cpgp3.SmithVicente.QAY 1081..12

a17.8 Product Class 8: 

Porphyrins and Related Compounds 

K. M. Smith and M. G. H. Vicente 

General Introduction 

Previously published information regarding this product class can be found in Houben– 

Weyl, Vol. 4/1b, p 828 and Vol. E 9d, pp 577–833. 

Porphyrins and related compounds, such as chlorins, are tetrapyrrole systems which 

provide the basic chromophore for a host of biologically important natural products. 

Principal examples are the hemes (iron complexes found in hemoglobins, myoglobins, 

cytochromes, catalases, and peroxidases) and the chlorophylls and bacteriochlorophylls 

(dihydro- and tetrahydroporphyrin–magnesium complexes found in photosynthetic organisms). 

There also exist a number of nonnatural contracted and expanded porphyrin 

systems, which have been invented as vehicles for comparative investigation of the effects 

of ring size on the chemistry and spectroscopy of porphyrins. Examples of contracted 

systems are the corroles, which have one of the porphyrin interpyrrolic carbon atoms 

missing, and sapphyrins and pentaphyrins, both of which have no less than five pyrrole 

subunits within their chromophores. 

The field has been extensively reviewed in the very recent past; The Porphyrin Handbook 

(published in 2000) is a 10-volume, 3500-page, 61-chapter treatise dealing with all aspects 

of porphyrins and related compounds; [1] volumes 11 through 20 were published in 

2003. Prior to these, two versions of Porphyrins and Metalloporphyrins were published (in 

1975 [2] and 1964 [3] ) and a multivolume series, The Porphyrins, appeared between 1977 and 

1979. [4] From time to time, reviews of specific areas of the porphyrin research field have 

appeared, and four which are relevant to the present chapter can be found in Rodd s Chemistry 

of the Carbon Compounds, [5,6] and Total Syntheses of Natural Products. [7,8] 

There are two systems currently in use for nomenclature of porphyrins. These are 

the IUPAC-approved system [9] and the so-called Fischer system; both are shown in 

Scheme 1. 

Scheme 1 The IUPAC and Fischer Systems of Nomenclature of Porphyrins 

23 

2 2 

2 1 

2 

3 

A 

4 

5 

6 

7 

B 8 

1 N 

21 

N 

22 

9 

20 

10 

19 

24 

N 

23 

N 

11 

18 D C 12 

17 

16 

15 

14 

13 

IUPAC 

N N 

N N 

K. M. Smith and M. G. H. Vicente, Section 17.8, Science of Synthesis, 2003 Georg Thieme Verlag 

1 

δ 

2 α 3 

The IUPAC nomenclature system assigns every carbon atom in the cyclic chromophore 

with a unique number from 1–20. The nitrogen atoms are numbered 21–24. The Fischer 

system, which was used in almost all of the rich historical literature before 1960, and is 

still used to a certain extent in the North American literature, numbers the carbon at the 

pyrrole b-positions 1–8, and labels the four interpyrrolic carbons (the so-called meso-carbons) 

as , b, g, d. While one can see that the assignment in the IUPAC system of a number 

to every single carbon atom in the chromophore would be advantageous, for example in 

8 

7 

γ 

Fischer 

6 

4 

β 

5 

1081 

for references see p 1223

1082 Science of Synthesis 17.8 Porphyrins and Related Compounds 

abiosynthetic studies, the earlier Fischer system carried with it a very convenient subnomenclature 

of trivial names; whether or not the IUPAC system is being used by an investigator, 

these trivial names are still used in abundance! The examples protoheme IX 

(“heme”, 1), protoporphyrin IX (2), coproporphyrin III (3), uroporphyrin I (4), chlorophyll 

a (5, R 2 = Me), chlorophyll b (5, R 2 = CHO), chlorin e 6 (6, R 1 = Me), and rhodin g 7 (6, 

R 1 = CHO) are shown in Scheme 2. 

Scheme 2 Typical Natural Porphyrin Derivatives 

HO 2C 

HO 2C 

HO 2C 

5 R 1 = 

N N 

Fe 

N N 

1 

NH N 

N HN 

R 1 O 2C 

R 2 = Me, CHO 

3 

CO2H 

CO2H 

N N 

Mg 

N N 

13 2 

MeO 2C 

CO 2H 

R 2 

E 13 1 

O 

Et 

NH N 

N HN 


HO2C 

HO 2C 

HO 2C 

HO 2C 

HO 2C 

HO2C 

2 

NH N 

N HN 

4 

CO 2H 

CO 2H 

NH N 

N HN 

CO 2H 

CO2H 

R 1 

CO 2H 

CO2H 

CO2H 6 R 1 = Me, CHO 

Though Scheme 2 might appear to indicate otherwise, there is in fact a system hidden 

within Fischer s trivial nomenclature. Porphyrins that have the same two different substituents 

on each pyrrole subunit, for example, methyl and ethyl, can have a maximum 

of four so-called “primary type-isomers” (structures 7–10) as indicated in Roman 

numerals in Scheme 3. 

Et

17.8.4 Isomeric, Contracted, and Expanded Porphyrin Systems 1083 

aScheme 3 The Four Primary Type-Isomers of the Etioporphyrins 

Et 

Et 

Et 

Et 

NH N 

I 

N HN 

7 

NH N 

III 

N HN 

9 

Et 

Et 

Et 

Et 

Et 

Et Et 

NH N 

N HN 


Et 

II 

8 

Et Et 

NH N 

IV 

N HN 

When the substituents on each pyrrole subunit are methyl and ethyl, the series is called 

“etioporphyrin”. If instead, the substituents are methyl and propanoic acid the series is 

“coproporphyrin” or if they are acetic and propanoic acids they are “uroporphyrins”. 

These names are historically derived. For example, coproporphyrins are not very watersoluble 

and are therefore excreted in the feces, while uroporphyrins are extremely water-soluble 

and are excreted in the urine. The normal metabolites of heme are of the “primary 

type-isomer III” orientation, though “type I” is occasionally found in some disease 

states. If one has three (rather than two) types of substituent spread around the chromophore, 

with one identical substituent (usually methyl) common to each pyrrole subunit, 

there are 15 possible type-isomers. Protoporphyrin IX is the natural “secondary type-isomer” 

in heme metabolism and this can be seen to be related to “primary type-isomer III” 

by further modification of the non-methyl substituents of rings A and B in coproporphyrin 

III in the latter (Scheme 2). “Proto” simply refers to the importance of this molecule; its 

protiodevinylated analogue (3,8-di-H in place of 3,8-divinyl) is named “deuteroporphyrin 

IX” because it was regarded as the second most important porphyrin, and contrary to the 

assumption of many journal editors, deuteroporphyrin contains no deuterium! The trivial 

nomenclature employed for chlorophyll a and b derivatives, such as chlorin e 6 and rhodin 

g 7, is unfathomable, and is best left alone (though it is worth knowing that the subscript 

Arabic numeral refers to the number of oxygen atoms in the molecule). 

