) of vacuum second of remaining deoxy sites. This behaviour is reminiscent of the cooperative oxygen binding of hemoglobin. Various sation other of Collman (136), et by al. fonyl chloride complexes at directed quent have reaction rous oxygen sterically hindered TPP derivatives have meso-a,a,a,a-tetra(o-aminophenyl)porphyrin 134 into both C This the cavity, iso-phthaloyl 38). Despite exhibited attributed to only the series the amide of of the TPP bulky 133 bulky the conden- acid chlorides. and and H2(TTOSPP) p-toluenesul- "picket-fence", oxidation protons which coordinated derivatives by (135) dichloride irreversible acidic protona ion similar prepared with H2(TphthPP) compounds, with (Scheme allowing A the (129) compounds was oxidation104*. heme prepared H2(TAmPP) respectively of 0 25 also of been 129 on were dioxygen 137a-g have the fer- exposure to presumably and conse- been syn he- sized under identical conditions by Bogatskii et al.117-118. The reaction yielded be the separated CH3I, o-H2(TAmPP) of tetra-isonicotinamide by followed (129) TPP chromatography. by anion The and meta deriva ives a exchange, were excess statistical to yield (138) also isonicotinic mixture isonicotinamide isonicotinamidophenyl)porphyrin-tetracation para with as groups the and chloride hen soluble 39). reduction hydrochloride atropisomers were water (Scheme prepared of which methylated could with tetrakis-(N-methyl- The corresponding potentials, basicity and reactivity with metal ions of the isomers were compared119. Ort/iosubstituted choosing suitable TPP derivatives substituents on the have been phenyl used rings. For as binuclear example, ligand treatment H2(TAmPP) 129 with maleic anhydride gave the tetrakis(o-maleamoylphenyl)porphyrin systems of by a,a,a,a- 153 (139) in insertion the 90% yield (Scheme at a rate much copper by the carboxylates 40). faster In aqueous than for holds the DMF this unsubstituted metal ion porphyrin porphyrins. in a undergoes Rapid position copper complexation favourable for of rapid intramolecular transfer to the porphyrin nucleus120'. Binuclear synthetic porphyrins models for capable the of iron/copper binding site iron of and copper cytochrome have oxidase. consists of a tetraphenylporphyrin ring with a covalently attached tetrapyridine ligand been One inves igated such model as 141 154 system, (140) ring and claim tion obtained and copper magnetic that of the the nicotinamide tions to be by treating 41)121. (Scheme The a,a,a,a-H2(TAmPP) mixed coordinated susceptibility to of metal the four the complex conditions necessary for groups123. Instead, used which for the locks the introduction with excess with iron inserted nicotinamide nicotinamide groups, (129) compound examined12'. metal insertion these "pickets" of into the porphyrin ring, without fear of isomerization. groups divalent In into authors into prepared, contrast, this have place and was nicotinic into more first-row porphyrin the EPR and cause coordinated allowing trivalent and Elliott complex anhydride the Krebs isomeriza- Ru" to the forcing condi- transition metals 155 Iron porphyrin oxidants is catalysis believed have attempted chiral "picket-fence" strate olefin to the to catalytic the a,b,a,b-H2(TAraPP) high very yield little chosen as an the porphyrin was reacted This (95%). selectivity catalyst core. which The was in diacid chiral active chiral epoxidation olefins porphyrins acid of 9-31%). form a (142), efficient of and various Instead large of the and iodosylarenes Groves using of suitably (Scheme olefins relatively with binaphthyl rigid chiral l,l'-binaphthyl-2,2'-dicarboxylic followed by methanolysis enantiomeric observed for variously substituted styrenes and aliphatic olefins. excesses the by 42). 143a as Meyens substituted of prepared porphyrin the and approach were chloride appendage (%ee, using intermediate. stereochemistry chloride -H2(TAmPP) more the The the could hydroxyla ion iron-oxo epoxidation optically the obtained a,b,a,b 143b an and reac ive control as However, was a species124. with group appendage with to iron-oxo (142) epoxidation via asymmetric porphyrins (R)-2-phenylpropanamido in of proceed sub- reacting With was an formed iodosylbenzene group was cavity about acid (144) and iron insertion. of 20-50% were 156 More ence ence recently of of HCl acid converted to Tabushi H2-Colloidal and chlorides its al.125 et as epoxide a have platinum cytochrome and slow used supported P450 on mimic. reduction Felll(TpivPP)Cl in the pres- poly(vinylpyrrolidone) in he pres- oxygenated Under such the ferric complex faces of of conditions cyclohexene followed by is formation of the dioxygen ferrous complex completes the catalytic cycle. A porphyrin (Scheme 43; with bis-ortho the on 145 bearing pickets = CH3)126. However, R' substituted phenyl both only rings so two it the opposite is unlikely ring has meso-positions that this been prepared are compound substituted will be a successful oxygen binding model. 4.B. "Tailed Picket-Fence" Porphyrins While the direct solid state, such oxygenation studies prevent six-coordination base necessary is complex formation.) to in in the ensure To of five-coordinate solution presence complete control were not of FeII excess coordination coordination, "picket-fence" possible on Collman since sterically the "open" et was the al., observable "picket-fence" unhindered face and adopted heme" approach. Dispensing with external ligand, the base was covalently attached to in the could not base. (Excess prevent the (μ-oxo "chelated the position ortho-phenyl intramolecular binding of to TPP, the and porphyrin so constrained metal. The into other a three position promoting meso-phenyl rings carry the "pickets" necessary to prevent irreversible oxidation. a,a,a,a-H2(TAmPP) Treating "3-picket" tion for 2 h atropisomers isomer urea ing re-equilibrated an imidazole to yield gave (S a = 2) iron(II) diamaenetic free = H-NMR (Momenteau. 0) but 148 on complex not 1:1 of confirmed metal the the the observed, presumably had observed such (3 a- amide of using "tail proposed and chains insertion temperature a he solu- unwanted Using by iron(II) were Travlor. of (The 147 gave benzene b-product.) five-coordinate decreasing chloride in mixture the Direct the spectra but a P-aminoporphyrin 149. of pivaloyl Refluxing chromatography. yield he and to by the to yields formulation, (S increase of 44). group separated attached porphyrins 1 equivalent (Scheme aminophenyl to was 3.2 (35%) were quantitative 15174. e.g. Drocess. the nearly with 146 which be porphyrins, to the 147 could leng h spin equilibrated 146, linkages FeBr2 (129) a-aminophenylporphyrin or vary- anhydrous picket-fence" five-coordinate high 25 due (due °C) to dimerization peaks a dimerization in the chelated heme systems.) Addition the of oxygen expected peak pattern plexes, to spectra for the presumably solutions of a "pickets" towards of the high diamagnetic the suggests open spin compound that side the of five-coordinate for the oxygen the may pocket, iron(II) oxygenated a be compounds species ordered suggestion in gave 151. The these which is com- awaiting confirmation by X-ray crystallography. A similar pyridine series covalently of "tailed attached to picket-fence" the porphyrins porphyrin 150 has via urea periphery been synthesized linkages127. O2 with a and CO of alkyl binding to both series of porphyrins has been carried outl27_l29. The and Sect. use aryl meso-(0-aminophenyl)triphenylporphyrin of mercaptan-tail 3.B. A similar porphyrins series of tripivalamide-|3-aminophenylporphyrin fence" porphyrins thioether dioxygen74. chain has 154 also as cytochrome compounds 147 to (Scheme 45)82. been prepared has give A and similar is 57 P450 been the to prepare models prepared alkyl series been by 155 capable described acylation mercaptan compound reportedly a has "tailed with of an reversibly of in the picketappended binding 5. "Capped" Porphyrins and Related Species 5.A. "Capped" Porphyrins The direct rins was condensation exploited molecules a by benzene of aromatic Baldwin ring and was aldehydes co-workers covalently and to attached pyrrole prepare to all to form "capped" four tetraphenylporphy- porphyrins. or//io-positions of In these the meso- phenyl rings, enclosing a volume of space above one face of the porphyrin ring. If the cap was sufficiently prevented nate the species. On under was tight on the cap, recognized the the that attempts would probably to "cap" rin "capped" ring to porphyrin. to result give bases the provide Unlike on in low very alkylimidazoles, open barrier benzene tetraaldehyde face dioxygen physical a the (e.g. the smaller a condense a is the last step of the not required. of binding hand, should attached the face; other which linkages the binding enclosed yields. which "picket-fence" ring result in molecule would be to [x-oxo with Instead was pyridine) would a complex porphyrin the condensed porphyrin, cyclization able to fit It four