Lionel G. King

Novel heterocyclic systems from selective oxidation at the β-pyrrolic position of porphyrins

Novel heterocyclic systems in which a porphyrin pyrrole has been ring-expanded to a morpholine derivative (5), ring-contracted to an azetine derivative (6), and converted into the oxazolone derivatives (4) and (9) result from selective oxidation of 2-amino-5,10,15,20-tetraphenylporphyrin (1).

A new and highly efficient synthesis of hydroxyporphyrins

Abstract A new synthesis of hydroxyporphyrins is reported. The method involves nucleophilic displacement of a nitro group using the sodium salt of E-benzaldoxime and is a general process allowing the synthesis of both β-hydroxyporphyrins and meso-hydroxyporphyrins. Activation of the porphyrin system towards nucleophilic attack is achieved by complexation of the macrocycle with the relatively electronegative nickel(II) or copper(II) ions. Thus, treatment of either the copper(II) or the nickel(II) chelates of 2-nitro-5, 10,15,20-tetraphenylporphyrin with the sodium salt of E-benzaldoxime gave the corresponding 2-hydroxyporphyrin in high yield. Similar treatment of the copper(II) or the nickel(II) chelates of 5-nitro-2, 3,7,8,12,13,17,18-octaethylporphyrin gave the corresponding 5-hydroxyporphyrin, again in high yield. These reactions show that metallo-nitroporphyrins display similar electrophilic properties to much simpler nitro-arene systems. The nickel(II) 5-hydroxyporphyrin 10 was cleanly demetallated on treatment with concentrated sulfuric acid to give the corresponding free-base oxophlorin thereby greatly increasing the general utility of the hydroxylation methodology. Conversion of (5-methoxy-15-nitro-2,3,7,8,12,13,17,18-octaethylporphyrinato) nickel(II) 16 into (5-acetoxy-15-methoxy-2,3,7,8,12,13,17,18-octaethyl-porphyrinato) nickel(II) 18 established that the reaction mechanism involves regiospecific replacement (i.e., ipso-substitution) of the nitro group by the oxygen nucleophile.

Control of reactivity at the porphyrin periphery by metal ion co-ordination: a general method for specific nitration at the β-pyrrolic position of 5,10,15,20-tetra-arylporphyrins

The site of nitration by nitrogen dioxide on a range of metalloporphyrins has been found to be dependent on the co-ordinated metal; copper(II), nickel(II), and palladium(II) complexes are nitrated specifically on the porphyrin β-pyrrolic position while magnesium(II), zinc(II), chloroiron(III), and cobalt(II) complexes also give products which result from reaction at the meso-position.

Investigation of a ‘reverse’ approach to extended porphyrin systems. Synthesis of a 2,3-diaminoporphyrin and its reactions with α-diones

A 2,3-diaminoporphyrin has been synthesised for the first time and its reaction with α-diones has been examined. Two regioselective routes to the precursor 2-amino-3-nitroporphyrins have been established. 2-Aminoporphyrins are directly nitrated on the porphyrin ring in the 3-position while 2-nitroporphyrins react with acylamide ions regioselectively at the 3-position and can be converted to the required 2-amino-3-nitroporphyrins by hydrolysis of the amide bond. 2,3-Diamino-5,10,15,20-tetraarylporphyrins are prepared by transfer hydrogenation of the corresponding 2-amino-3-nitroporphyrins but are relatively unstable. Electrochemical measurements show that 2,3-diaminoporphyrins are easily oxidised and this probably accounts for their instability. Condensation of the 2,3-diaminoporphyrin 29 with the α-diones benzil and cyclohexane-1,2-dione occurs readily and in good yield to give the ring annulated systems 31 and 32, respectively. Reaction with o-benzoquinone, however, causes decomposition of the diaminoporphyrin 29 making ‘reverse’ synthesis of quinoxalinoporphyrins and related polyporphyrin systems much less attractive than the alternate approach involving condensation of a porphyrin-2,3-dione with o-phenylenediamine and related diamines.