Scheme 4 Structures of Porphyrin, Chlorin, Bacteriochlorin, and Isobacteriochlorin 

R 1 

R 8 

R 2 R 3 

R 7 

NH N 

N HN 

11 

R 6 

R 4 

R 5 

R 2 

R 1 

R 10 

10 

R4 R3 R 9 

N HN 

NH N 

12 

Et 

R 5 

R 8 

Et 

R 6 

R 7 



R 2 

aN 

R 

HN 

1 

R 12 

R4 R3 R 11 

NH N 

13 

R 5 

R 6 

R 7 

R10 R9 R8 N N 

NH HN 


R 2 

R 1 

R 12 

R4 R3 R 11 

14 

R6 R5 

Porphyrins 11 are aromatic macrocycles containing a total of 22 conjugated p-electrons. 

At any one time only 18 p-electrons participate in the delocalization pathway, two other 

double bonds being cross conjugated. Porphyrins conform with Hückel s [4n+2] rule for 

aromaticity (n = 4). Therefore, one or two of the peripheral double bonds of porphyrins 

can undergo addition reactions to form chlorins 12, bacteriochlorins 13, or isobacteriochlorins 

14 (shown in Scheme 4), without interfering with the delocalization pathway 

or introducing any major loss of aromatic character. Chlorins and bacteriochlorins are, 

however, progressively less aromatic than porphyrins qualitatively because fewer resonance 

structures can be drawn for the more reduced chromophores. The positions 

around the porphyrin periphery available, for example for electrophilic aromatic substitution, 

are the unsubstituted b-pyrrolic positions (at 2, 3, 7, 8, 12, 13, 17, and 18 in 11), 

and the four meso positions at 5, 10, 15, and 20. X-ray studies [10,11] indicate that the numerous 

C—C and the C—N bonds in 1 are almost equivalent. NMR spectroscopic, [12] X-ray, and 

theoretical studies [13,14] show that the thermodynamically most-favored tautomers for 

symmetrically substituted porphyrins are the degenerate trans-NH-tautomers depicted 

in 15 and 17 (Scheme 5). The mechanism for N–H migration between porphyrin trans-tautomers 

appears to proceed in a stepwise manner, via the less-favored cis-tautomers, such 

as 16. [15] 

The favored pathways for delocalization of the p-electrons in free-base porphyrins, in 

metal porphyrinates, and in porphyrin dications are also shown in Scheme 5. The peripheral 

b-positions of metal porphyrinates and porphyrin dications display similar reactivities, 

whereas the two opposite b–b¢ double bonds in free-base porphyrins experience 

more double-bond character. In the case of free-base chlorins, the most stable trans-tautomers 

(e.g., 18) appear to be those in which the imine-type nitrogens are on the reduced 

pyrrole subunit D and its opposite ring B. Though both forms of chlorin trans-tautomers 

18 and 19 have been observed experimentally, X-ray studies [10,11] and ab initio calculations 

[16] indicate that 18 is the major tautomer. The predominant p-electron delocalization 

pathway for free-base chlorins 18 causes the double bond of ring B to be the preferred 

site for electrophilic aromatic substitutions and addition reactions. In metal chlorinates, 

based on experimental observations, the preferred b-pyrrolic reaction sites are 

those in rings A and C, either side of the reduced pyrrole subunit. In metal porphyrinates, 

consideration of the various resonance structures leads to structure 20 as the resonance 

hybrid. 

Scheme 5 Tautomeric and Resonance Forms of Porphyrin, Metal Complex, Dication, and 

Chlorin 

NH N 

N HN 

15 

NH HN 

N N 

16 

R 10 

R 7 

R 8 

R 9 

N HN 

NH N 

17

A B 

aNH N 

17.8.1 Porphyrins 1085 

R 1 

R 2 

R 3 R 4 

N HN 

D C 

N N 

M 

N N 

N N 

M 

N N 

R 1 

R 2 

N N 

M 

N N 

N N 

M 

N N 

R 3 R 4 

NH N 

N HN 


18 

N N 

M 

N N 

N N 

M 

N N 

R 1 

R 2 

R 3 R 4 

N HN 

NH N 

19 

N N 

M 

N N 

20 M = metal, 2H + 

Although they have been shown to be more electron-rich than the b-positions, the meso 

positions of the porphyrin system 11 are often sterically hindered, especially when two of 

the abutting b-positions are occupied by substituents. The b-pyrrolic positions, therefore, 

are sterically favored and tend to undergo electrophilic substitution and addition reactions. 

In metal-free porphyrins, the central nitrogen atoms readily react with electrophilic 

reagents and are easily protonated and metalated. In metal porphyrinates the central 

nitrogen atoms play an important role (both chemically and biologically) in the transmission 

of electronic information from the metal ion and its axial ligands to the porphyrin psystem, 

and vice versa. In chlorins, the meso positions adjacent to the reduced (nonaromatic) 

pyrrole unit are more electron rich and are correspondingly more reactive toward 

electrophilic reagents. [17] 

17.8.1 Product Subclass 1: 

Porphyrins 

There are many methods available for the synthesis of porphyrins, and these have been 

reviewed in the recent past. [18–21] The synthetic route to be used should depend upon the 

symmetry and the complexity of the various peripheral substituents on the target porphyrin. 

For example, it would be wasteful in time and resources to attempt the synthesis 

of 2,3,7,8,12,13,17,18-octaethylporphyrin (OEP, 21; Scheme 6) by way of a laborious multistep 

fabrication of an open-chain tetrapyrrolic intermediate, followed by cyclization to 

produce the porphyrin macrocycle; symmetrically substituted compounds such as 21 are 

most efficiently synthesized by polymerization of a suitable monopyrrole. On the other 

hand, without help from enzymes which participate in the biosynthesis of heme and 

chlorophylls, there is no possibility that protoporphyrin IX (2) could be synthesized by a 

monopyrrole self-condensation route; with such complex asymmetric target molecules, 

highly sophisticated multistep chemical approaches are the only way that this can be accomplished. 



aScheme 6 Structures of Octaethylporphyrin and meso-Tetraphenylporphyrin 

Et 

Et 

Et Et 

Et 

NH N 

N HN 

21 

Et 

Et 

Et 

Ph 

NH N 

N HN 

The porphyrin field has a very rich history, which has produced numerous Nobel laureates. 

