Chemical Syntheses Of Porphyrins

Porphyrin chemical synthesis will be discussed here in connection with two series of compounds: (i) those porphyrins which have been most often used in connection with model studies, e.g., 5,10,15,20-tetra-phenylporphyrin (TPP) [51] and 2,3,7,8, 12,13,17,18-octaethylporphyrin (OEP) [52]; and (ii) those related to protoporphyrin IX [1]. Simply based on the symmetry in the substituent arrays of [51] and [52] and the lack of symmetry in [1], it is obvious that it would be a waste of time to approach the synthesis of both series of compounds using the same strategy. To attempt the synthesis of OEP [52] by labo rious multistep construction of an open-chain tetrapyrrolic intermediate would be plainly unwise—such symmetrically substituted compounds are most efficiently obtained by tetramerization of a suitable monopyrrole (see below). On the other hand, there is no way (in the absence of enzymes) that protoporphyrin IX [1] can be synthesized chemically by monopyrrole chemical self-condensation, so a more sophisticated chemical approach is essential. As it happens, porphyrins [51] and

[52] can be synthesized by self-condensation of monopyrroles, while protopor-phyrin IX [1] can be accessed by a number of routes, the most simple (and the one to be used as an example in this chapter) being from dipyrroles.

4.1. Syntheses of Pyrroles

For both series of compounds mentioned above, it is first essential to synthesize monopyrroles. Pyrrole itself

[53] is commercially available. Syntheses of two common examples of useful pyrroles (from the many dozens in the literature) (5,20,32,37,38) will be illustrated here.

Pyrroles bearing peripheral substituents are those which are most useful for application to dipyrrole and porphyrin synthesis. The Johnson—Kleinspehn synthesis (11,43) is perhaps the most useful for tetra-substituted pyrroles. For example, pyrrole

[54], bearing very useful methyl and pro-pionate groups, is prepared by the reaction of dione [55] with benzyl oximinoacetoac-etate [56]—compound [56] is in turn obtained by the reaction of benzyl acetoac-etate [57] with sodium nitrite in the presence of acetic acid. Slow admixture of equimolar amounts of [55] and [56] and excess zinc powder and sodium acetate in hot acetic acid results in reduction of the oximinoderivative [56] to the amine, followed by in situ condensation with [55] to give pyrrole [54]. Simply pouring the cooled reaction mixture into iced water causes precipitation of the product pyrrole. The reaction works with a variety of sub-stituents on the central (i.e., 2-) carbon of the 1,3-dione and with a variety of esters on the acetoacetate. The reaction described above (using acetoacetates) is the Johnson version, while the Kleinspehn modification employs oximinomalonic esters in place of the acetoacetates.

Compared with the above synthesis of pyrroles, methodology for preparing pyrroles such as [58] is relatively new. A major advance in the field was made when the Barton—Zard pyrrole synthesis was reported (8); the importance of this route was related to the substituent patterns which could be accessed using it. Thus, treatment of a nitroalkene [59a] or its synthetic precursor, an acetoxynitroalkane [e.g., 59b], with an isocyanoacetate [e.g., 60] affords excellent yields of pyrroles such as [58].

❖ Procedure 2. Synthesis of Ethyl 3,4-Diethylpyrrole-2-Carboxylate [58] (55)

1. A mixture of 3-acetoxy-4-nitrohexane [59b] (8)(16.3 g), ethyl isocyanoacetate [60] (9.8 g; Sigma, St. Louis, MO, USA), and 1,8-diazabicyclo[5.4.0] undec-7-ene (26.4 g; Sigma) in tetrahy-drofuran (100 mL) is stirred at 20°C for 12 hours.

2. The mixture is poured into water containing 1 M HCl and then extracted with ethyl acetate.

3. The extracts are washed with water and dried over anhydrous magnesium sulfate.

4. After evaporation of the solvents, the residue is chromatographed on a column of silica gel eluted with hexane: dichloromethane mixtures.

5. Evaporation of the eluates containing the red band will give the required pyrrole [58], with an average yield of 14.2 g.