ester units were pyrrole of synthesis, so chromatographic separation of be five-coordi- formation. by necessary with should a the to give porphy- atropisomers is The required with bromoethanol 159. Reaction of tetraaldehyde to the yield 156 158, tetraaldehyde was prepared followed with by pyrrole by alkylation condensation in refluxing of with salicylaldehyde pyromellitoyl propionic acid (157) chloride yielded the "capped" porphyrin 160 after chromatographic purification (Scheme 46) (Fig. 5)130,131. Fig. 5. Two perspective views of the "capped" porphyrin 160 as the free base. Adapted from Ref. 140 The same sponding reaction sequence "homologous" or using "C3-capped" 2-(3-hydroxypropoxy)benzaldehyde porphyrin 161 in which yielded there is an the corre- extra methy- lene group in each link of the cap131. In the latter case the yield of the cycliza ion reaction was much larger cap. lower (5%), probably reflecting the extra entropy factors To provide steric hindrance on he uncapped face required a to form the "naphthyl-C2-capped" porphyrin 165 was similarly prepared (Scheme 47) from 159 and 162 via 163 and 164131. Inser ion of iron crystalline four-coordinate containing excess axial into the high base "C2-capped" spin the iron(II) porphyrin, porphyrin five-coordinate heme followed 166 was by (Scheme formed reduction, 46). which reversible dioxygen binding at 25 0C The stability of the dioxygen adduct depended on was In gave a solutions capable of the nature and concentration 48130. Scheme axial base, that they Unlike the the larger size were small, appeared that a side the cap. of of e g., second of the axial "C2-capped" the "C3-Cap" propylamine. base Oxygen could binding base porphyrin permitted For weakly was and 166 the position which could binding intermediate of size two bases coordinate to the reported to occur, still of iron, the equilibria only bind axial bases, such as probably giving a a in single provided l-Melm, through it the pseudo-seven- coordinate complex132-134). The been natural O2, CO and 131 137,l38 studied - porphyrins H2(NapC2-Cap) . NO affinities It was and other (165) > of found that synthetic H2(C2-Cap) a series of FeII O2 affinities models e.g., (160) > and were the Fe" CoII capped much lower complexes H2(C2-CapNO2) (161). In contrast CO bound more quickly than O2, and the rate of binding was indepen- (167) porphyrins than of > have those of H2(TAP) > H2(C3-Cap) Fig. 6. Perspective view OfFe111Cl(C2-Cap). Adapted from Ref. 141 dent of the cap in terms ra ionalized H2(C2-Cap) (160) cap-porphyrin more of expanded too must the might of to the unhindered cap. FeIIICl(C2-Cap) small exist cap be effect and was version comparable steric 5)140 (Fig. under system and a separation accommodated Fe-O-O size in argued destabilized to the (Fig. 6)14 either solution. by Although accommodate against That a a porphyrins139. model crystal indicated CO the linear Fe-C-O "central" steric effect. "peripheral" steric that O2, or This structures the a system of both phenyl considerably However, effect was of the could be the bent methylene chain linkages. Studies142,143 used to NapC2-Cap of deduce > the the C2-Cap paramagnetic cap-porphyrin > C3-Cap, shifts in separation. which 1 the The H-NMR relative correlates with of cavity the CoIICap size porphyrins was relative in oxygen the were order affinity of the iron(II) "capped" porphyrins. Recently144 ified the "C2-capped" "capped porphyrin porphyrin" approach in a which has pyridine been is extended covalently to bound meso-aromatic rings of the parent "C2-capped" porphyrin, forming some kind of "strap" prepare to two a mod- opposite (see Chap. 6) over porphyrins were lowed reduction. by functions the porphyrin prepared before by For face solubility condensation opposite condensation reasons with the to of a it was the "cap". Bis-amino dinitro-tetraaldehyde necessary appropriate 3,5 to pyridine with "C2-capped" pyrrole benzylate diacid the folamino compound. Both of the corresponding iron(II) C2-Capped strapped porphyrins 168a, b exhibit reversible oxygen binding autoxidation in toluene reactions C4-Strapped of the not result in a solution complex μ-oxo at C5-Strapped (the 168a complex, room complex is the temperature 168b several strap and has months). cap and a t½ show of good several Furthermore, preventing dimer stability days while decomposition formation. to that does Although a kinetic study has not been made, it appears that the stability to autoxidation is due to the low affinity that of of iron(II) introduction of the iron(II) C2-Capped the strap complexes complex decreases for dioxygen. (166) the (which O2 Comparison also affinity by has a a factor of low of P½ values with affinity) shows that the O2 4 for C5-Strapped the complex 168b, and by a factor of 40 for the C4-Strapped complex 168a. This is due to a combination of complex in porphyrin upon metal offers more steric tic rings a steric interactions. domed configuration oxygenation. further resistance interaction preven ing The may motion to the presence which presence occur of The the of the movement between pyridine of resists the the cap movement strap of the and the binding the metal on pyridine towards locks of the more severe for the shorter C4-Strap, resulting in lower dioxygen affinity. side-chains porphyrin the metal of unoxygenated towards pyridine oxygenation. and center. the This to the the Further- meyo-aromawould be 5.B. "Pocket" and "Tailed Pocket" Porphyrins To prepare Collman rin is a et approach used linked to to system which discriminates have used a al. to prepare provide only the pocket ide can steric three by a be series of encumbrance raera-phenyl orientation only of against combina ion of at one the face of leaving bent Fe-O-O by bending of binding CO "picket-fence" porphyrins145.l46. "pocket" groups, accommodated the the the an unit As side. toward the tilting the but a in Oxygen open of to of O2, porphy- benzene this may side. he that "capped" above, porphyrin, open and/or relative and ring case it bind Carbon is within monox- linear Fe-C-O unit one equivalent leading to decreased CO affinity. Treatment of pivaloyl chloride with benzene a a,a,a,a-H2(TAmPP) formed tris-acid porphyrins 171 in choice acid chloride of irreversible oxidation. good A the chloride yield and (129) with "mono-picket" 170 (>60%). the similar sligh ly porphyrin under The high dilution volume of the single presence of strategy was more 169 employed than (Scheme conditions the pocket picket to 49). afforded was provided prepare porphyrins 172. However, in these compounds, the remaining ortho-ammo group is used the dictated protection the of Condensation pocket by the against "tailed-pocket" to attach the base, leaving no protection on the open face of the pocket. In contrast to the "tailed picket-fence" porphyrins, these complexes undergo rapid oxida ion to the μ-oxo complex145. For the the size Piv) iron(II) of derived Although Visible from 171a remained medium ranges and could nant species. were compared147. O2 a similar he model two coordination and coordinate even pockets showed within which CO binding of the O2 affinities for CO systems, affinity. the of in the data the "pocket" both Since systems CO iron(II) of excess was similar, and solvent was attributed on Fen(Poc- that base. concen- he "picket-fence" were affinity depended six-coordination, and electronic in iron showed presence increasing five-coordinate the reduction state spectral size determined reduced MCD five and While showed the absorption large be The porphyrins in porphyrins, pocket. the tration "pocket" the domi- porphyrins the "pocket" effects were to steric the hindrance of the cap which distorted the Fe-C-O unit from linearity. “ 5.C. Bis-Pocket" Porphyrins Eventual occurs this, steric the irreversible because of encumbrance both is octa-ort/io-substituted TPP bulk substituents for porphyrin molecules but stabilizing the FeII(P) oxidation steric (where the ortho ring. The would (P2-) complexes pockets form oxygenated a barrier the tetrakis[2,4,6-tris(ethoxy)phenyl]porphyrin) a "picket-fence" only have s ill to be the by one of and side may penetrated be Vaska "capped" the By by approach and the of prepared. pocket close Amundsen dianion on been protected could porphyrin. is the present choosing formed axial of two have porphyrins molecule. on To he both sides bases and metal centres, prepared the avoid correct thus hemes tetrakis[2,4,6-tris(methoxy)phenyl]porphyrin condensation of the stituted benzaldehyde with pyrrole148. Balch has shown by 1H-NMR that although the appropriate of diatomic or trisub- or ho-methoxy ature substituents proceeds prepared role to by in Suslick refluxing gave sterically hindered was However, natural base, of oxygen systems, to porphyrin species 173 is reversible very observation which gave at room hindered 1% to non-polar other to the pyr- Metallation and of iron(II) complex solvents model was with Addition five-coordinate in attributed yield. temper- complex yield. 