Hans Fischer [22–24] was unquestionably the major personality in porphyrin synthesis 

and chemistry in the 20th century. Fischer s group in Munich was responsible for 

much of the fundamental porphyrin synthetic chemistry that has been used since. New 

principles of contemporary organic chemistry and new reagents have been developed 

(benzyl esters, tert-butyl esters, diborane, catalytic hydrogenation, etc.), but Fischer must 

be credited with the basic philosophy that we all still employ. For porphyrin synthesis, 

Fischer s choice of intermediates were dipyrromethenes (see Section 17.8.1.1.1.1), and in 

the 1920s and 1930s the Munich school developed many approaches based on these dipyrrolic 

intermediates. However, methodologies for differential protection of reactive functional 

groups had not yet been developed, so syntheses of unique porphyrins without 

contamination by other isomers and congeners were usually not possible in Fischer s 

time. The problems of symmetry inherent when two dipyrromethenes are used to construct 

a porphyrin were fully understood; when syntheses were ambiguous and mixtures 

of porphyrins resulted, methods were developed to enable the separation of these mixtures. 

Ingenious use of substituent polarity differences usually allowed the mixtures to 

be separated. Moreover, in Fischer s time it was a straightforward matter to synthesize 

porphyrins (and mixtures of porphyrins) on the gram scale, thereby permitting development 

of separation methodology such as countercurrent distribution, solvent extraction, 

based on Willstätter s acid numbers, crystallization, and later, chromatography. 

Modern practitioners of the art of porphyrin synthesis have preferred to design their 

routes so that one unique porphyrin is the product; the scale of a research reaction also 

rarely exceeds 100 milligrams of product porphyrin. Separation of synthetic porphyrin 

mixtures, these days, is regarded as inelegant, even though chromatographic methods 

for separation (including high-performance liquid chromatography) have improved dramatically. 

Hence, very complex porphyrins with diverse substituents have, in the recent 

past, been approached via routes involving characterizable open-chain tetrapyrrolic intermediates. 

The task then reduces to a search for conditions, which will allow relatively 

labile side chains to be carried through reaction sequences intact, and will not scramble 

the often acid-labile pyrrole rings in oligopyrrole intermediates. 

Scheme 7 depicts the various bond-forming strategies of syntheses of porphyrins. Approaches 

A and B involve the tetramerization of monopyrroles. Case A utilizes a pyrrole 

(which must have identical substituents on its 3- and 4-positions to avoid production of 

mixtures) and an interpyrrolic one-carbon unit; the classic example here is the reaction 

of pyrrole with benzaldehyde to give 5,10,15,20-tetraphenylporphyrin (TPP, 22; Scheme 

6). In Scheme 7, case B, the interpyrrolic carbon is already affixed to the 2-position of the 

pyrrole; strangely enough, because of acid-catalyzed pyrrole ring redistribution reactions, 

the 3- and 4-positions must also usually possess identical substituents, and such an approach 

is the method of choice for synthesis of 2,3,7,8,12,13,17,18-octaethylporphyrin 

(OEP, 21). Mode C represents a new development in which two different pyrroles (one 

with two interpyrrolic carbons, and one with none) are condensed together to give one 

porphyrin only. Methods D–F in Scheme 7 employ dipyrrolic precursors. In case D, a sin- 


Ph 

Ph 

22 

Ph


agle dipyrromethane is treated with a reagent carrying a one-carbon linker (e.g., a formaldehyde 

equivalent, or benzaldehyde); in this case the dipyrromethane self-condenses, so 

use of two dipyrromethanes will yield a mixture of three porphyrins. Example E involves 

reaction of two different dipyrromethanes or dipyrromethenes with each other; in this 

case the two required interpyrrolic carbons are attached to one or other of the dipyrromethanes, 

and for synthesis of a unique porphyrin product, one or other of the dipyrromethanes 

must be symmetrically substituted about the dipyrromethane 5-(meso)-carbon. 

When dipyrromethanes are used in case E, the approach is one of the variations of the socalled 

MacDonald [2+2] route; use of dipyrromethenes in this approach was pioneered by 

Fischer. Scheme 7, case F also depicts the MacDonald route [25] when a dipyrromethane is 

used, or a variation of the Fischer method when a dipyrromethene is used. In this case, a 

single dipyrromethane or dipyrromethene bearing one interpyrrolic carbon is self-condensed 

to give a centrosymmetric porphyrin; use of two dipyrromethanes or dipyrromethenes 

will afford a mixture of three porphyrin products. 

Scheme 7 Common Bond Formations in Porphyrin Syntheses 

N N 

N N 

A 

N N 

N N 

D 

N N 

N N 

G 

N N 

N N 

B 

N N 

N N 

E 

N N 

N N 

H 

N N 

N N 


C 

N N 

N N 

F 

N N 

N N 

Mode G in Scheme 7 depicts the so-called [3+1] route to porphyrins, and methods H and I 

illustrate two examples of the open-chain tetrapyrrole route (using bilenes or a,c-biladienes, 

see Sections 17.8.1.1.3.2 and 17.8.1.1.3.3). Case H shows the approach when the 

final interpyrrolic carbon is added separately (as a formaldehyde or orthoformate equivalent, 

or simply as benzaldehyde), and in mode I the interpyrrolic carbon is pre-attached to 

the open-chain tetrapyrrole (seco-porphyrin). 

17.8.1.1 Syntheses of Intermediates Used in Porphyrin Syntheses 

No matter how simple or complex the target may be, porphyrin syntheses require the 

ready availability of functionalized monopyrrole building blocks. Syntheses and functionalization 

of such monopyrroles are outside the scope of this chapter, but these issues have 

been reviewed comprehensively by Black in Section 9.13, Science of Synthesis, Vol. 9 (Fully 

I 



aUnsaturated Small-Ring Heterocycles and Monocyclic Five-Membered Hetarenes with 

One Heteroatom). The functionalization reactions of monopyrroles are also of key importance 

because approaches to porphyrins via oligopyrroles require that monopyrroles be 

selectively linked to other pyrroles in a rational and unambiguous way. 

17.8.1.1.1 Dipyrroles 

Previously published information regarding this product subclass can be found in Houben–Weyl, 

Vol. E 9b, pp 585–588. 

There are four types of dipyrrole unit that have been used extensively in syntheses of 

porphyrins and their ring-contracted and -expanded derivatives. These are dipyrromethenes 

(usually handled as the highly crystalline hydrobromide salts 23), dipyrromethanes 

24, dipyrroketones 25, and bipyrroles 26 (Scheme 8). An added level of complexity 

is related to whether or not the dipyrroles are symmetrically substituted about 

some central point in the molecule (e.g., the 5-position in 23–25). For the purposes of generality 

in the syntheses of porphyrins, the unsymmetrically functionalized dipyrroles are 

clearly the most useful; it also follows that they are the most difficult to prepare. Unsymmetrical 

dipyrromethenes and dipyrromethanes are invariably approached using methodology 

that employs differential protection of substituents on the two constituent pyrrole 

rings. Symmetrical examples, on the other hand, can often be obtained by some kind 

of self-condensation of a monopyrrole, or by treatment of two moles of a monopyrrole 

with a one-carbon reagent which will provide the 5-carbon. Both types of approach will 

be discussed here. In the case of bipyrroles 26, which are not actually synthetic precursors 

of normal porphyrin systems, only symmetrical routes have been developed to date. 