4.2. Syntheses of Dipyrromethanes

Unsymmetrically substituted dipyrromethanes, [e.g., 61], can be prepared by condensation of 2-acetoxymethylpyrroles [62] with 2-unsubstituted pyrroles [63] in acetic acid containing a catalytic amount (<0.1 equiv.) of toluene ^-sulfonic acid (13). Montorillonite K-10 clay has also been shown to be a very useful acid catalyst in dipyrromethane syntheses (30,36); the advantage of using the clay is that it can be removed simply by filtration after the reaction is complete. Compound [62] is obtained from the corresponding methyl-pyrrole [64] simply by treatment with lead tetra-acetate. Note that pyrrole [64] possesses the same "symmetry pattern" as does pyrrole [54]; its synthesis is relatively straightforward (21). Pyrrole [63] can be obtained from [64] by following a sequence of reactions as shown in Scheme 1. The dipyrromethane [61] will form rings A and B of protoporphyrin IX dimethyl ester [2] in the synthesis, which will be described later. The 1- and 9-car-

boxylate substituents are differentially protected, and the future vinyl groups are protected as 2-chloroethyls.

Symmetrically substituted dipyrrometh-anes [e.g., 65] are best prepared in one step by self-condensation of bromomethyl-pyrroles [e.g., 66] in hot methanol (21), or by heating 2-acetoxymethylpyrroles [e.g., 67] in methanol-hydrochloric acid (50). The 1- and 9-benzyl esters can be cleaved using catalytic hydrogenation with hydrogen gas and 5% (or 10%) palladium-carbon as catalyst. The resulting 1,9-dicar-boxylic acid [68] can then be formylated using the Vilsmeier reagent (phosphoryl chloride or benzoyl chloride mixed with equimolar amounts of dimethylforma-mide) to give [69]. The 1- and 9-formyl groups serve as the bridging carbons in the MacDonald porphyrin macrocyclization, which will be described later.

4.3. Porphyrins via Monopyrrole Tetramerization

By definition, tetramerization of mono-pyrroles must result either in a single symmetrically substituted porphyrin (if the 3-and 4-substituents are identical) or in a mixture of porphyrins (if the 3- and 4-sub-stituents are different—see later). By far, the easiest way to prepare a porphyrin involves the reaction of pyrrole [53] with benzaldehyde. The product is the almost legendary TPP [51]. This simple route was first reported by Rothemund (57,58) and, after modification by Adler, Longo and colleagues (involving use of refluxing propi-onic acid instead of sealed tube chemistry) (1), was finally optimized as a two-step procedure by Lindsey's group (48). The nonexpert procedure that is easiest to follow for the synthesis of [51] involves addition of equimolar amounts of crude (undis-

tilled) pyrrole [53] and benzaldehyde to refluxing propionic acid. After heating for about 30 minutes, the mixture is allowed to cool, and the TPP is filtered off, usually in 20% to 22% yield. The propionic acid can be recovered by distillation and then reused. Higher yields of TPP can be obtained by use of more elaborate and expensive chemistry, but, for TPP, quick and dirty seems to work well. The product

from the Rothemund and Adler—Longo (propionic acid) approaches is somewhat impure (though highly crystalline) and contains (4) about 5% or less of meso-tetraphenylchlorin [70]. Brief treatment (6) of the crude product with DDQ accomplishes transformation of [70] into [51]; earlier methodology involved the separation of these two components on a chro-matography column, but transformation of [70] into [51] instead of separation of [51] from [70] is much more sensible. Using this kind of methodology, literally kilograms of TPP can be prepared. TPP can, in any case, be purchased either "chlorin-free" or crude. Additionally, with only relatively few exceptions, the reaction tolerates substitution of other arylaldehydes for benzaldehyde, and good yields of a variety of tetra-arylporphyrins can be obtained (47).

❖ Procedure 3. Synthesis of Chlorin-Free TPP [51] (6)

1. Benzaldehyde (66.5 mL) and pyrrole (46.5 mL) are simultaneously added to refluxing propionic acid (2.5 L), and the mixture is refluxed for a further 30 minutes before being allowed to cool overnight to room temperature.

2. The crude TPP is filtered off, washed with hot water, and then washed with methanol until the filtrate is colorless, to give 20.4 g (20% yield) of purple glistening crystals.

3. Concentration of the propionic acid filtrate affords a second crop of crystals.

4. The crude TPP (20 g) is dissolved in refluxing ethanol-free chloroform (2.5 L) before addition of DDQ (5 g) in dry toluene (150 mL).

5. The mixture is refluxed for 3 hours before filtration of the yellowish solution, under suction, through a sintered glass funnel containing Grade I alumina (300 g).

6. The alumina is washed with dichloro-methane (200 mL), and the combined filtrates are concentrated to approximately 200 mL before addition of 200 mL of methanol.