80% a compared was in in oxygenation low more 2,4,6-triphenylbenzaldehyde the 1,2-dimethylimidazole, affinity an obtain oxidation A condensed iron(II) completely formation, Fe111(P)Cl11. who four-coordinate capable he acid complex and Fox149, and the μ-oxo FeIII(P)OH propionic reduction which prevent form at 0 30 complexes non-polar the C and the of the nature binding site. Covalent to attachment prepare by porphyrin Lindsey separation 175 between was reaction porphyrin bases by (129). The after porphyrin gated and for at was 177. rate of room four a cofacial fluoranil of for constant for the was h. and then transfer of Subsequent from yield with of a,a,a,a- the of in the Schiff yield furnished to base "capped" 80-95% compound porphyrin the Schiff reduction 176 this used adopted where the insertion of be was quinone-tetraaldehyde reacted 85% metal also system The nature reaction; properties electron may approach . porphyrin-quinone groups photochemical TPP an 10Å which 24 desired amino be intramolecular yield the of Such porphyrin-quinone to 174, the temperature The structure. estimated high the orr/iopositions rigid and the of the a prepare yielded Acetylation he to rings reversibility stirring quinone to having alkoxylation NaBH3CN 50). group two responsible with (Scheme the prepared were a Mauzerall150 and H2(TAmPP) of complexes the were quinone zinc investi- was esti- mated151. 6. Strapped Porphyrins The strapped which porphyrin some porphyrin formed group macrocycle. porphyrin, cyclophane, class is of heme protein covalently linked to The thus crowned, usual strategy has great versatility in basket-handle, embraces corners synthetic allowing pagoda, models two been he etc.). all (usually to tie types The those diagonally the of compounds opposite) strap to structures porphyrins may be in of an a already made (e.g. singly- or doubly-strapped and may be classified according to the nature of the chain: (i) Simple non-functionalized alkyl chains whose role is to span one face of the porphy- rin, discouraging μ-oxo bridging and providing a more hydrophobic environment. (ii) Straps incorporating some bulky group which will provide more steric encumbrance than a simple alkyl chain. (iii) Functionalized interacting with five-coordina ion straps which the metal or to incorporate at form the some porphyrin six-coordinate group core. capable These mixed may ligand of be binding used systems to L-M-L', to or maintain where one ligand binds poorly to the metal. 6.A. Non-Functionalized Alkyl Straps A number of research groups have reported the synthesis of simple Ogoshi et al.152-154'condensed long-chain diamines with a difunctional etio-type porphy- strapped porphyrins. rin 178 obtain in the the (Scheme short 51). used at 0 C same (Scheme ester or yield. complexes to the in THF ferric porphyrin model to iodosyl benzene. ligand 185a models by investigate prepared in cases strain 0 the into an Using (shorter 185b. A to served similar 5-7 mimic was the of as of units of spectroscopy Fe-CO chains by Dieckmann 184 in good the ferrous irreversible oxidation strapped a cytochrome P450 alkanes substrate, series 25% amide-linked as he with in or unactivated differentiation Raman and rapid an por- (180) side 183, for al.135' et 182 oxygenate used methylene the resonance straps) only to giving ferrous II coupling prepared hydroxylation itself the Battersby carboxyl to that, inhibited, porphyrin porphyrins showed claimed mesoporphyrin attempts dilu ion chromatography was to bridged oxidative system strap was strap porphyrin also the containing attempt C have high after complex. of strapped 20 156 instance prepared systems. steric the sideways at Kuo this transformed been of it binding the intramolecular under yield he μ-oxo chloride give porphyrin-catalyzed some also natural increased In the being has were the In and the to move acetone under oxygen of amide-linked easily Chang 53). by 20-30% spectroscopy ligand bis-acid dilution or can aqueous (Scheme the triethylamine in observe elaboration ester-, or to followed strap state. 185a porphyrins the axial forma ion high and 12) absorption bulky rapid under 6-10, visible Alternatively, the = Attempts in formation, chloroformate (n reacting (181) gave of species. 52). Because 179 second strategy, amide condensation a resulted 1,12-aminododecane yield isobutyl basis of iron(II) 15 the the binding five-coordinate of porphyrins On straps, phyrins presence strapped by the porphyrin amide-linked strapped in the strap157. O2 and CO displayed correlation between a stretching and Fe-C-O Such bending vibrations has been observed158. A different synthetic porphyrins where Unlike previous of the the porphyrin intramolecular sation of the anion 186. ylate afforded to syntheses, cyclization 187 unstable to and of Acid he "alkyl-strapped" the alkyl In strap the it is by Baldwin opposite the strap In the final step the strap is stretched into This presence not of is prepared with immediately 190 able in to excess the to initially position which condensed 23% overall enforce base the prepare rings the ring is (Scheme gave strapped linked159,160. are and porphyrin benzyl bis-dipyrromethane, was al., 1,12-dibromododecane condensation porphyrin was which with et meso-phenyl ends. chain-linked 189. give complex. of salicylaldehyde examples iron(II) adopted both catalyzed the tetraacid was ortho-positions attached dialdehyde" the strategy the two halves formed 54). he by Conden"strapped- 3,4-dimethylpyrrole-2-carboxafter hydrogenolysis with yield. trimethyl As five-coordination six-coordinate formed which did not bind oxygen. Reducing the concentration of base led to an increase in of gave orthoformate the the species previous respective 191 was 172 173 of the four-coordinate oxygenation was species observed at which -550C underwent similar to irreversible unhindered oxidation. porphyrins, While warming reversible to room temperature caused μ-oxo bridge formation (Scheme 55). A a similar porphyrin porphyrin. would, at approach with very Obviously best, give in was short this very used by alkyl chains case, poor et al.161,162), short enough Wijesekera - linking yields. opposite Instead the who to corners two were cause attempting deformation of a preformed halves of the to of strap the porphyrin porphyrin were assembled at each end of the strap, and only at the last step was the porphyrin 192 formed by acid-catalyzed intramolecular cyclization under high dilution conditions (Scheme 56). Visible and 1 H-NMR spectroscopy and X-ray crystallography (Fig. 7) all point to increas- ing distortion of the ring as the length of the strap is decreased (192, n = 11, 10, 9). A 174 chain length of nine methylene units appears to be the lower limit; attempts to prepare even more strained porphyrins with shorter straps were the metal complexes showed that the straps provided no steric protection. Fig. 7. Ortep drawings of 192 (n = 9). Adapted from Ref. 162 unsuccessful. Ligand binding to 175 6.B. Straps Containing Bulky Blocking Groups Porphyrins strapped with simple alkyl chains are poor models for oxygen binding heme proteins. In most cases the strap is too "floppy" and can be pushed to one side allowing \ioxo bridge leading The to logical formation. oxygen In addition, binding extension is to on base the incorporate is not open prevented face some bulky and, group from binding consequently, into the under the irreversible strap to strap, oxidation. increase the steric encumbrance about one face. One of the initial examples of the strapped porphyrin approach models was the cyclophane porphyrin 193 of Diekmann et al.l63). In this example steric to heme protein 176 encumbrance strap, poor was porphyrin yield porphyrin provided cyclization (5% was not for by the used a was biphenyl delayed cyclization as a heme group until step in the after protein the strap. final step repeated model. To ensure (Scheme chromatographic Instead an a 57). fitting Because purification) anthracene across a preformed porphyrin (194) by means of amide linkages (Scheme 58). For the tigh ly was of this strapped 177 anthracene-heme[6,6]cyclophane ~4.5Å apart. dione (196) of second a A gave complexes 195 Diels-Alder the axial "pagoda base 198 two porphyrin" 197 the and the the rings possessing even homologous[ were anthracene anthracene five-coordinate 198a aromatic on underneath being heme[6,6]cyclophane the addition an ring in even was I M 7,7] estimated with tighter not pocket. observed, I-MeIm. compound 198b to be l-phenyl-triazine-2,5- The were Binding the iron(II) anthracene- used to study the binding of isonitriles, CO and O2 within the pocket as models for the distal side steric effects in heme proteins164_166. The Fe[6,6] compared effect), This to and due to between steric that postulate that bent heme bulky diatomic reported effects the differentiate and bending large Fe[7,7] manifested steric