Scheme 8 Common Dipyrrolic Intermediates 

R 2 

R 2 

R 3 R 4 

R 

NH HN 

5 

R1 R6 + 

Br − 

R 3 R 4 

NH HN 

R 1 R 6 

24 

17.8.1.1.1.1 Method 1: 

Dipyrromethenes 

R 5 

R 2 

23 


R 2 

R3 R4 O 

NH HN 

R 1 R 6 

25 

R 3 R 4 

R 

NH HN 

5 

R1 R6 + 

Br − 

For historical reasons, dipyrromethene synthesis will be dealt with first, though they are 

little used in contemporary porphyrin synthesis. 

17.8.1.1.1.1.1 Variation 1: 

Condensation of 2-Formyl-1H-pyrroles with 2-Unsubstituted 1H-Pyrroles 

The best and most commonly used method for the preparation of unsymmetrically substituted 

dipyrromethenes (e.g., 29) is the condensation of a 2-formyl-1H-pyrrole 27 with a 

2-unsubstituted 1H-pyrrole 28 in the presence of acid; the product is often obtained in virtually 

quantitative yield, provided it is isolated as the salt 29 (Scheme 9). [26] Because of 

R 5 

R2 4 

R 1 

5 

R3 3 

N 

H 

2 2' 

26 

R 4 

3' 

N 

H 

5' 

R5 4' 

R 6


atheir acid–base chemistry, dipyrromethenes tend to spread widely on chromatography 

columns, so crystallization is usually the best method for isolation, and recrystallization 

for purification. 

Scheme 9 Condensation of 2-Formyl-1H-pyrroles with 2-Unsubstituted 1H-Pyrroles [26,27] 

HO2C 

N 

H 

27 

Et 

CHO 

+ 

N 

H 

28 

NH HN 

+ 

Br − 

29 

3-Ethyl-2,8,9-trimethyldipyrromethene-1-carbocylic Acid Hydrobromide (29); Typical 

Procedure: [27] 

4-Ethyl-5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid (27; 2.4 g, 13.25 mmol) and 2,3-dimethyl-1H-pyrrole 

(28; 1.2 g, 12.61 mmol) were suspended in AcOH (6 mL) and treated, after 

cooling, with 48% HBr (2 mL). Scratching the container with a glass rod caused the dipyrromethene 

hydrobromide to crystallize from soln. After 1 h the solid was collected by 

filtration and washed with AcOH/Et 2O. The dipyrromethene salt 29 was obtained by recrystallization 

(AcOH); yield: 3.3 g (77%); mp 1708C. 


HBr 

77% 

Et 

HO 2C 

17.8.1.1.1.1.2 Variation 2: 

Reaction of 2-(Bromomethyl)-1H-pyrroles with 2-Bromo-1H-pyrroles 

Heating of 2-(bromomethyl)-1H-pyrroles, e.g. 31 (obtained in situ by bromination of the 

corresponding 2-methyl-1H-pyrrole 30), with the same 2-bromo-1H-pyrrole 30 (synthesized 

by bromination of 2-unsubstituted 1H-pyrrole 32) and bromine affords good yields 

of dipyrromethene hydrobromides 33 (Scheme 10). [28] 

Scheme 10 Reaction of 2-(Bromomethyl)-1H-pyrroles with 2-Bromo-1H-pyrroles [28] 

Br 

Br 

N 

H 

30 

N 

H 

31 

Br 2 

CO2Et 

CO2Et 

Br 

+ 

Br 

N 

H 

32 

N 

H 

30 

Br 2 

CO2Et 

CO2Et 

Br 2, AcOH 

37% 

EtO2C 

Br 

NH HN 

+ 

Br − 

33 

CO 2Et 

Diethyl 1-Bromo-2,7,9-trimethyldipyrromethene-3,8-dicarboxylate Hydrobromide (33); 

Typical Procedure: [28] 

Ethyl 5-bromo-2,4-dimethyl-1H-pyrrole-3-carboxylate (30; 1.2 g, 4.88 mmol) was dissolved 

in AcOH and treated with Br 2 (0.8 g, 5.00 mmol). The soln turned red and HBr gas was given 

off. The solid product was collected by filtration and washed with EtOH then Et 2O. Recrystallization 

(acetone/H 2O) gave 33; yield: 0.66 g (37%); mp >2608C. 



a17.8.1.1.1.1.3 Variation 3: 

Self-Condensation of Monopyrroles 

Very useful dipyrromethenes, the so-called “brominated kryptodipyrromethenes” 35 and 

36, can be obtained by treatment of kryptopyrrole 34 with bromine in hot acetic acid 

(Scheme 11). [29] If the 2-tert-butyl ester 1H-pyrrole 37 is used, [30] dipyrromethene 36 can 

be obtained pure. These dipyrromethene salts can be separated by crystallization (based 

upon the relative insolubility of the perbromide salt 35), or used as a mixture in formic 

acid for the synthesis of etioporphyrin I (see Section 17.8.1.2). 

Dipyrromethenes (e.g., 39) which are symmetrically substituted about the 5-(meso)carbon 

are prepared by self-condensation of 2-unsubstituted 1H-pyrroles 38 (R 1 =H) or 

1H-pyrrole-2-carboxylic acids 38 (R 1 =CO 2H) in boiling formic acid containing hydrobromic 

acid. [31] 

Scheme 11 Self-Condensation of Monopyrroles [29–33] 

Et 

Et 

Et 

N 

H 

34 

N 

H 

37 

N 

H 

CO2Bu t 

R 1 

38 R 1 = H, CO2H 

Br 2, AcOH, heat 

Br 2, Et 2O 

56−70% 

1. HCO2H, heat 

2. HBr 

R1 = H 37% 

Et 

NH HN 

+ 

Br − 


Et 

Br 

35 

Et 

Br 

NH HN 

+ 

Br − 

36 

Et 

Br 

Et Et 

NH HN 

+ 

Br − 

39 

+ 

Et 

Br 

NH HN 

+ 

Br − 

1-Bromo-9-(bromomethyl)-3,8-diethyl-2,7-dimethyldipyrromethene Hydrobromide (36); 


A rapidly stirred soln of tert-butyl 4-ethyl-3,5-dimethyl-1H-pyrrole-2-carboxylate (37; 20g, 

89.6 mmol) in Et 2O (600 mL) was treated with Br 2 (4.8 mL, 93.4 mmol) in Et 2O (400 mL), 

adding the Br 2 soln over a period of 2 or 3 min. The soln was stirred for a further 30 min 

and then added dropwise over a period of 1 h to a stirred soln of Br 2 (9.6 mL, 187.1 mmol) 

in Et 2O (800 mL). After 30 min the mixture was placed in a refrigerator and left overnight. 

The product was collected by filtration, washed with ice-cold Et 2O, and then dried in vacuo 

to give 36; yield: 12–15 g (56–70%); mp >300 8C. 