Reaction of 5-nitro-octaethylporphyrins with nucleophiles

An investigation of the reactions of metallo-5-nitro-2,3,7,8,12,13,17,18-octaethylporphyrins with Grignard reagents, benzyl oxide, phenoxide and benzenethiolate nucleophiles shows that, except for benzenethiolate reactions, they are less efficient than related reactions of metallo-2-nitro-5,10,15,20-tetraarylporphyrins. Treatment of free-base and nickel(II) 5-nitro-octaethylporphyrin with the “soft” nucleophile benzenethiolate in DMF affords the corresponding 5-phenylthioporphyrins in 61 and 72% yield, respectively, by ipso-substitution of the nitro group. In contrast, with methylmagnesium iodide and benzyl oxide, “hard” nucleophiles, attack is at the diagonally opposite 15-position of the ring to give 15-substituted 5-nitroporphyrin while with phenoxide and more substituted Grignard reagents, electron-transfer reactions lead to denitration to (metallo)-octaethylporphyrin or reduction to the corresponding 5-aminoporphyrin. The lower efficiency of the latter reactions, compared to those on 2-nitro-tetraarylporphyrin analogues, is a consequence of two factors, higher energies being required for initial nucleophilic attack as macrocyclic aromaticity is lost in intermediates and the susceptibility of the resultant “non-aromatic” intermediates to further attack.

C-hydroxyarylation of tetraphenylporphyrin - convenient introduction of a functionality which is oriented towards the porphyrin centre

2-Nitro-5,10,15,20-tetraphenylporphyrin 1 and its copper(H) and nickel(II) chelates, 2 and 3 respectively, undergo nucleophilic substitution with sodium aryloxides in the corresponding phenol to afford mainly the 2-(o-hydroxyphenyl)porphyrin derivatives. This functionality is useful because it directs subsequently-attached substituents towards the porphyrin centre, as is demonstrated by a comparison of the average conformations of the 9Z-octadecenoic acid esters 14 and 15.

Solvent-dependent ambident nucleophilicity of phenoxide ion towards nitroporphyrins: synthesis of 2-hydroxyaryl- and 2-aryloxy-5,10,15,20-tetraphenylporphyrins by displacement of a nitro group

The reaction of phenoxide ion with the copper(II), nickel(II) and free-base 2-nitro-5,10,15,20-tetraphenylporphyrins, 1–3 respectively, has been investigated as a means of introducing inwards-directed functionality to the periphery of pre-existing porphyrin systems. It has been found that phenoxide ion shows highly selective solvent-dependent ambident nucleophilicity towards the nitroporphyrin system. Porphyrins 1–3 react with phenoxide ion in refluxing phenol to afford the corresponding 2-(o-hydroxyphenyl)- and 2-(p-hydroxyphenyl)-5,10,15,20-tetraphenylporphyrins in good yields; in each case the ortho isomer is the major product and none of the meta isomer is detected. The scope of the reaction has been extended by the use of the substituted phenols which are blocked from reaction para to the hydroxy (p-cresol and 2,4-dimethylphenol) or blocked from reaction in the ortho-positions (2,6-dimethylphenol). In this way the copper(II) 2-(2-hydroxy-5-methylphenyl)porphyrin 14 (86%), 2-(2-hydroxy-5-methylphenyl)porphyrin 15 (65%), copper(II) 2-(2-hydroxy-3,5-dimethylphenyl)porphyrin 16 (77%), 2-(2-hydroxy-3,5-dimethylphenyl)porphyrin 17 (69%) and 2-(4-hydroxy-3,5-dimethylphenyl)porphyrin 19 (63%) have all been obtained in good yields by reaction of the appropriate 2-nitroporphyrin 1 or 3 with the requisite substituted phenolate in the corresponding phenol. Reaction of the metalloporphyrins 1 and 2 with phenoxide ion in refluxing HCONMe2 in contrast gives the corresponding 2-phenoxy-metalloporphyrins 10 and 11 in good yield. The results of mechanistic studies using the deuteriated compound, nickel(II) 2-nitro-5,10,15,20-tetraphenyl[3-2H]porphyrin, 37, suggest that both sets of products (from phenoxide as a C-nucleophile and as an O-nucleophile) can arise from ipso-substitution of the nitro group.