to a ( he was side access could linear showed hemes effect distal limited compounds 198a unhindered this suggested but to cyclophane flat primarily are not face. in due isocyanide or of the to bound ligand in effects led CO in CO the could Traylor heme and only a rate167. bound state, the model in not and O2 small association steric they results for showed repulsion distal ligands, These affinity 198b in While molecules. tilting reduction cyclophane differen iate his proteins colleagues may be of minor chemical significance. Baldwin benzene capped" which did adapted ring porphyrin did not his above not 160, prevent prevent strapped one u-oxo face the porphyrin absence of six-coordination bridge the by formation. synthesis 59)160. (Scheme two extra ligands An to prepare Although a system 199 structurally similar to linkages such even as more resulted I-MeIm bulky in or a "floppy" pyridine strap, with the and a "C2- strap which incorporating a naphthalene ring as in 200, was no more successful. Dolphin durene and group his colleagues161,162) protecting one face have (201) prepared (Scheme a series 60). of strapped Incorporation dard methods168 gave the corresponding heme complexes 202a-c. The crystal structure of porphyrins iron using with a stan- of the hemin porphyrin that chloride some porphyrin derivative derived planarity169. from 201c is from The distortion exists essentially flat. 7/7-base 201c is analogs 201b and 201a. The to their interaction with binding respect constants Me2Im) to durene series the closer of to also 1 (Fig. spectra in H-NMR porphyrin heme showed for the the durene-5/5 suggest plane derivatives with 8) data than of the imidazoles, 1,5-dicyclohexylimidazole unhindered despite he 202a optical in considerable free base free base that the the durene (DcIm) side of the four-coordinate differences in the porphyrin plane 201b, durene tighter and hemes CO, of while the in the and -4/4 5/5 have been are these imidazoles do not coordinate on the capped (or distal) side of the heme. The size of similar for The (1,2- within steric 7/7- studied O2114170. and 1,2-dimethylimidazole distortion; the indicate moiety capped porphyrins isocyanides, distortion porphyrins the reasons, 179 180 Fig. 8. A SNOOPI diagram (E. K. Davies, plotting rou ine, 1984, Chemical Crystallography Laboratory, 9 Parks Road. Oxford. England) of the hemin chloride of 202a (50% probability contours for all atoms; hydrogen atoms have been omitted for clarity; the dashed bonds are used to distinguish between the "strap" and the porphyrin skeleton) 202 the distal (TMIC) cavity and extremely coordination was examined t-butylisocyanide restrictive of distal either (t-BuNC), environment isocyanide. using the which of The the bulky differ in durene-4/4 isocyanides, their system, Fe"(durene-7/7)(DcIm) tosylmethylisocyanide spatial requirements. however, complex 202c exhibits a reduced overall affinity for CO relative to simple flat, open hemes; this is inhibited obtained The the from 181 manifested steric in effect a depressed as a result association of the rate durene-cap. for CO, The durene-5/5 and was interpreted170 and -4/4 as systems a distal derived from 202a and 202b also show reduced CO affinities compared to open hemes, but this results predominantly from Fe(P)(DcIm)CO complexes increased dissociation because of rates the for proximal CO steric from strain the induced six-coordinate by the porphy- rin plane distortion. The five-coordinate hemes 202a • B - 202c • B (B = DcIm or 1,2Me2Im) bind skeletal distortion. 202b B • relative heme O2 (or to reversibly A other values) less within O2 complexes to distal environments. within the distal similar • - 202c encumbered This hemes) severely B is binding extents, entirely arises B show proximal with the ■ polar the amide of and porphyrin relative of to CO five-coordinate kco/k°2 ratios functions in higher concept moiety of discrimination Significantly, the Fe-O2 effect B complex steric considerably incorporate consistent stabilizing negligible 202a system. all that a by the from distorted • hemes pocket implying affinity for CO distorted his 202a relative to 10-fold reduced electronic (M their interactions increasing the affinity used strap of the heme toward O2, relative to CO114'170. The same adamantane phane. the The strap greatly synthetic group the reduced differentiation porphyrin; rates. between (as one structure171 crystal and strategy across of in a Scheme of the free base O2 and isocyanides and the O2 58) porphyrin CO, However CO shown face (Fig. adamantane binding. For to 9) CO the to to a bulky l,3-adamantane[6,6] showed bind strap was give no the free Fe" displayed binding cavity complex no constant cyclobetween 203 significant was with steric controlled by the association rate, dissociation not being increased by the steric effects of the strap. In Chap. et contrast 6.C.), al.172, to a the ligand singly showed no strapped evidence behaviour of the pyridine-[5,5] of either pyridine cyclophane internal or straps heme external of 204 257 and prepared iron-pyridine 259 (see by Traylor complex forma- tion. Indeed even the binding of CO to 204 failed to induce pyridine ligation even though the strap binding in this of CO case and bases induces to sufficient iron(II) strain porphyrins to prevent is synergistic. internal binding Obviously and the shorter compound behaves more like the anthracene and adamantane cyclophanes 198 and 203. The Fig. 9. Perspective view of a l,3-adamantane[6,6] cyclophane porphyrin. Adapted from Ref. 171 204 182 pyridine heme manifested between 204 in CO displays lower and O2 severe association binding steric rates. than other hindrance to Furthermore models, both 204 the O2 and shows lower CO a binding binding, greater ratio which is differentiation being possibly due to enhanced binding of O2 in the tight polar pocket114. Dolphin and Morgan173 have prepared the series of strapped Fig. 10 and Scheme 61. As a consequence of postponing porphyrin ring formation (a porphyrins illustrated in 183 Fig. 10. Ortep drawings of a strapped porphyrin containing a thioether linkage. Morgan, B., Dolphin, D., Einstein, F. W. B., Jones, T., manuscript in preparation specific example is given in Scheme 61) till the later stages on the synthesis, (i) a range of strap (ii) ester lengths are hydrocarbon linkages available, straps and Compounds including strap been have may (iii) some be increased thioethers prepared of which employed, may stability is to any obtained (Fig. 10), phenol (Scheme 61) as and photosynthetic charge separation, respectively. lead precluding 205 potential and distortion polar due to quinone models of effects for the 206 the porphyrin, due to hydrocarbon groups174 cytochrome and amide c, or strap. in the catalase 184 6. C Straps Containing Interactive Groups The incorporation of potential ligands into the porphyrin strap has three advantages, (i) A stoichiometric amount of ligand is built into the system, ensuring five-coordination without the addition of external ligand. In the case of nitrogen bases, mixtures of six- and four-coordinate complexes are avoided. (H) For ligands which bind poorly to iron(II) (e.g. thiolate), coordination would be favoured by constraining the ligand into a position suitable for binding to the metal, (iii) Because the strap is fixed to the porphyrin and the ligand in two positions, complications due to ligand replacement or dissociation will be minimized. The strapped-porphyrin approach is also useful for orientating other interactive groups (e.g., metal binding sites, electron donor/acceptor groups) into specific geometries with respect to the porphyrin. 