2,8-Diethyl-3,7-dimethyldipyrromethene Hydrobromide (39); Typical Procedure: [32,33] 

3-Ethyl-4-methyl-1H-pyrrole (38, R 1 = H; 3 g, 27.5 mmol) was treated with dry HCO 2H 

(30 mL) and heated for 5 min on a boiling water bath. After cooling, the mixture was treated 

with aq HBr (6 mL) and left to stand for 12 h. The product 39 was collected by filtration; 

yield: 1.57 g (37%); mp 1708C 

36 

Et 

Br


a17.8.1.1.1.1.4 Variation 4: 

Oxidation of Dipyrromethanes 

Controlled oxidation of dipyrromethanes 40, for example with iron(III) chloride or bromine, 

[26,34] also provides a convenient route to dipyrromethenes 41 (Scheme 12). The bromine-promoted 

oxidation method has also been widely used for the identification of dipyrromethanes 

on analytical thin-layer chromatography plates; exposure of a developed 

plate to bromine vapor causes colorless dipyrromethanes to turn red-pink (dipyrromethene 

salt) thereby enabling their identification in mixtures of products. 

Scheme 12 Oxidation of Dipyrromethanes [26,34] 

R 2 

R 3 

NH HN 

40 

R 4 

R 1 R 6 

17.8.1.1.1.2 Method 2: 

Dipyrromethanes 

R 5 

FeCl3 or Br2 


R 2 

R 3 

R 

NH HN 

5 

+ 

X − 

R1 R6 17.8.1.1.1.2.1 Variation 1: 

Unsymmetrically Substituted Dipyrromethanes by Reaction of 2-Substituted 

1H-Pyrroles with 2-Unsubstituted 1H-Pyrroles 

Unsymmetrically substituted dipyrromethanes, e.g. 44, can be prepared by condensation 

of 2-(acetoxymethyl)-1H-pyrroles 42 with 2-unsubstituted 1H-pyrroles 43 in methanol or 

acetic acid containing a catalytic amount (


aScheme 13 Unsymmetrically Substituted Dipyrromethanes by Reaction of 2-Substituted 

1H-Pyrroles with 2-Unsubstituted 1H-Pyrroles [35,38–43] 

BnO 2C 

BnO2C 

R 1 

R 1 

R 1 

R 2 

R 2 

R 2 

Et 

N 

H 

47 

N 

H 

50 

N 

H 

42 

N 

Me 

45 

R 3 

R 3 

CO 2Me 

Et 

SePh 

Br 

OAc 

OAc 

+ 

+ 

+ 

Et 

Et 

N 

H 

43 

N 

H 

43 

R 4 R 5 

N 

H 

48 

R 6 

CO 2Bn 

CO2Bn 

R 4 R 5 

A B 

HO2C A 

N 

H 

51 

py 

R 3 

+ 

N 

Br − 

+ 

LiO 2C 

N 

H 

52 

R 4 R 5 

B 

N 

H 

53 

LiOMe 

MeOH 

TsOH, MeOH 

MeO 2C 

BnO2C 

NH HN 


93% 

K-10 clay 

CH2Cl2 90% 

A: CuOTf•benzene 

CH2Cl2, −78 oC B: benzene, heat 

R 6 

R 6 

heat 

Et 

BnO 2C 

R 2 

R 2 

R 1 

R 1 

Et 

R 3 

R 3 

44 

NMe HN 

46 

NH HN 

49 

A B 

NH HN 

54 

Et 

Et 

R 4 

R 4 

CO2Bn 

CO 2Bn 

Dibenzyl 7-Ethyl-3-[2-(methoxycarbonyl)ethyl]-2,8-dimethyldipyrromethane-1,9-dicarboxylate 

(44); Typical Procedure: [35] 

A suspension of benzyl 5-(acetoxymethyl)-4-[2-(methoxycarbonyl)ethyl]-3-methyl-1H-pyrrole-2-carboxylate 

(42; 373 mg, 1.0 mmol) and benzyl 4-ethyl-3-methyl-1H-pyrrole-2-carboxylate 

(43; 243 mg, 0.95 mmol) in MeOH (5 mL) was treated with TsOH (10 mg) and heated 

at 408C under N 2 with stirring for 5 h. The soln was diluted with H 2O (0.5 mL) and the 

dipyrromethane was collected by filtration. Recrystallization (CH 2Cl 2/hexanes) gave 44; 

yield: 520 mg (93%); mp 89–90 8C. 

Dibenzyl 2,3,7-Triethyl-N A,8-dimethyldipyrromethane-1,9-dicarboxylate (46); Typical 


Benzyl 5-(acetoxymethyl)-3,4-diethyl-1-methyl-1H-pyrrole-2-carboxylate (45; 1.70 g, 

4.95 mmol) was added to a well-stirred soln of benzyl 4-ethyl-3-methyl-1H-pyrrole-2-carboxylate 

(43; 1.20 g, 4.93 mmol) in CH 2Cl 2 (100 mL) containing a suspension of montmorillonite 

K-10 clay (20 g). After being stirred for 30 min the mixture was filtered free from 

R 6 

R 6 

R 5 

R 5


athe clay and concentrated to dryness to afford the dipyrromethane 46 as a viscous oil; 

yield: 2.34 g (90%). 

Dipyrromethanes from 2-[(Phenylselenyl)methyl]-1H-pyrroles and 2-Unsubstituted 1H- 

Pyrroles; General Procedures: [40] 

Using Copper(I) Triflate: To a soln of 2-[(phenylselenyl)methyl]-1H-pyrrole (47; 0.2 mmol) 

and 2-unsubstituted 1H-pyrrole (48; 0.21 mmol) in dry degassed CH 2Cl 2 (5 mL) containing 

powdered CaCO 3 (0.24 mmol) at –78 8C under argon was added the benzene complex of 

copper(I) trifluoromethanesulfonate (0.12 mmol) in dry degassed benzene (0.5 mL) (CAU- 

TION: carcinogen). The mixture was stirred for 1–2 min at –788C, then poured into H 2O 

(20 mL), and extracted with CH 2Cl 2 (4 ” 10 mL). The combined organic extracts were washed 

with H 2O (20 mL). The solvent was removed and the product 49 was purified by preparative 

TLC (silica gel, hexanes/Et 2O 1:9). 

Thermal Method: The 2-[(phenylselenyl)methyl]-1H-pyrrole (47; 0.2 mmol) and 2-unsubstituted 

1H-pyrrole (48; 0.21 mmol) were heated in dry degassed benzene (10 mL) 

(CAUTION: carcinogen) under argon for 5 h. The workup was then as above for the copper(I) 

trifluoromethanesulfonate method. 