Penicillin biosynthesis: stereochemistry of desaturative and hydroxylative pathways from L-α-aminoadipoyl-L-cysteinyl-D-isodehydrovaline with isopenicillin N synthase

Transformation of L-α-aminoadipoyl-L-cysteinyl-D-(Z)-[4-2H]isodehydrovaline (5b) and L-α-aminoadipoyl-L-cysteinyl-D-(E)-[4-2H]isodehydrovaline (5c) with isopenicillin N synthase gave rise to specifically deuteriated exomethylene cepham (6) and α-hydroxymethyl penam (7) products via the concomitant operation of stereospecific desaturative and hydroxylative ring closure pathways. The stereochemistries observed are in accord with competing ‘Ene’ and [2π+ 2π]cycloaddition of the proposed iron-oxo intermediate.

Efficient synthesis of 2-oxy-5,10,15,20-tetraphenylporphyrins from a nitroporphyrin by a novel multi-step cine-substitution sequence

(2-Nitro-5,10,15,20-tetraphenylporphyrinato)copper(II)(1) reacts with sodium benzylate or sodium methoxide in dimethylformamide by a novel aromatic nucleophilic substitution-nucleophilic addition sequence in which hydrogen is the leaving group to give the corresponding 2,2-dialkoxy-3-dihydroporphyrins which are efficiently converted into 2-alkoxyporphyrins in two steps; the overall sequence accomplishes a cine-substitution.

Reaction of metallo-2-nitro-5,10,15,20-tetraphenylporphyrins with oxyanions. Temperature-dependent competition between nucleophilic addition and single-electron transfer processes

The outcome of the reaction of metallo-2-nitro-5,10,15,20-tetraphenylporphyrins with oxyanions is dependent both on the nature of the coordinated metal ion and on the reaction temperature. Metallo-2-nitro-5,10,15,20-tetraphenylporphyrins with relatively electronegative chelated metal ions (CuII, NiII and FeIIICl)react with methoxide ion in N,N-dimethylformamide to afford mainly the corresponding metallated 2-methoxy-3-nitroporphyrins and 2,2-dimethoxy-3-nitro-2,3-dihydroporphyrins. The zincII chelate 7 is unreactive towards methoxide under identical conditions. When the room temperature reaction of (2-nitro-5,10,15,20-tetraphenylporphyrinato)nickel(II) 5 with methoxide is quenched with water after 1 min, the trans-(2-methoxy-3-nitro-2,3-dihydroporphyrinato)nickel(II) 14 is obtained. Inclusion of nitrobenzene in the reaction of the copper(II) chelate 4 with methoxide is beneficial and results in the formation of the 2,2-dimethoxy-3-nitro-2,3-dihydroporphyrin 8 in 90% yield. Reaction of 4 with benzyl oxide ion gives analogous products but in lower yield, while the major product from reaction of 4 with hydroxide ion is the 2-hydroxy-3-nitroporphyrin 16. At elevated temperatures the nature of the reaction of the copper(II) chelate 4 with methoxide changed to afford the corresponding copper(II) 2-alkoxyporphyrin 10 and the denitrated parent porphyrin 20; the later compounds arise from radical reactions. A mechanistic rationale for the processes involved in these temperature-dependent reactions is presented. The ease with which these reactions occur is a consequence of the fact that all the reaction intermediates are able to retain macrocyclic aromaticity.