185 Battersby substituted et corresponding 38% yield syntheses (Scheme al. pyridine pyridine (Scheme is have shown 63)177. A prepared ligands175. diol 207 62). in The Fig. suitably a Reac ion gave series strapped the the ester-linked molecular 11176). of of A functionalized porphyrin structure cytochrome diol 211 porphyrins bis-acid pyridine of a straps crystalline P450 was model reacted bearing chloride 180 208a-c in side-product was under the bis-acid chloride of mesoporphyrin II (180) to give the strapped porphyrin 212 in 25% prepared high variously with the up of to these similarly dilution with 186 yield. The protected-sulfur group with potassium S-acetyl group the iron(II) species. whose visible monoxy 450 was On 13 The 213 After cleaved exposure absorption cytochrome nm. derivative thioacetate. with to CO spectrum P450 C-NMR was iron obtained insertion dimsyl a spectrum of a the split to CO of to produce iron(II) major hyper 13 the displacement reduction sodium six-coordinate reproduced spectrum by and Soret tosyloxy iron(II) the five-coordinate species 214 characteristics complex the the of band with also supported an state, was formed the carbon- intense band at RS—FeII-CO the formulation. Several binding formed bind binucleating two metal in by the addition of a transition diaza-18-crown-6 ether also complexes, face strapped ions of metal ring) some bulky Iigands porphyrin the give from over 216 to and metal face of a five-coordinate species. capable of Chang178, bis-acid chloride 215, may IA 217 or binding the are of group 1-triphenylmethylimidazole) which porphyrin the a its one prepared, "crowned" e her ring) Apart control (e.g., been The porphyrin 64). steric to have proximity. bis-amino crown (in (Scheme exerts the a ion porphyrins close IIA cation capability porphyrin. For (in the the crown the iron(II) bind only on the unhindered Oxygen may then bind under the crown to give a reasonably stable oxygen species (t1/2 > 1 hr at 250C in DMA). o Recently, he another condensation 65)179. (Scheme and cationic cations rate 225b The of Bimetallic FeIII, Cu", (see diamines porphyrin Scheme corresponding species. e.g. salts crown-strapped of similar with metalloporphyrin complexes fluorescence indicated 219 67) were quenching attachment of 217 is a has bis-amino potential prepared was the to the and, observed. perchlorate been prepared crown ether host for for at anionic paramagnetic Studies salt both with the by 218 the guest perchlo- porphyrin metal site and complexation of the ammonium species at the crown ether. The et combination al.180, routes (Scheme refluxing acetic dichloride tively. metals. who 222 This of crown have 66). acid provided compound e her prepared and porphyrin the w«o-tetra(benzo-18-crown-6)porphyrin Condensation or the is of reac ion of tetra-crown reported to has also been 4'-formylbenzo-18-crown-6 carried 220 tetra(3,4-dihydroxyphenyl)porphyrin ether form porphyrin 223 complexes in with 4% out by Bogatskii 223 wi h (221) by two pyrrole in with the and 10% yield transition and group respecI, II The ton et combination of al.1B1 macrotetracyclic biphenyl-linked pyridine at The bis-crown 55 0 C crown ether under ether 224 high and porphyrin cryptand with dilution the 226 has was recently been prepared by di-p-nitrophenyl conditions (45-54% ester after tion to the tetra-amine 227 was effected by treating the zinc complex with diborane extended by condensa ion porphyrin 225a, chromatography). Hamilof the b in Reduc- 188 followed by selective substrate diammonium within the demetallation salts, cavity (Scheme binding: + H3N(CH2)nNH3+ does 67). transition indeed This metal (n occur = was multisite cations 8-10), complexing are bound within evidenced by the the by species the is capable porphyrin and central cavity. That large upfield shifts methylene protons due to the shielding effects of the porphyrin and biphenyl rings. of alkyl binding of the 189 A copper mimic the binding EPR The copper-binding cine 228 the in high strap was attached of chloride under chromatography porphyrin iron(III) and and investigated a by has the was covalently to of the one side copper(II) dilution 68). strap of ion. Gunter give The et ions a extent al.183, for of of rather with metal an 231 the different in phthalylglybinding XII 72% two similar Fe/Cu strapped porphyrin (Scheme 69). Condensation of the tetramethyldipyr- to bis-acid after into the high spin centers was a metal approach site, corners. yield introduced containing to oxidaseI82 opposite mesoporphyrin complex attempt from copper than to differentially between somewhat in cytochrome obtainable porphyrin be coupling porphyrin site 229, ring 229 could a a non-square-planar strapped dinuclear used a porphyrin sulfide the to iron-copper derivative need the gave Metal to attached the bis-thiazole of diaminothiazole the EPR. a Because high (Scheme into been characteristics strap yield. Condensation (230) site spectral prepare a 190 romethane 232 wi h o-nitrobenzaldehyde nitrophenylporphyrin. ers were by chromatography. The chloride) (234), separated Insertion of followed reduction 2.6-pyridylbis(4'thia-5'-pentanoyl 235. (53), After iron and copper to and by the the oxidation amino cc,a-isomer and afforded 233 was yielded introduction the derivative of finally the bridging 5,15-meso(ortho- the atropisomers condensed strapped ligands with porphyrin gave species of the type 236, whose magne ic properties were investigated184. As a esh185,186 model have for photosynthetic prepared a and electron-transfer quinone-capped porphyrin. tersby group, 1.4-dialkoxybenzene deriva ives 237 bis-acid chloride (180) strapped porphyrins on strap length hydroquinones studies the to (Scheme which on the metal ion give were magnesium and that the 70). oxidized complexes theretore were Deprotection to the 239 d in with and wi h 7 b that Sanders approach and boron 239a, suggest quinone the reacted 238 quinones c, the systems, Using the porphyrin Gan- the Bat- mesoporphyrin 15% yield trichloride with and of lead quinone II depending afforded dioxide. carbonyl chromophores the 'H-NMR binds are to perpen- dicular187. Since zinc oxygen is ligands, sponding zinc auenchine is exclusively intramolecular complexes observed parallel approach nesium complexes of in the five-coordinate binding 239e,f the where in base and chromophores with 239a,b is the porphyrins the especially free chromophores 239c.d of added and possible, chromophores 239e,f is are a lessened ligands zinc but has is much low affinity in the present. complexes reduced perpendicular"*'. for corre- Fluorescence where for The the close, mag- quenching is more efficient for the longer chain 239b. f than for the shorter chain 239a. e; because of intramolecular binding of the chromophores in 239c,d the quenching efficiency is similar for both chain lengths. High dilution coupling of the bipyridyl diols 240 with 180 gave porphyrins 241 (Scheme 71) in 40-50% yield189 191 Treatment with iodomethane fur- the bipyridyl strapped 191 192 nished the donor (porphyrin) potential ~200 assumed strapped and an photosyn hetic reduced was methylviologen fold that model. relative efficient porphyrins electron Indeed to of The of an close (methylviologen fluorescence mixtures trapping 242. acceptor emissions methylviologen excited electron proximity of dication) makes of 241 and an and unstrapped occurred to electron this 242 a were porphyrin. give the two the condensation It radical cations of the connected chromophores. Hamilton mesoporphyrin strapped resulted , al.192, et II porphyrin in have diacid 245 also chloride 244 with (Scheme 72). prepared 180 a binuclear with the Ru(byp)2Cl2 followed by The proximity of close complex bipyridyl by diol metal the 243. Reaction insertion into metal centers, two of the of the porphyrin estimated at 4Å is reflected in both the luminescence and electrochemical properties of the complex. 6.D. Doubly-Strapped Porphyrins We have oxo already seen bridge face. formation Steric systems of that sterically encumbered porphyrins if encumbrance Amundsen any on and four-coordinate both faces Vaska148 species of the in porphyrin, Suslick149, and may still solution as may be binds in the prevent susceptible to oxygen on he "bis-pocket" this a μ open porphyrin bimolecular oxida- tion pathway. Momenteau TPP derivatives Baldwin's and his having "capped" aldehyde was derivatives 246a-e colleagues two and "strapped" reacted to straps give with a have on used each porphyrin variety chain-linked a combination porphyrin ring193. syntheses159-160), of dialdehydes dibromoalkyl 247. The of In approaches a the strategy sodium and TPP by condensing the dialdehydes with pyrrole in refluxing propionic acid (Scheme 73). to prepare reminiscent salt of of salicyl- p-(dibromoalkyl)benzene ring was then formed 193 After in removal low minant of polymeric overall yield. isomer. To formation of (Scheme 74). The the increase the bridges was phenyl)porphyrin DMF at three isomers adjacent yield of (10% the delayed (250). 100°C, yield) Alkyla ion followed obtained product more until 248c interesting after (249) and with by were cis-linked Tetra(o-methoxyphenyl)porphyrin o-methoxybenzaldehyde in materials, unwanted the the dibromo cross to to the pyrrole provide 246 isomers 248. In this case the major product of each reaction was and tetra(o-hydroxy- under of predoisomers, condensation from isolation the trans-linked obtained derivatives led chromatography often porphyrin-forming was demethylated chromatography by was high the dilution hree porphyrin he desired cross trans- linked isomer 248a. The starting porphyrin 250 was used as a mixture of the four possible atropisomers since the conditions of the condensation would lead to equilibra ion. The degree tion of the and is easily of iron diatomic molecules, insertion derivative tion the under O2 less (1 The In contrast chains iron(II) atm), t1/2 do is the other not trans-linked of rates of 248c has isomers, u-oxo 248a complex. faces room t½ Similarly, oxida- unhindered are hindered, bases temperature. for 7-54 iron(II) and face nitrogenous at to six-coordinate one of he compared metallation both ligation oxidation isomer the where preventing minutes the oxidation the isomer irreversible 1.5-10.5 to by cis-linked inhibit isomers for illustrated While cross FeIII(P)OH hindered is adjacent reluctantly. the four-coordinate hematin of encumbrance isomers. metallated. undergo the steric various oxidation seconds in toluene complex to for the oxida- at is or For 25 11-25 0 C min for the cross trans-linked isomer compared to 1.5-12 min for the other two isomers194. The basket-handle metallation try. and Detailed paralleling studies the and binding earlier picket-fence of on small the porphyrins molecules electrochemistry electrochemical studies but show in of the on dramatic their the redox iron effects and complex free base, not only during coordination have been magnesium chemismade195' and zinc complexes of 192 and 201196. A similar triglycolic not doubly-strapped atropisomer a,b,a,b dichloride cause at significant of room porphyrin has been reported by meso-tetra(o-aminophenyl)porphyrin temperature isomerization of in the the presence atropisomer. 