Dipyrromethanes from Pyrrole Pyridinium Salts and Lithium Carboxylate; General Procedure: 

[42] 

A soln of the 1H-pyrrole-2-carboxylic acid (52; 0.01 mol) and LiOMe (0.38 g, 0.01 mol) in 

warm aq MeOH (100 mL, 50%) was added to the 2-(bromomethyl)-1H-pyrrole (50; 

0.01 mol) in pyridine (3.2 mL, 0.04 mol). The mixture was refluxed on a steam bath for several 

hours under N 2. On cooling to rt the dipyrromethane crystallized and was collected 

by filtration, washed with H 2O, and dried. When ethylene glycol or HCONH 2 was used as 

solvent, the mixture was worked up by dilution with H 2O (ca. 1 L) and extracted with Et 2O 

(4 ” 150 mL). The Et 2O was dried (MgSO 4), concentrated to dryness, and the residue was 

chromatographed [alumina, petroleum ether (bp 60–80 8C)/toluene] to give 54. 

17.8.1.1.1.2.2 Variation 2: 

Unsymmetrically Substituted Dipyrromethanes by Reduction of 

Dipyrromethenes 

Reduction of dipyrromethenes, e.g. 55, with sodium borohydride also furnishes dipyrromethanes 

56 (Scheme 14). [44] Both symmetrical and unsymmetrical dipyrromethenes are 

available; this method is applicable to both. 

Scheme 14 Unsymmetrically Substituted Dipyrromethanes by Reduction of 

Dipyrromethenes [44] 

+ 

H3N CO2Me 

NH HN 

+ 

2Br − 

55 

NaBH4, H2O 

H2N CO2Me 

NH HN 

56 

for references see p 1223 

K. M. Smith and M. G. H. Vicente, Section 17.8, Science of Synthesis, 2003 Georg Thieme Verlag


a2-(2-Aminoethyl)-8-[2-(methoxycarbonyl)ethyl]-3,7-dimethyldipyrromethane (56); Typical 


2-(2-Aminoethyl)-8-[2-(methoxycarbonyl)ethyl]-3,7-dimethyldipyrromethene dihydrobromide 

(55; 1.0 g, 2.08 mmol) in deoxygenated distilled H 2O (60 mL) was treated with 

NaBH 4 (1.7 g, 44.9 mmol) in H 2O (30 mL) while a stream of N 2 was being passed through 

the soln. Effervescence took place and the red dipyrromethene color was immediately discharged. 

CH 2Cl 2 (100 mL) and 10% aq NaHCO 3 (30 mL) were added rapidly and, after separation, 

the organic phase was dried (Na 2SO 4), concentrated to dryness, and used immediately 

in the next reaction (to form the porphyrin in Woodward s chlorophyll a synthesis). 

17.8.1.1.1.2.3 Variation 3: 

Symmetrically Substituted Dipyrromethanes by Self-Condensation of 

2-Substituted 1H-Pyrroles 

Dipyrromethanes 59 which are symmetrically substituted about the 5-carbon are obtained 

in good yield by self-condensation of 2-(bromomethyl)-1H-pyrroles 58 (obtained 

from the corresponding 2-methyl-1H-pyrrole 57 by bromination in diethyl ether) in hot 

methanol, [45] or by heating 2-(acetoxymethyl)-1H-pyrroles 42 [obtained by treatment of 

the corresponding 2-methyl-1H-pyrrole 60 with lead(IV) acetate in acetic acid] in methanol/hydrochloric 

acid to give, for example, 61 [46] (Scheme 15); the mechanism for formation 

of 59 and 61 involves loss of one 2-CH 2X group. 

Scheme 15 Symmetrically Substituted Dipyrromethanes by Self-Condensation of 

2-Substituted 1H-Pyrroles [45–48] 

N 

H 

57 

CO 2Bn 

Br 2, Et 2O 

Br 

MeOH 

heat 

BnO 2C 

NH HN 

59 56% 

CO 2Bn 


N 

H 

58 

CO 2Bn 

MeO2C MeO2C 

N 

H 

60 

CO2Bn 

Pb(OAc) 4 

AcOH 

AcO 

N 

H 

42 

CO2Bn 

BnO 2C 

MeOH, HCl, heat 

88% 

MeO 2C CO2Me 

NH HN 

61 

CO2Bn 

Dibenzyl 2,3,7,8-Tetramethyldipyrromethane-1,9-dicarboxylate (59); Typical 


Benzyl 3,4,5-trimethyl-1H-pyrrole-2-carboxylate (57; 2.0 g, 8.22 mmol) in rapidly stirred 

anhyd Et 2O (45 mL) was treated with Br 2 (0.5 mL, 9.73 mmol) in Et 2O (10 mL). The 2-(bromomethyl)-1H-pyrrole 

58 immediately precipitated from the soln, but the mixture was stirred 

for an additional 1.5 h before evaporation of the Et 2O(CAUTION: HBr gas) to give an 

orange residue of benzyl 5-(bromomethyl)-3,4-dimethyl-1H-pyrrole-2-carboxylate (58).


aThe solid was dissolved in MeOH (25 mL) and refluxed for 4 h, then set aside at rt overnight. 

The product 59 was collected by filtration and recrystallized (CH 2Cl 2/petroleum 

ether); yield: 1.1 g (56%); mp 178–1798C. 

Dibenzyl 3,7-Bis[2-(methoxycarbonyl)ethyl]-2,8-dimethyldipyrromethane-1,9-dicarboxylate 


Benzyl 5-(acetoxymethyl)-4-[2-(methoxycarbonyl)ethyl]-3-methyl-1H-pyrrole-2-carboxylate 

(42; 320 mg, 0.857 mmol) in MeOH (5 mL) and HCl (d 1.18; 0.3 mL) was heated on a 

water bath for 4 h. After cooling the dipyrromethane 61 was collected by filtration; yield: 

230 mg (88%); mp 99–1008C. 

17.8.1.1.1.2.4 Variation 4: 

Symmetrically Substituted Dipyrromethanes from 2-Unsubstituted 

1H-Pyrroles 

2-Unsubstituted 1H-pyrroles such as 62, when treated with formaldehyde, give dipyrromethanes, 

e.g. 63. [49,50] A general method for 5-alkyldipyrromethane synthesis is available; 

[51] high yields of dipyrromethanes 64 and 65 can be obtained by using a 2-unsubstituted 

monopyrrole (e.g., 43 or 62, respectively) with dimethylacetals of aliphatic aldehydes 

and an acid catalyst (Scheme 16). 5-Substituted dipyrromethanes (usually 5-aryl derivatives, 

e.g. 66) can also be synthesized by treatment of an aldehyde (e.g., benzaldehyde) 

with an excess of 2-unsubstituted 1H-pyrrole (e.g., pyrrole) and an acid catalyst. [52] 

Scheme 16 Symmetrically Substituted Dipyrromethanes from 2-Unsubstituted 1H- 

Pyrroles [39,49–52] 

Et Et 

Et 

N 

H 

62 

N 

H 

43 

Et Et 

N 

H 

N 

H 

62 

CO 2Et 

CO2Bn 

CO2Et 

HCHO 

MeO 

PhCHO, TFA (cat.) 