7. Filtration results in the chlorin-free product as glistening purple crystals, with an average yield of 19.2 g.

Approaches to so-called octaalkylpor-phyrins (such as OEP [52]) are a little more complicated, but only with regard to the difficulty of preparing the pyrrole starting materials. In this case, the future meso-(i.e., interpyrrolic) carbons can either be present already on the pyrrole, or as in the case with TPP (wherein the meso-carbons were provided by the formyl carbon in benzaldehyde), the meso-carbons can be added separately from the pyrrole. A primary stricture, as mentioned above, is that a monopyrrole tetramerization approach can only be used to give structurally unique product if the substituents at positions 3-and 4- in the monopyrrole are identical.

Thus, fully symmetrical porphyrins such as octaethylporphyrin [52] can be prepared easily using two major routes. The first approach, which chronologically was developed first, involves the tetramerization of pyrroles [71] bearing 2-CH2R substituents; the "R" group must be a good leaving group, and the methylene carbon of the 2-substituent will eventually be the source of the 5,10,15, and 20-carbons of the product porphyrin. After the condensation reaction, an oxidation step is necessary to afford good yields of symmetrical porphyrin. Useful examples for attachment of CH2R groups to pyrroles are (i) the Mannich reaction of pyrrole [72] with formaldehyde and dimethylamine [or better, with commercially available (N,N-dimethylmethylene)am-monium iodide, Eschenmoser's reagent (56,59)] to give the 2-(N,N-dimethy-laminomethyl)pyrrole [73]; heating of this in acetic acid gives a 52% yield of [52]

(18,70); and (ii) hydrolysis of the pyrrole [74] to give pyrrole [75] which is tetramer-ized to give [52] in 44% yield by heating in acetic acid containing potassium ferri-cyanide (35,63). Most recently, the Bar-ton-Zard pyrrole synthesis (see above) (8) has greatly simplified preparative approaches to monopyrroles of the type [58]; lithium aluminum hydride (CAUTION: reacts violently with moisture) reduction, followed by tetramerization of the resulting pyrrole-2-carbinol [76] under acidic conditions, gives [52] in 55% yield (2,55).

❖ Procedure 4. Synthesis of OEP [52] from Pyrrole [58] (54)

1. Ethyl 3,4-diethylpyrrole-2-carboxylate [58] (see above, 657 mg) is added drop-wise at 0°-5°C to a stirred solution of lithium aluminum hydride (320 mg; Sigma) in dry tetrahydrofuran (15 mL). The mixture is stirred for 2 hours at 0°-5°C before destroying the excess lithium aluminum hydride by addition of ethyl acetate.

2. It is then poured into saturated aqueous ammonium chloride, extracted with ethyl acetate (3 times 10 mL), washed with aqueous sodium chloride, and dried over anhydrous magnesium sulfate.

3. The solution is evaporated to dryness under vacuum before addition of dichloromethane (15 mL).

4. To this solution is added dimethoxy-methane (0.7 mL; Sigma) and toluene p-sulfonic acid (110 mg), and the mixture is stirred for 12 hours at room temperature. Aerial oxidation occurs under these conditions, but chloranil (Sigma) can also be used, although without any improvement in yield.

5. The mixture is washed with aqueous sodium bicarbonate, and the organic layer is dried over anhydrous magnesium sulfate.

6. Evaporation gives a residue which is chromatographed on silica gel, eluted with dichloromethane to give OEP

Alternatively, tetramerization of 2,5-di-unsubstituted pyrroles [e.g., 72] in the presence of reagents that can provide the four meso-methine carbons of the product can be used. Cyclization of 3,4-diethylpyr-role [72] with formaldehyde affords 55%-75% yields of OEP [52] (61).

If the 3- and 4-substituents on the monopyrrole component are not identical, mixtures will usually result due to acid catalyzed pyrrole ring scrambling reactions (49). Thus, acid catalyzed tetramerization of pyrrole [77] will result in production of a mixture of the four etioporphyrin type isomers [6—9]. However, a method has been devised which does produce only etioporphyrin I [6] from tetramerization of a pyrrole related to [77]; treatment of 2-(N,N-dimethylaminomethyl)pyrroles [e.g., 78] with methyl iodide gives [79], which has a leaving group that is labile even under neutral conditions (i.e., no acid), which would cause pyrrole ring scrambling, is present (53,54). This, quaternized in methanol containing potassium ferricyanide (to accomplish rapid in situ oxidation of the labile porphyrinogen intermediate), gives a good yield of pure etioporphyrin I [6].