251 was obtained in 32% yield after chromatography (Scheme 75). (142) of Zhilina was pyridine, The et al. . acylated conditions doubly-strapped hat The with do porphyrin In a contrast one-step units. yielded desired the synthesis Thus, a to sequential to prepare condensation mixture cross characteristic of of trans-linked a the oligomers of porphyrin H-NMR 252 polymers, obtained spectrum. bridging straps, sandwiched bis-aldehyde and porphyrin, 1 symmetric introduction with and in Weiser between pyrrole three in two parallel refluxing doubly-strapped ~0.1%, was Deme hylation and Staabl98 and easily used quinone propionic acid porphyrins. The identified oxidation by then its yielded the desired bis-quinone porphyrin 253 (Scheme 76). A further doubly-strapped globin, of the refinement models incorporation natural of system to he production containing a nitrogen while the mimic the distal, oxygen-binding face. different base steric of heme straps. into one protein models As models strap would encumbrance provided was for simulate by the the synthesis hemoglobin or the proximal second strap of myoface would Momenteau's compounds in route which to an doubly-strapped axial base tion of tetra(o-hydroxyphenyl)porphyrin lent of 1.12-dibromododecane on whether mixture adjacent was linked isomer 257 porphyrin 259 case straps the Following with iron a opposite by from tied the insertion of of and to tic easily one four two (254) preparative prepared were (mixture mixture was into of (5% adapted 256 isomers) overall wi h the yield) porphyrin reduction, skeleton visible by were (Scheme amide absorption 1 and one H-NMR cross 77). (142); linkages equivadepending linked. desired a,b.a,(3-tetra(o-aminophenyl)porphyrin produce Condensa- porphyrins, groups and to straps199' the singly-linked meso-phenyl 3,5-bis(3-bromopropyl)pyridine isolated was or incorporated (250) gave (255), reacted porphyrins was A This transsimilar in this (Scheme 78). spectra of both compounds were consistent with a five-coordinate high spin (S = 2) iron(II) complex. The by rate constants for the laser flash photolysis. The association O2 and affinity of dissociation of O2 and CO were determined the "amide" linked system was higher than that of the "ether" linked compound p½ 18.6 vs 2 torr) as a result of a difference of a factor stability of ca. of 10 the in he "amide" O2 dissociation oxygenated rates species (10~4 was koffO2 attributed 4 vs to s_l). 0.5 the This presence group and the possibility of hydrogen-bonding with the terminal oxygen atom. The low increase of the in N-H temperature (-27°C) quivalence of 1 H-NMR spectrum supported he pyrrole protons as well as this hypothesis, the observed ine- he shifts of the amide protons suggesting a preferred orientation of the oxygen molecule towards the amide N-H groups200. To better model the hemoglobin and myoglobin active sites a doubly strapped heme 260 was prepared incorporating a pendant imidazole (Scheme 79)201. 260 was capable of binding oxygen to give a rela ively stable oxygenated species (lifetime was about one day in dry toluene under 1 atm O2). The kinetics of O2 and CO binding have been determined and initial comparisons with the comparable "pendant pyridine" porphyrins show: (i) O2 and CO combina ion rates are practically constant in the three pendant base (ii) a reduction in konO2 in the imidazole porphyrin due to a combination of hydrogen porphyrins, and bonding with the amide N-H and the greater basicity of imidazole over pyridine. Comparison of the pendant imidazole model with myoglobin or isolated hemoglobin chains shows that the model reacts 10 times faster with O2 and that the dissociation rate is approximately 100 times faster than in the natural systems. With the availability of the differentially protected coproporphyrin I 261, Battersby and Hamilton adapted heir syntheses to the production of doubly-strapped porphyrins 80)202. (Scheme ridine yielded esters and 263 to with acid give difficult so aqueous temperature an CH2Cl2- was cycles in In after the judged to by 264 the species compound with a a of the oxygenated could be repeated the resistance more species of = of t1/2 the on 2) of the was the the found strap. basis of five-coordinate. accomplished by significant min CO-porphyrin passage complexes visible at the of to room formed into irreversible be Reduction the was CO diol to Exposure 15 species by passing benzyl anthracene pyridine oxygenated without unhindered with approximately displaced was times 3,5-bis(3-hydroxypropyl)py- insertion of which (S stable could be six Iron introduc ion iron(II) with Hydrogenolysis condensation (27%). spin O2 261 (33%). high DMF to 262 be h at 20°C). The contrast chloride followed porphyrin furnished was was inserted oxygenated regeneration O2-CO bis-acid porphyrin formation was dithionite in the doubly-bridged metal approximately 2 and chloride spectrum gave of pyridine-strapped the the absorption oxygen Reaction the (t1/2 solution, O2. Such oxidation. This to displacement of CO by O2. The further reported203'. the As anthracene esters and substituted yield of significant diol 81). of the 263 treatment imidazole (Scheme cycles refinement before, with to incorporating differen ially give oxalyl diol 266. The iron(II) the oxidation imidazole the (by occurred. was 265 (57%). bis-acid capable of the the was still been was removal was 267 of the with oxygen with benzyl the obtained being oxygenated recently reacted reacted was reversible pressure) for t1/2 has 261 After chloride porphyrin reducing The ligand coproporphyrin doubly-bridged complex oxygenation-deoxygenation irreversible porphyrin chloride, The an protected in binding, possible species N22% four before was ca. 24 h at room temperature in DMF solution. Recognizing straps (Scheme imidazole that containing 81)203). 268b with the a pendant-imidazole 1,5-disubstituted Coupling he bis-acid strap imidazole 1,5-bis(4-hydroxybutyl) chloride of the 268 268a somewhat were floppy, prepared or anthracene-strapped doubly-bridged systems 269a, b in 23% and 6% yield. Distortion of the porphyrin ring more as rigid before l,5-bis(3-hydroxypropyl)porphyrin gave he 198 from planarity to accommodate the shorter strap was believed responsible for the low yield of 269b and also for the lesser stability of the oxygenated iron(II) species. For 269a, the iron(II) ture. Ten dation was complex could reversibly oxygenation-deoxygenation significant, and only bind oxygen in cycles could be 20% irreversible DMF solution performed oxida ion at ambient before occurred tempera- irreversible after 2 days oxiin solution. Acknowledgements. This work was supported by the United States National Institute of Health (AM 17989) and the Canadian Natural Sciences and Engineering Research Council. 7. List of Abbreviations acac AQ bipy 1-n-Bulm 4-t-BuIm t-BuNC BO CO Cys cyt DCIM DDO DMA acetylacetonate Anthraquinone bipyridyl 1-n-Butylimidazole 4-t-Butylimidazole t-Butvlisocyanide Benzoquinone Carbon monoxide Cysteine cytochrome 1,5-Dicyclohexylimidazolc 2,3-Dichloro-5,6-dicyano-l,4benzoquinone N1N-DimethyIacetamide DMF DMSO DNA ee Et3N EXAFS N1N-DimethyIformamide Dimethylsulfoxide Deoxyribonucleic acid enantiomeric excess Triethylamine Extended X-Ray Absorption Fine Structure H2(OEP) Octaethylporphyrin general porphyrin H2(P) H2(TAP) Tetra(p-methoxyphenyl)porphyrin H2(T(OH)PP) Tetra(o-hydroxyphcnyl)porphyrin H2(TPP) Tetraphenylporphyrin H2(TTP) His Hm Im MCD I-MeIm l,2-Me2Im MeOH Met NQ Tetra(p-tolyl)porphyrin Histidine Heme Imidazole Magnetic Circular Dichroism I-Methylimidazole 1,2-Dimethylimidazole Methanol Methionine Naphthoquinone phth piv THF THT TMIC Tos Tr l-trityllm Tyr phthaloyl pivalamido Tetrahydrofuran Tetrahydrothiophene Tosylmethylisocyanide Tosylate Trityl I-Tritylimidazole Tyrosine 8. References 1. 2. 3. 4. 5. Hemoglobin and Oxygen Binding (Ho, C, Ed.), Elsevier Biomedical, New York 1982 Mathews, F. S.: Prog. Biophys. Mol. Biol. 45, 1 (1985) Hatefi, Y.: Ann. Rev. Biochem. 