N-Alkyl porphyrins

The synthesis of homoporphyrins in which one methine bridge of the parent porphyrin is extended to a two-carbon bridge is one of the earliest and simplest examples of an expanded porphyrin.3a b>4 The synthesis of homoporphyrin 4 is based on the ability of N-alkylated porphyrin 1 to undergo nickel-induced rearrangement to form an expanded macrocycle 2. De-metalation of 2 by means of concentrated hydrochloric acid yields the cyclically conjugated [20]porphyrin(2.1.1.1) 4 and a macrocyclic side product 3 in which the cyclic conjugation is interrupted. 

Diazoalkanes are u.seful is precursors to ruthenium and osmium alkylidene porphyrin complexes, and have also been investigated in iron porphyrin chemistry. In an attempt to prepare iron porphyrin carbene complexes containing an oxygen atom on the /(-carbon atom of the carbene, the reaction of the diazoketone PhC(0)C(Ni)CH3 with Fe(TpCIPP) was undertaken. A low spin, diamagnetic carbene complex formulated as Fe(TpCIPP)(=C(CH3)C(0)Ph) was identified by U V-visible and fI NMR spectroscopy and elemental analysis. Addition of CF3CO2H to this rapidly produced the protonated N-alkyl porphyrin, and Bit oxidation in the presence of sodium dithionitc gave the iron(II) N-alkyl porphyrin, both reactions evidence for Fe-to-N migration processes. ... 

Collapse of N-alkylated porphyrins [80] is an alternative to metal insertion into normal porphyrins. Thus, IV-benzylprotoporphyrin IX-dimethylester reacts in refluxing methanol with PdCl2 to yield 92% Pd(Proto-DME) within 10 min. 

N-alkylated porphyrins can also serve as catalytic bases in the asymmetric addition of thiophenols to enones [55c], In the most selective example (addition of 2-methylthiophenol to cyclohexenone), 55% ee was achieved. 

N-substituted iron porphyrins form upon treatment of heme enzymes with many xenobiotics. The formation of these modified hemes is directly related to the mechanism of their enzymatic reactivity. N-alkyl porphyrins may be formed from organometallic iron porphyrin complexes, PFe-R (a-alkyl, o-aryl) or PFe = CR2 (carbene). They are also formed via a branching in the reaction path used in the epoxidation of alkenes. Biomimetic N-alkyl porphyrins are competent catalysts for the epoxidation of olefins, and it has been shown that iron N-alkylporphyrins can form highly oxidized species such as an iron(IV) ferryl, (N-R P)Fe v=0, and porphyrin ir-radicals at the iron(III) or iron(IV) level of metal oxidation. The N-alkylation reaction has been used as a low resolution probe of heme protein active site structure. Modified porphyrins may be used as synthetic catalysts and as models for nonheme and noniron metalloenzymes. 

In the early 1970s it was discovered that P-450 cytochromes are irreversibly inhibited during the metabolism of xenobiotics (1). The formation of a modified heme prosthetic group is associated with enzyme inhibition and subsequent studies have identified these modified complexes as N-alkylated protoporphyrin-IX (2). The chemistry of N-sub-stituted porphyrins was comprehensively reviewed by Lavallee in 1987 (3). Since that time, there have been many significant contributions to this field by several groups. The goal of this chapter is to summarize some of this work as it relates to the mechanism of formation and reactivity of iron N-alkyl porphyrins. Biomimetic model complexes have played an important role in elucidating the chemistry of N-alkyl hemes in much the same way that synthetic iron tetraarylporphyrins have aided... 

From Iron(III) Tetraarylporphyrins and Alkenes. N-alkyl porphyrins are formed via side reactions of the normal catalytic cycle of cytochromes P-450 with terminal alkenes or alkynes. N-alkylpor-phyrins formed from terminal alkenes (with model iron porphyrin catalysts under epoxidation conditions) usually have a covalent bond between the terminal carbon atom of the alkene and a pyrrole nitrogen. The double bond is oxidized selectively to an alcohol at the internal carbon. Mansuy (23) showed that, in isolated examples, terminal alkenes can form N-alkylated products in which the internal carbon is bound to the nitrogen and the terminal carbon is oxidized to the alcohol. Internal alkenes may also form N-alkyl porphyrins (24, 25). 

The N-alkylation reaction represents a bifurcation of the normal alkene epoxidation reaction cycle and, therefore, N-alkylation is a suicide event that leads to catalytic inhibition in the native system. With synthetic tetraarylporphyrins that mimic the N-alkylation reaction, the use of halogen-substituted catalysts that are stable toward oxidative degradation (26, 27) provide the most useful model systems because the heme model remains intact for a significantly greater number of turnovers than the partition number. The partition number is the ratio of epoxidation cycles to N-alkylation cycles, i.e., N-alkyl porphyrins are formed before the heme is oxidatively destroyed. 