49% 

OMe 

77% 

Et 

CO 2Me 

TsOH, toluene, heat 

OMe 

MeO CO 2Me 

EtO 2C 

NH HN 


Et 

TsOH, K-10 clay, 1,4-dioxane, 70 o C 

66% 

Ph 

NH HN 

66 

63 

BnO 2C 

Et 

Et 

Et 

CO 2Et 

NH HN 

Et 

64 

EtO 2C 

CO2Me 

Et 

Et 

CO 2Bn 

CO2Me 

Et 

NH HN 

65 

Et 

CO 2Et 



aDibenzyl 3,7-Diethyl-5-[(methoxycarbonyl)methyl]-2,8-dimethyldipyrromethane-1,9-dicarboxylate 


Benzyl 4-ethyl-3-methyl-1H-pyrrole-2-carboxylate (43; 3.31g, 13.6 mmol) in toluene 

(50 mL) was treated with TsOH (326 mg) and methyl 3,3-dimethoxypropanoate (1.0 mL, 

7.05 mmol). The mixture was heated at 120 8C for 5 h then CH 2Cl 2 was added and the organic 

layer washed with H 2O, brine, and then dried (Na 2SO 4). The solvent was removed 

under reduced pressure and the residue was flash chromatographed (silica gel, EtOAc/cyclohexane 

first 1:9, increasing to 1:5) to give 64 as a yellow foam; yield 2.98 g (77%). 

Diethyl 5-(Methoxycarbonyl)-2,3,7,8-tetraethyldipyrromethane-1,9-dicarboxylate (65); 


Ethyl 3,4-diethyl-1H-pyrrole-2-carboxylate (62; 632 mg, 3.24 mmol) in 1,4-dioxane (7 mL) 

was treated with methyl dimethoxyacetate (0.15 mL, 3.24 mmol) and TsOH/K-10 clay (see 

below; 3 g). The mixture was stirred at 708C for 5 h before filtering off the clay. Evaporation 

of the filtrate gave a residue which was dissolved in CH 2Cl 2 and washed with aq NaH- 

CO 3 and then with brine. After drying (Na 2SO 4) the solvent was removed to give an oil 

which was then chromatographed (silica gel, CH 2Cl 2 then increasing amounts of THF). 

The appropriate eluates were collected and concentrated to give the product, which was 

crystallized (CHCl 3) to give 65; yield: 493 mg (66%); mp (slowly melts) 169–2118C. 

TsOH/K-10 clay: Dioxane (1 L) was saturated with TsOH. Montmorillonite K-10 clay 

was added until the mixture almost became too stiff to stir with a stirrer bar. The mixture 

was stirred overnight and then concentrated to dryness. The residual mixture was suspended 

in CH 2Cl 2 and then filtered and rinsed with THF and 1,4-dioxane to remove the 

excess of non-adsorbed TsOH from the clay. The clay was dried overnight in a vacuum 

oven at 528C. 

5-Phenyldipyrromethane (66); Typical Procedure: [52] 

A soln of benzaldehyde (0.1 mL, 1 mmol) and 1H-pyrrole (2.8 mL, 40 mmol) was degassed 

by bubbling argon through it for 10 min and then treated with TFA (0.008 mL, 0.1 mmol). 

The soln was stirred for 15 min at rt (TLC monitoring), before being diluted with CH 2Cl 2 

(50 mL), washed with 0.1 M aq NaOH and H 2O, and then dried (Na 2SO 4). The solvent was 

removed under reduced pressure, and unreacted 1H-pyrrole was removed by vacuum distillation 

at rt. The resulting yellow amorphous solid was dissolved in a small amount of 

the eluent and then purified by flash chromatography [silica gel (230–400 mesh), cyclohexane/EtOAc/Et 

3N 80:20:1). The dipyrromethane-containing fractions were collected 

and evaporated to give 66; yield: 110 mg (49%); mp 100–1018C. 

17.8.1.1.1.3 Method 3: 

Dipyrroketones 

The most efficient method for the synthesis of unsymmetrical dipyrroketones (e.g., 68, 

R 1 = O) involves a modification of the Vilsmeier–Haack reaction. Condensation of the 

phosphoryl chloride complex of a pyrrole N,N-dimethylcarboxamide 67 with a nucleophilic 

2-unsubstituted 1H-pyrrole (e.g., 34) followed by hydrolysis of the intermediate 

imine salt 68 (R 1 =NMe 2 + Cl – ) gives the dipyrroketone 68 (R 1 = O) in very good yield 

(Scheme 17). [53] Alternatively, treatment of a pyrrole acid chloride 69 with a pyrrole Grignard 

derivative 70 (or with the 2-unsubstituted 1H-pyrrole in the presence of a Friedel– 

Crafts catalyst) gives dipyrroketones 71 [53,54] (Scheme 17). 

Symmetrically substituted dipyrroketones (e.g., 73) are generally obtained by treatment 

of pyrrole Grignard reagents 72 with phosgene, [55] or, for example in the preparation 

of 76, by oxidative hydrolysis of dipyrrothiones 75, which can in turn be obtained 

directly from 2-unsubstituted 1H-pyrroles 74 by treatment with thiophosgene (Scheme 

17). [56] 



aOxidation of dipyrromethanes (e.g., 77) with lead(IV) oxide, lead(IV) acetate, [57] sulfuryl 

chloride, or bromine/sulfuryl chloride [58] also gives good yields of dipyrroketones 78. 

Reduction of dipyrroketones 78 with sodium amalgam [57] or diborane yields the corresponding 

dipyrromethanes 77. 

Scheme 17 Dipyrroketone Syntheses [53–57] 

Et 

BnO2C CONMe2 

N 

H 

67 

EtO2C 

N 

COCl 

H 

Et 

N 

H 

74 

N 

H 

72 

69 

Et 

MgX 

S 

Cl Cl 

benzene 

EtOH 

64% 

+ 

O 

XMg 

Cl Cl 

EtO2C CO 2Et 

EtO2C CO 2Et 

NH HN 

EtO 2C CO2Et 

77 

1. POCl3 

Et 

2. 