54, 1015 (1985) Frew, J. E., Jones, P.: Adv. Inorg. Bioinorg. Mech. 3, 175 (1984) Murray, R. T.. Fisher. M. T., Debrunner, P. G., Sligar. S. G.: Top. Mol. Struct. Biol. 6 (Metalloproteins, Pt. 1). 157 (1985) 6. The Porphyrins (Dolphin, D., Ed.), Academic Press, New York, Vol. VII, Part B, 1978 8. NATO Adv. Study Inst. Ser., Ser. C, 89 (The Biological Chemistry of Iron) (1981) 8. Kao, O. H. W., Wang, J. H.: Biochemistry 4, 342 (1965) 9. Hammond, G. S., Wu, C H. S.: Adv. Chem. Ser. 77, 186 (1968) 10. Cohen, I. A., Caughey, W. S.: Biochemistry 7, 636 (1968) 11. Latos-Grazynski. L., Cheng, R.-J., La Mar, G. N., Balch, A. L.: J. Am. Chem. Soc 104, 5992 (1982) 12. Holquist. D. E., Saunes, L. J., Juckett, D. A.: Curr. Top. Cell. Regul. 24, 287 (1984) 13. Brunori. M., Falcioni, G., Fioretti, E., Giardina, B., Rotilio, G.: Eur. J. Biochem. 53, 99 (1975) 14. Fee, J. A.: Metal Ion Activation of Dioxygen (Ed. Spiro, T. G.), Wiley Interscience. 209-237 (1980) 15. Phillips, S. E. V., Schoenborn, B. P.: Nature (London) 292, 81 (1981) 16. Shaanan, B.: Nature (London) 296, 683 (1982) 17. Perutz, M. F.: Scientific American 239{6), 68 (1978) 18. Brault, D., Rougee, M.: Biochemistry 13, 4591 (1974) 19. Brault, D., Rougee, M.: ibid. 13, 4598 (1974) 20. Scheidt, W. R., Reed, C A.: Chem. Rev. 81, 543 (1981) 21. Stynes, D. V., Stynes, H. C, James, B. R., Ibers, J. A.: J. Am. Chem. Soc 95, 1796 (1973) 22. Anderson, D. L., Weschler, C J., Basolo, F.: ibid. 96, 5599 (1974) 23. Almog, J., Baldwin, J. E., Dyer, R. L., Huff, J.. Wilkerson, C J.: ibid. 96, 5600 (1974) 24. Brinigar, W. S., Chang, C K.: ibid. 96, 5595 (1974) 25. Wagner, G. C, Kassner, R. J.: ibid. 96, 5593 (1974) 26. Traylor, T. G., Chang, C. K., Geibel, J., Berzinis, A.. Mincey, T., Cannon, G.: ibid. 101, 6716 (1979) 27. Gibson, Q. H.: Prog. Biophys., Biophys. Chem. 9, 1 (1959) 28. Basolo, F., Hoffman, B. M., Ibers, J. A.: Acc Chem. Res. 8, 384 (1975) 29. James, B. R.. Addison, A. W., Cairns, M.. Dolphin. D., Farreli, N. P.. Paulson, D. R., Walker, S.: Fundamental Research in Homogeneous Catalysis (Tsutsui, M.. Ed.), Plenum Press: New York, Vol. 3, p. 751 (1979) 30. Wang, J. H.: Ace Chem. Res. 3, 90 (1970) 31. Leal, O., Anderson, D. L., Bowman, R. G., Basolo, F., Burwell, R. L.: J. Am. Chem. Soe 97, 5125 (1975) 32. Collman, J. P.: Ace Chem. Res. 10, 265 (1977) 33. Jones, R. D., Summerville, D. A., Basolo, F.: Chem. Rev. 79, 139 (1979) 34. Smith, P. D., James, B. R., Dolphin, D. H.: Coord. Chem. Rev. 39, 31 (1981) 200 36. Traylor, T. G.: Acc Chem. Res. 14, 102 (1981) 37. Bogatskii, A. V., Zhilina, Z. I.: Russ. Chem. Rev. 57, 592 (1982) 38. Collman, J. P., Halpert, T. R., Suslick, K. S.: Metal Ion Activation of Dioxygen (Spiro, T. G., Ed.), Wiley: New York, p. 1 (1980) 39. Lautsch, V. W., Wiemer, B., Zschenderlein, P., Kraege, H. J.. Bandel, W., Gunther, D., Schulz, G., Gnichtel, H.: Kolloid. Z. 161, 36 (1958) 40. Losse, G., Muller1 G.: Hoppe-Scyler's Z. Physiol. Chem. 327, 205 (1962) 41. Van der Heijden, A., Peer, H. G., Van den Oord, A. H. A.: J. Chem. Soc., Chem. Commun., 369 (1971) 42. Warme, P. K., Hager, L. P.: Biochemistry 9, 1599 (1970) 43. Momenteau, M., Rougee, M., Loock, B.: Eur. J. Biochem. 71, 63 (1976) 44. Castro, C E.: Bioinorg. Chem. 4, 45 (1974) 45. Molokoedov, A. S., Fillippovich, E. I., Mazakova, N. A., Evstigneeva, R. P.: Zhur. Obshch. Khim. Ed. Engl. 47, 1070 (1977) 46. Kazakova, N. A., Radyukhin, V. A., Luzgiva, V. N., Filippovich, E. I., Kamyshan, N. V., Kudryavtseva, E. V., Evstigneeva, R. P.: ibid. 52, 1896 (1982) 47. Momenteau, M.. Loock, B.: Biochim. Biophys. Acta 343, 535 (1974) 48. Selve, C, Niedercorn, F.. Nacro, M., Castro, B., Gabriel, M.: Tetrahedron 37, 1893 (1981) 49. Selve, C, Niedercorn, F., Nacro, M., Castro, B., Gabriel, M.: ibid. 37, 1903 (1981) 50. Gabriel, M., Grange, J., Niedercorn. F., Selve, C, Castro, B.: ibid. 37, 1913 (1981) 51. Goulon, J., Goulon, C, Niedercorn. F.. Selve, C, Castro, B.: ibid. 37, 2707 (1981) 52. Chang. C K., Traylor, T. G.: Proc Natl. Acad. Sci. U.S.A. 70, 2647 (1973) 53. Chang, C K., Traylor, T. G.: J. Am. Chem. Soc 95, 5810 (1973) 54. Chang, C K., Traylor, T. G.: ibid. 95, 8475 (1973) 55. Brinigar, W. S., Chang, C K., Geibel, J., Traylor, T. G.: ibid. 96, 5597 (1974) 56. Geibel, J., Chang, C K., Traylor, T. G.: ibid. 97, 5924 (1975) 57. Dolphin, D., Hiom, J., Paine III, J. B.: Heterocycles 16, 417 (1981) 58. Traylor, T. G., Campbell, D., Sharma, V., Geibel, J.: J. Am. Chem. Soc 101, 5376 (1979) 59. Traylor, T. G., White, D. K., Campbell. D. H., Berzinis, A. P.: ibid. 103, 4932 (1981) 60. Traylor, T. G., Mitchell, M. J., Cicone, G. P., Nelson, S.: ibid. 104, 4986 (1982) 61. Traylor, T. G., Tatsuno, T., Powell, D. W., Cannon, J. B.: J. Chem. Soe Chem. Commun., 732 (1977) 62. Traylor. T. G., Berzinis, A. P.: J. Am. Chem. Soe 102, 2844 (1980) 63. Tabushi, I., Sasaki, T.: Tetrahedron Lett. 23, 1913 (1982) 64. Tabushi, I., Kugimiyua, S., Kinnaird, M. G., Sasaki, T.: J. Am. Chem. Soe 107, 4192 (1985) 65. Tabushi, I., Kugimiya, S., Sasaki, T.: ibid. 107, 5159 (1985) 66. Denniss, J. S., Sanders, J. K. M.: Tetrahedron Lett., 295 (1978) 67. Boxer, S. G., Wright, K. A.: J. Am. Chem. Soe 101, 6791 (1979) 68. Momenteau, M., Loock, B., Bisagni, E.. Rougee, M.: Can. J. Chem. 57, 1804 (1979) 69. Callot, H. J.: Tetrahedron, 899 (1973) 70. Lavalette, D., Tetreau, C, Momenteau, M.: J. Am. Chem. Soe 101, 5395 (1979) 71. Lavalette, D., Momenteau, M.: J. Chem. Soe, Perkin Trans. 2, 385 (1982) 72. More, K. M., Eaton, S. S., Eaton, G. R.: Inorg. Chem. 20, 2641 (1981) 73. Damoder, R., More, K. M., Eaton, G. R., Eaton, S. S.: J. Am. Chem. Soe 105, 2147 (1983) 74. Damoder, R., More, K. M., Eaton, G. R., Eaton, S. S.: Inorg. Chem. 22, 2836 (1983) 75. Collman, J. P., Brauman, J. I., Doxsee, K. M., Halbert, T. R., Bunnenberg, E., Linder. R. E., LaMar, G. N.. Del Gaudio, J., Lang, G., Spartalian, K.: J. Am. Chem. Soe 102, 4182 (1980) 76. Mashiko, T., Reed, C A., Haller, K. J., Kastner, M. E., Scheidt, W. R.: ibid. 103, 5758 (1981) 77. Walker, F. A.: ibid. 102, 3254 (1980) 78. Walker, F. A., Benson, M.: ibid. 102, 5530 (1980) 79. Santon, R. J., Wilson, L. J.: J. Chem. Soe, Chem. Commun., 359 (1984) 80. Molinaro, F. S., Little, R. G., bers, J. A.: J. Am. Chem. Soe 99, 5628 (1977) 81. Goff, H.: ibid. 102, 3252 (1980) 82. Traylor, T. G., Mincey, T. C Berzinis, A. P.: ibid. 103, 7084 (1981) 83. Collman, J. P., Groh, S. E.: ibid. 104, 1391 (1982) 84. Buckingham, D. A., Rauchfuss, T. B.: J. Chem. Soe, Chem. Commun., 705 (1978) 201 86. Smith K. M., Bisset, G. M. F.: J. Chem. Soc., Perkin Trans. 1, 2625 (1981) 87. Kong, J. L. Y., Loach, P. A.: J. Heterocycl. Chem. 17, 737 (1980) 88. Mcintosh, A. R., Siemiarczuk, A., Bolton, J. R., Stillman. M. J., Ho, T.-F., Weedon, A. C: J. Am. Chem. Soc 105, 7215 (1983) 89. Mcintosh, A. R., Siemiarczuk, A., Bolton, J. R., Stillman, M. J., Ho, T.-F.. Weedon, A. C: ibid. 105, 7224 (1983) 90. Wang, C-B., Tien, J. T., Lopez, J. R., Lui, Q.-Y., Joshi, N. B., Hu, Q.-Y.: Photobiochem. Photobiophys. 4, 177 (1982) 91. Joshi, N. B., Lopez, J. R., Tien, H. T., Wang. C-B., Lui, Q.-Y.: J. Photochem. 20, 139 (1982) 92. Tabushi. I., Koga, N.. Yanagita, M.: Tetrahedron Lett., 257 (1979) 93. Wasielewski, M. R., Niemczyk, M. P.: J. Am. Chem. Soc 106, 5043 (1984) 94. Wasielewski, M. R., Niemczyk, M. P., Svec, W. A., Pewitt, E. B.: ibid. 107, 1080 (1985) 95. Joran, A. D., Leland, B. A.. Geller, G. G., Hopfield, J. J., Dervan, P. B.: ibid. 106, 6090 (1984) 96. Nishitani, S., Kurata, N., Sakata, Y.. Misumi, S., Migita, M., Mataga, N.: Tetrahedron Lett. 22,2099 (1981) 97. Mataga, N., Karen, A., Okada, T., Nishitani, S., Kurata, N., Sakata, Y., Misumi, S.: J. Phys. Chem. 22, 5138 (1984) 98. Nishitani, S., Kurata, N., Sakata, Y., Misumi, S., Karen. A., Okada, T., Mataga, N.: J. Am. Chem. Soc 105, (1983) 99. Moore, T. A., Gust, D., Mathis, P., Mialocq, J.-C, Chachaty, C, Bensasson. R. V., Land, E. J., Doizi, D., Liddel, P. A., Lehman, W. R., Neme h, G. A., Moore, A. L.: Nature (London) 307, 630 (1984) 100. Maiya, G. B.. Krishnan, V.: Inorg. Chim. Acta 77, L13 (1983) 101. Kobayashi, N., Akiba, V.. Takatori, K., Veno, A., Osa, T.: Heterocycles 19, 2011 (1982) 100. Eshima, K., Matsushita, Y., Sekine. M., Nishide, H., Tsuchida, E.: Nippon Kayaku Kaishi. 214 (1983) 101. Lown, J. W., Joshua, A. V.: J. Chem. Soc., Chem. Commun., 1298 (1983) 102. Hashimoto, Y., Lee, C-S., Shudo, K., Okamoto, T.: Tetrahedron Lett. 24, 1523 (1983) 103. Collman, J. P., Gagne, R. R., Halbert, T. R., Marchon, J.