Given the similarities in chemical shifts and linewidths, as well as the contributions of symmetry to the appearance of the spectrum, the electronic and molecular structure of new iron complexes of N-alkyl-porphyrins may be ascertained, to a first approximation, from NMR data. Thus for low-spin iron(III) complexes one would expect at least four sharp resonances upfield of the diamagnetic region. Iron(IV) complexes should have at least four resonances upfield of the diamagnetic region. Iron(III) can be differentiated from iron(IV) by measurement of the solution susceptibility (51). 

Oxidation of ]V-MeTTPFenCl (46, 52). Catalytic alkene oxidation by iron N-alkylporphyrins requires that the modified heme center can form an active oxidant, presumably at the HRP compound I level of oxidation. To show that iron N-alkyl porphyrins could form highly oxidized complexes, these reactive species were generated by chemical oxidation and examined by NMR spectroscopy. Reaction of the (N-MeTTP)FenCl with chlorine or bromine at low temperatures results in formation of the corresponding iron(III)-halide complex. Addition of ethyl- or t-butyl-hydroperoxide, or iodosylbenzene, to a solution of N-MeTTPFenCl at low temperatures has no effect on the NMR spectrum. However, addition of m-chloroperoxybenzoic acid (m-CPBA) results in the formation of iron(III) and iron(IV) products as well as porphyrin radical compounds that retain the N-substituent. 

Formation of an Iron Complex of an N-alkyl Porphyrin ir-Radical (46, 52). In the absence of sodium methoxide, the reaction between (N-MeTTP)FenCl and m-CPBA takes two different paths. When 1.1 equivalents of the peroxy acid are added, the Fe11 complex is converted into a high-spin, five-coordinate Fem complex. However,... 

Given the observation of catalysis of alkene epoxidation by iron N-alkyl porphyrins, it is likely that these complexes may yield synthetically useful catalysts (32, 65). The possibility of chiral induction by using either a chiral N-alkyl group (66) or a chiral macrocycle such as N-Me etioporphyrin (67) is an area that should prove fruitful in the near future. 

A number of diazo compounds are known to be decomposed by Zn(II), Co(II), Co(ni) and Rh(III) complexes of porphyrins (409) to give 1 1 and 1 2 adducts between the porphyrin and the formal carbene unit. Depending on the metal ion, different products may result (Scheme 42) Zinc octaethylporphyrin or meso-tetraphenylporphyrin yield N-alkylated porphyrins 410 with ethyl diazoacetate and ethyl 2-diazopropionate In the latter case, a homoporphyrin 411 is obtained additionally. Cu(I)-catalyzed decomposition of diazomethane or alkyl diazoacetates in the presence of zinc me.yo-tetraphenylporphyrin leads to cyclopropanation of a pyrrolic pp double bond, besides an N-alkylated product of type 410 The... 

Mansuy, D., L. Devocelle, 1. Artaud, and J.P. Battioni (1985). Alkene oxidations by iodosylben-zene catalyzed by iron-porphyrins Fate of the catalyst and formation of N-alkyl-porphyrin green pigments from monosubstituted alkenes as in cytochrome P-450. Nouv. J. Chim. 9, 711-716. 

De Matteis, E, C. Hollands, A.H. Gibbs, N. de Sa, and M. Rizzardini (1982). Inactivation of cytochrome P-450 and production of N-alkylated porphyrins caused in isolated hepatocytes by substituted dihydropyridines Structural requirements for loss of haem and alkylation of the pyrrole nitrogen atom. FEES Lett. 145, 87-92. 

De Matteis, E, A.H. Gibbs, P.B. Farmer, and J.H. Lamb (1981). Liver production of N-alkylated porphyrins caused by treatment with substituted dihydropyridines. FEBS Lett. 129, 328-331. 

F. De Matteis (1990). Copper-induced dealkylation studies of biologically N-alkylated porphyrins by fast atom bombardment mass spectrometry. Anal. CA/m. cra 241, 233-239. 

Halogenated Hydrocarbons - The destruction of cytochrome P-450 by CCl, first attributed to lipid peroxidation, has been shown to occur even under conditions where lipid peroxidation is not detectable.one possible explanation for this inactivation is that the trlchloromethyl radical or a related species obtained by reduction of the halocarbon reacts with the heme moiety or the apoprotein. The ill-defined radio-labeled porphyrins reported in Incubations of labeled CCI4 with hepatic microsomes would provide support for a heme alkylation mechanism were it not for the conflicting report that fluorescent N-alkylated porphyrins similar to those obtained with AIA are not isolated from CCl -incubated microsomes by procedures that result in isolation of the AIA adducts. ... 

---