❖ Procedure 5. Synthesis of

Etioporphyrin I [6] from Pyrrole [78]

1. Benzyl 4-ethyl-5-(N,N-dimethylamino-methyl)-3-methylpyrrole-2-carboxylate (53,54) (1.88 g) is dissolved in tetrahydrofuran (600 mL), and 10% palladium on carbon (500 mg; Sigma) is added.

2. The resulting mixture is stirred under hydrogen at room temperature for 12 hours before the catalyst is removed, and the solvent is evaporated to dryness.

3. Recrystallization from dichlorometh-ane/hexane affords 4-ethyl-5-(N,N-di-alkyl-aminomethyl)-3-methylpyrrole-2-carboxylic acid as an off-white powder in quantitative yield. Note that because of spontaneous decarboxylation at room temperature to give [78], this must be used immediately.

4. The pyrrole carboxylic acid (1.29 g) is dissolved in a solution of methanol (200 mL) and triethylamine (2 mL) and heated under reflux for 15 minutes.

5. Potassium ferricyanide (3.8 g) is added, and the reaction is continued at reflux for another 10 hours.

6. After removal of the solvent, the residue is redissolved in chloroform, the insoluble material filtered off, and the red solution is passed through a short column of silica gel (eluted with chloroform).

7. The solvent is evaporated, and the residual porphyrin is recrystallized from

dichloromethane/methanol to afford etioporphyrin-I in 36% yield (284 mg).

4.4. Porphyrins via Dipyrromethane Intermediates

If two dipyrromethane units with appropriate bridging carbons are condensed together, there are three possible products because the dipyrromethanes can either react with themselves or with each other. If the dipyrromethanes individually possess an unsymmetrical array of sub-stituents, even greater mixtures can occur because there is no control over which end of one dipyrromethane reacts with the end of another. These symmetry limitations are common with all so-called "2 + 2" syntheses; in a porphyrin synthesis involving an A-B and a C-D dipyrromethane is to be condensed, the symmetry problems can be avoided if the A-B or C-D dipyrromethane unit is symmetrical about the interpyrrolic (5-) carbon atom. Arsenault, MacDonald, and coworkers showed (3) that a 1,9-difor-myldipyrromethane, [e.g., 69], can be condensed with a 1,9-di-unsubstituted dipyrromethane or its 1,9-dicarboxylic acid [80] in the presence of an acid catalyst to give pure porphyrin [e.g., 81], often in high yields. MacDonald used hydriodic acid, but since that time, toluene ^-sulfonic acid has been shown (14,15) to be a much better choice and more convenient too.

This 2 + 2 route using dipyrromethanes is probably the most widely used pathway to synthetic porphyrins. Thus, for example, treatment of dipyrromethane [82] (obtained from [61] by catalytic debenzyla-tion followed by treatment with trifluo-roacetic acid) with 1,9-diformyldipyrro-methane [69] gives a good yield of porphyrin [83] after oxidation of the intermediate porphodimethene [84]; no mixtures are produced because both of the future linking meso-carbons are sited on the same dipyrromethane (preventing either of the two individual dipyrrometh-anes from reacting with themselves) and dipyrromethane [69] is symmetrical about its 5-carbon. Conversion of the 3,8-bis(2-chloroethyl)porphyrin [83] into protopor-phyrin IX dimethyl ester [2] is accomplished simply by treatment with base (40)—just in case this base treatment also accomplished hydrolysis of the methyl esters, the product is then set aside in methanol containing 5% sulfuric acid (CAUTION: add the acid to the methanol, cooled and slowly). Workup and chromatography [NOTE: protoporphyrin is photolabile (see above), so the column should be run in the dark or with aluminum foil wrapped around it] then produces the product, [2].

It has been my intention to provide a summary of fairly simple procedures that can be used, given a certain competence in synthetic organic chemistry, to obtain by extraction or by total synthesis some useful porphyrins with defined symmetry and structural characteristics. But competence in organic chemistry is not easily earned. If the procedures still look too complex, or (more likely) if you do not have the basic laboratory equipment with which to carry out the procedures described, then the best bet is to collaborate. Just remember, most organic chemists would not know where to start if they needed to run a gel or if they needed to do a northern blot. They will want to collaborate also if they need these things.

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