-C, Reed, C A.: J. Am. Chem. Soc 95, 7868 (1973) 104. Collman, J. P., Gagne, R. R., Reed, C A., Halbert, T. R., Lang, G., Robinson, W. T.: ibid. 96, 1427 (1975) 105. Anzui, K., Hatano, K.: Chem. Pharm. Bull. 32, 1273 (1984) 106. Freilag, R. A., Whitten, D. G.: J. Phys. Chem. 87, 3918 (1983) 107. Freilag, R. A., Whitten, D. G.: J. Am. Chem. Soe 103, 1226 (1981) 108. Collman, J. P., Gagne, R. R., Reed, C A., Robinson, W. T., Rodley, G. A.: Proe Natl. Acad. Sci. U.S.A. 71, 1326 (1974) 109. Jameson, G. B., Molinaro. F. S., Ibers, J. A., Collman, J. P., Brauman, J. I., Rose, E., Suslick, K. S.: J. Am. Chem. Soe 102, 3224 (1980) 110. Collman, J. P., Gagne, R. R., Gray, H. B., Hare, J. W.: ibid. 96, 6522 (1974) 111. Collman, J. P., Brauman, J. I., Halbert, T. R., Suslick, K. S.: Proe Natl. Acad. Sci. U.S.A. 73, 3333 (1976) 112. Gmai, H., Nakata, K., Nakatsubo, A., Kakagawa, S.. Vcrmori, Y., Kyuno, E.: Synth. React. Inorg. Met.-Org. Chem. 13, 761 (1983) 113. Baldwin, J. E., Perlmutter, P.: Top. Curr. Chem. 121 (Host Guest Complex Chem. 3), 181 (1984) 114. David, S., Dolphin, D., James. B. R.: in Frontiers of Bioinorganic Chemistry (ed. Xavier, A. V.), VCH Verlagsgesellschaft, Weinheim, pp. 163-182 (1985) 115. Collman, J. P., Gagne. R. R.. Reed, C A.: J. Am. Chem. Soe 96, 2629 (1974) 116. Collman, J. P., Brauman, J. I., Suslick, K. S.: ibid. 97, 7185 (1975) 117. Bogatskii, A. V., Zhilina, Z. I., Danilina, N. I.: Dokl. Akad. Nauk. S.S.S.R. (Engl. Ed.)252, 127 (1980) 118. Bogatskii, A. V., Zhilina, Z. I., Krasnoshchekaya, S. P.. Zakharova, R. M.: Zh. Org. Khim. Engl. Ed. 18, 2035 (1982) 119. Valiotti, A., Adeyemo, A., Williams, F. A., Ricks, L., North, J., Hambright, P.: J. Inorg. Nucl. Chem. 43, 2653 (1981) 202 121. Buckingham, D. H., Clark, C R., Webley, W. S.: J. Chem. Soc Chem. Commun., 192 (1981) 122. Buckingham, D. A., Gunter, M. G.. Mander, L. N.: J. Am. Chem. Soc 100, 2899 (1978) 123. Gunter, M. G., Mander, L. N., McLaughlin, G. M., Murray, K. S.. Berry, K. J., Clark, P. E., Buckingham, D. A.: ibid. 102, 1470 (1980) 124. Elliott. C M.. Krebs, R. R.: ibid. 104, 4301 (1982) 125. Groves, J. T., Myers, R. S.: ibid. 105, 5791 (1983) 126. Tabushi. I., Kodera. M.. Yokoyama, M.: ibid. 107, 4466 (1985) 127. Lecas-Nawrocka. A., Levisalles, J., Mariacher, C, Renko, Z., Rose, E.: Can. J. Chem. 62, 2054 (1984) 128. Collman, J. P., Brauman. J. I., Doxsee, K. M.. Sessler, J. L.. Morris. R. M.. Gibson, O. H.: Inorg. Chem. 22, 1427 (1983) 129. Collman, J. P.. Brauman, J. I., Doxsee, K. M., Halbert, T. R.,Suslick, K. S.: Proc. Natl. Acad. Sci. U.S.A. 75, 564 (1978) 130. Collman, J. P., Brauman, J. I., Doxsee. K. M.: ibid. 76, 6035 (1979) 131. Almog, J., Baldwin, J. E., Dyer, R. L., Peters, M.: J. Am. Chem. Soc 97, 226 (1975) 132. Almog, J.. Baldwin, J. E., Crossley, MK. J., De Bernardis, J. F., Dyer, R. L., Huff, J. R., Peters, M. K.: Tetrahedron 37, 3589 (1981) 133. Ellis, Jr., P. E., Linard, J. E., Szymanski, T., Jones. R. D., Budge, J. R., Basolo, F.: J. Am. Chem. Soc 102, 1889 (1980) 134. Budge, J. R., Ellis, Jr., P. E.Jones, R. D., Linard, J. E., Basolo, F., Baldwin. J. E., Dyer. R. L.: ibid. 101, 4760 (1979) 135. Ellis, Jr., P. E., Linard, J. E., Jones, R. D., Budge, J. R., Basolo, F.: ibid. 102, 1896 (1980) 136. Hashimoto, T., Dyer, R. L., Crossley, M. J., Baldwin. J. E., Basolo, F.: ibid. 104, 2101 (1982) 137. Baldwin, J. E., Crossley, M. G., De Bernardis, J.: Tetrahedron 38, 685 (1982) 138. Shimizu, M., Basolo, F., Vallejo, M. N., Baldwin, J. E.: Inorg. Chim. Acta 91, 247 (1984) 139. Shimizu, M., Basolo, F.. Vallejo, N. M., Baldwin. J. E.: ibid. 91, 251 (1984) 140. Rose, E. J., Vankatasurbramanian, P. N., Swartz, J. C, Jones, R. D., Basolo, F., Hoffman, B. M.: Proc. Natl. Acad. Sci. U.S.A. 79, 5742 (1982) 141. Jameson, G. B., Ibers, J. A.: J. Am. Chem. Soc 102, 2823 (1980) 142. Sabat, M., Ibers, J. A.: ibid. 104, 3715 (1982) 143. Clayden, N. J., Moore, G. R., Williams, R. J. P., Baldwin. J. E., Crossley, M. J.: J. Chem. Soe, Perkin Trans. 2, 1693 (1982) 144. Clayden, N. J., Moore, G. R.. Williams. R. J. P.. Baldwin. J. E., Crossley, M. J.: ibid. 2, 1863 (1983) 145. Baldwin, J. E., Cameron, J. H., Crossley, M. J., Dayley, E. J.: J. Chem. Soe, Dalton Trans., 1739 (1984) 146. Collman, J. P., Brauman, J. I., Collins, T. J., Iverson, B. L., Sessler, J. L.: J. Am. Chem. Soe 103, 2450 (1981) 147. Collman, J. P., Brauman, J. I., Collins, T. J.. Iverson, B. L., Lang. G., Pettman. R. B., Sessler, J. L., Walters. M. A.: ibid. 105, 3038 (1983) 148. Collman, J. P., Brauman. J. I., Iverson, B. L., Sessler, J. L., Morris, R. M.. Gibson, O. H.: ibid. 105, 3052 (1983) 149. Amundsen, A. R., Vaska, L.: Inorg. Chim. Acta. 14, L49 (1975) 150. Suslick, K. S., Fox, M. M.: J. Am. Chem. Soe 105, 3507 (1983) 151. Lindsey, J. S., Mauzerall, D. C: ibid. 104, 4498 (1982) 152. Lindsey, J. S., Mauzerall. D. C, Linschitz, H.: ibid. 105, 6528 (1983) 153. Ogoshi, H., Sugimoto, H.. Yoshida, Z.: Tetrahedron Lett., 4481 (1976) 154. Ogoshi, H., Sugimoto, H.. Yoshida, Z.: ibid. 1515 (1977) 155. Ogoshi, H., Sugimoto, H., Miyake, M., Yoshida, Z. I.: Tetrahedron 40, 579 (1984) 156. Battersby, A. R., Buckley, D. G., Hartley, S. G., Turnbull, M.: J. Chem. Soe, Chem. Commun., 879 (1976) 157. Chang, C. K., Kuo, M.-S.: J. Am. Chem. Soe 101, 3413 (1979) 158. Ward, B., Wang, C-B., Chang, C K.: ibid. 103, 5236 (1981) 159. Yu. N.-T., Kerr, E. A., Ward, B., Chang, C K.: Biochemistry 22, 4534 (1983) 160. Baldwin, J. E.. Klose, T., Peters. M.: J. Chem. Soe, Chem. Commun.. 881 (1976) 161. Baldwin, J. E., Crossley, M. J., Klose. T.. O'Rcar III, E. A., Peters, M. K.: Tetrahedron^, 27 (1981) 203 163. Wijesekera. T. P.: Ph.D. Thesis. University of British Columbia 1980 164. Wijesekera. T. P., Paine III, J. B., Dolphin. D.. Einstein, F. W. B.. Jones, T.: J. Am. Chem. Soc. 105, 6747 (1983) 165. Diekmann, H.. Chang, C K.. Traylor, T. G.: ibid. 93, 4068 (1971) 166. Traylor, T. G.. Campbell. D.. Tsuchiya, S.: ibid. 101, 4748 (1979) 167. Traylor, T. G.. Campbell, D., Tsuchiya, S., Mitchell, M., Stynes, D. V.: ibid. 102, 5939 (1980) 168. Travlor. T. G.. Mitchell. M. J . Tsuchiya. S., Campbell. D. H.. Stynes, D. V., Koga. N.: ibid. 103. 5234 (1981) 169. Travlor. T. G.. Tsuchiva. S.. Campbell. D.. Mitchell. M., Stvncs, D.. Koga. N.: ibid. 107, 604 (1985) 170. Chanii. C K.. DiNeIIo. R. K.. Dolphin. D.: in Inorganic Syntheses (ed. Busch. D. H.). John Wilev & Sons. New York. Vol. XX. 147 (1980) 171. David. S.. Dolphin, D., James. B. R., Paine. J. B. Ill, Wijesekera. T. P.. Einstein. F. W. B.. Jones. T.: Can. J. Chem. 64. 208 (1986) 172. David. S.: Ph.D. Thesis. University of British Columbia 1985 173. Travlor. T. G.. Koga. N.. Dearduff. L. A.. Swepston, P. N., bers. J. A.: J. Am. Chem. Soc 106, 5132 (1984) 174. Travlor. T. G.. Koga. N.. Dearduff. L. A.: ibid. 107. 6504 (1985) 175. Morgan. B.: Ph.D. Thesis. University of British Columbia 1984 176. Morgan, B., Dolphin, D.: Angew. Chem. Int. Ed. 24, 1003 (1985) 177. Battersby, A. R., Hartley. S. G., Turnbull, M. D.: Tetrahedron Lett., 3169 (1978) 178. Cruse, W. B., Kennard. O., Sheldrick, G. M., Hamilton. A. D., Hartley. S. G., Battersby, A. R.: J. Chem. Soc, Chem. Commun., 700 (1980) 179. Battersby, A. R., Howson, W., Hamilton, A. D.: ibid. 1266 (1982) 180. Chang. C K.: J. Am. Chem. Soc. 99, 2819 (1977) 181. Richardson, N. M., Sutherland, I. O.. Camilleri. P., Page, J. A.: Ictrahedron Lett. 26, 3739 (1985) 182. Bogatskii, A. V.. Zhilina, Z. I., Stepanov, D. E.: Zh. Org. Khim. Engl. Ed. 18, 2039 (1982) 183. Hamilton, A. D., Lehn, J.-M., Sessler, J. L.: J. Chem. Soc., Chem. Commun., 311 (1984) 184. Chang. C K., Koo, M. S., Ward, B.: ibid. 716 (1982) 185. Guntcr. M. J.. Mander, L. N.: J. Org. Chem. 46, 4792 (1981) 186. Gunter, M. J., Mander, L. N., Murray. K. S., Clark, P. E.: J. Am. Chem. Soc. 103, 6784 (1981) 187. Ganesh, K. N., Sanders, J. K. N.: J. Chem. Soc, Chem. Commun., 1129 (1980) 188. Ganesh, K. N.. Sanders, J. K. N.: J. Chem. Soc, Perkin Trans. 1, 1611 (1982) 189. Ganesh. K. N.. Sanders. J. K. N.. Waterton. J. C: ibid. 1. 1617 (1982) 190. Sanders. J. K., Leighton, P.: J. Chem. Soc, Chem. Commun., 24 (1985) 191. Leighton, P., Sanders, J. K. M.: ibid. 854 (1984) 192. Abraham. R. J., Leighton, P., Sanders. J. K. M.: J. Am. Chem. Soc 107, 3472 (1985) 193. Leighton, P.. Sanders. J. K. M.: J. Chem. Soc. Chem. Commun.. 856 (1984) 194. Hamilton. A. D.. Rubin, H.-D.. Bocarsly. A. B.: J. Am. Chem. Soc 106, 7255 (1984) 195. Momenteau. M.. Mispclter. J., Loock. B.. Bisagni. E.: J. Chem. Soc. Perkin Trans. 1, 189 (1983) 196. Momenteau. M.. Loock, B.. Mispelter, J.. Bisagni, E.: Nouv. J. Chem. 3, 77 (1979) 197. Lexa, D., Momcnteau. M., Rentien, P., Rytz, G., Saveant, J. M.. Xu. F.: J. Am. Chem. Soc 106, 4755 (1984) 198. Becker. J. Y.. Dolphin, D., Paine. J. B. III. Wijeskera, T. P.: J. Electroanal. Chem. 164, 335 (1984) 199. Zhilina. Z. I., Bogatskii, A. V.. Vodzinskii, S. V., Abramovich, A. E.: Zh. Org. Khim. Eng. Ed. 18, 227 \ (1982) 200. Wciser, J., Staab, H. A.: Angew. Chem. Int. Ed. 23, 623 (1984) 201. Momenteau, M.. Lavalette D.: J. Chem. Soc, Chem. Commun., 341 (1982) 202. Mispelter. J.. Momcnteau, M., Lavalette, D. Lhoste. J.-M.: J. Am. Chem. Soc 105, 5165 (1983) 203. Momcnteau, M., Loock, B.. Lavalette, D.. Tetreau, C1 Mispelter, J.: J. Chem. Soc, Chem. Commun., 962 (1983) 204. Battersby, A. R., Hamilton, A. D.: ibid. 117 (1980) 205. Battersby, A. R., Bartholomew. S. A. J., Nitta. J.: ibid. 1291 (1983)