, CH2Cl2 

N 

H 

34 

N 

H 

70 

80% 

BnO2C 

NH HN 

68 R 1 = O, NMe 2 + Cl − 


Et 

O 

Et 

EtO 2C 

Et Et 

NH HN 

S 

NH HN 

75 

Pb(OAc) 4, PbO 2 

62% 

Zn/Hg or B 2H 6 

Zn/Hg: 20% 

73 

KOH, H 2O 2 

EtOH 

71% 

Et 

R 1 

NH HN 

78 

O 

NH HN 

71 

EtO2C CO2Et 

O 

Et 

NH HN 

76 

EtO2C CO 2Et 

O 

EtO2C CO2Et Benzyl 3,8-Diethyl-2,7,9-trimethyl-5-dipyrroketone-1-carboxylate (68,R 1 = O); Typical Procedure: 

[53] 

Benzyl 5-[(dimethylamino)carbonyl]-4-ethyl-3-methyl-1H-pyrrole-2-carboxylate (67; 10g, 

31.81 mmol) was dissolved in POCl 3 (15 mL) and stirred until the absorption at 374 nm 

was maximized (e 15,000). The excess of POCl 3 was removed by concentration under reduced 

pressure, then 1,2-dibromoethane (10 mL) was added and the soln concentrated to 

Et 



aremove the last traces of POCl 3. The oily product was dissolved in CH 2Cl 2 (15 mL) and 3ethyl-2,4-dimethyl-1H-pyrrole 

(34; 4.35 g, 35.31 mmol) in CH 2Cl 2 (15 mL) was added. After 

stirring until the absorption at 402 nm was maximized (e 7900), NaOAc (60 g) in H 2O 

(100 mL) was added and the mixture was refluxed with vigorous stirring for 2 h. The mixture 

was cooled, the organic layer was separated, and the aqueous layer was extracted 

with CHCl 3. The combined organic phases were washed with aq Na 2CO 3 (10%) and H 2O, 

dried (MgSO 4), and concentrated to dryness. The dark oil crystallized when triturated 

with MeOH, and the product was recrystallized (CHCl 3/petroleum ether) to give the product; 

yield: 9.7 g (80%); mp 1828C. 

1,2,3,7,8,9-Hexamethyl-5-dipyrroketone (76); Typical Procedure: [56] 

CAUTION: Thiophosgene is a severe respiratory irritant and very toxic by inhalation. 

A stirred soln of 2,3,4-trimethyl-1H-pyrrole (74; 5.0 g, 45.8 mmol) in Et 2O (100 mL) was 

treated dropwise at 0 8C with a soln of thiophosgene (1.78 mL) in benzene (20 mL) (CAU- 

TION: carcinogen). The mixture was stirred for 10 min before addition of aq EtOH (90%, 

100 mL) and stirring for another 30 min at rt. The mixture was concentrated to give a crystalline 

residue, which was recrystallized (aq EtOH) to give the dipyrrothione 75; yield: 

3.8 g (64%); mp 205–2078C. The thione 75 (50 mg, 0.19 mmol) in EtOH (95%, 10 mL) containing 

KOH (0.1 g) was treated with aq H 2O 2 (5%, 1 mL) and then heated on a steam bath 

for 5 min. H 2O (30 mL) was added and the mixture was extracted with CHCl 3 (3 ” 5 mL). 

Evaporation of the solvent gave a residue, which was purified by sublimation (2008C/ 

1 Torr) to give the dipyrroketone 76; yield: 33 mg (71%); mp 219–2218C. 

Diethyl 3,7-Bis[2-(ethoxycarbonyl)ethyl]-2,8-bis[(ethoxycarbonyl)methyl]-5-dipyrroketone-1,9-dicarboxylate 


A soln of diethyl 3,7-bis[2-(ethoxycarbonyl)ethyl]-2,8-bis[(ethoxycarbonyl)methyl]dipyrromethane-1,9-dicarboxylate 

(77; 2.0 g, 3.02 mmol) in AcOH (75 mL) was treated with 

Pb(OAc) 4 (2.9 g, 6.54 mmol) and stirred at rt for 4 d. PbO 2 (90%, 2.3 g, 8.65 mmol) was then 

added and stirring was continued for another 2 d. The mixture was centrifuged and the 

supernatant was poured into ice water (500 mL). The colorless precipitate was separated, 

washed with H 2O, dissolved in Et 2O, and then washed successively with H 2O, 5% aq NaH- 

CO 3, and H 2O, and then dried (Na 2SO 4). After concentration, crystals separated; these were 

then recrystallized (Et 2O) to give 78; yield: 1.27 g (62%); mp 152.5–153.5 8C. 

Diethyl 3,7-Bis[2-(ethoxycarbonyl)ethyl]-2,8-bis(ethoxycarbonylmethyl)dipyrromethane- 

1,9-dicarboxylate (77); Typical Procedure: [57] 

Diethyl 3,7-bis[2-(ethoxycarbonyl)ethyl]-2,8-bis(ethoxycarbonylmethyl)-5-dipyrroketone- 

1,9-dicarboxylate (78; 668 mg, 0.99 mmol) in EtOH (5 mL) was added to H 2O (1 mL) and 

concd HCl (1 mL) and Zn amalgam (780 mg). The mixture was refluxed for 3 h, cooled, 

and then filtered. The soln was concentrated and then refrigerated to give crystals of the 

dipyrromethane 77; yield: 146 mg (20%), mp 948C. 

17.8.1.1.1.4 Method 4: 

Bipyrroles 

Bipyrroles 26 are not used in porphyrin syntheses because they contain a direct pyrrole– 

pyrrole link. However, this direct link is present in corroles, which will be discussed later 

in the chapter. Bipyrroles are prepared using a variation [59–61] of the Ullmann reaction, in 

which treatment of iodopyrrole 79 with copper affords the symmetrical bipyrrole 80 in 

ca. 60% yield (Scheme 18). The yields in this Ullmann approach have been improved [62] by 

the use of iodopyrroles (e.g., 81), which are functionalized with electron-withdrawing 



agroups on the ring nitrogen (to give 82). Thus, treatment of 82 with copper powder in dimethylformamide 

at 1108C affords bipyrroles 83, which then can be pyrolyzed to give a 

good overall yield of bipyrroles 84. 

Scheme 18 Bipyrrole Synthesis [59–62] 

EtO 2C 

EtO 2C 

N 

H 

79 

R 1 R 2 

N 

H 

81 

CO2Et 

I 

I 

Cu powder, DMF, 110 o C 

Cu bronze, DMF, rt, 17 h 

63% 

DMAP, CH 2Cl 2, (t-BuO 2C) 2O 

EtO 2C 

EtO2C 


R 1 

R 2 

EtO 2C 

R 2 

N 

H 

N 

CO2Et 

N 

H 

80 

R 1 R 2 

R 1 

82 

R 1 

EtO 2C 

CO 2Bu t 

EtO 

N N 

2C 

CO2Et Bu 

83 

tO2C CO2But I 

N 

H 

R 2 

CO 2Et 

heat 

R 2 

N 

H 

84 65−83% 

R 1 

CO 2Et 

Tetraethyl 4,4¢-Dimethyl-2,2¢-bipyrrole-3,3¢,5,5¢-tetracarboxylate (80); Typical Procedure: 

[59] 

Diethyl 5-iodo-3-methyl-1H-pyrrole-2,4-dicarboxylate (79; 10.0 g, 28.48 mmol) in DMF 

(50 mL) was treated with powdered Cu bronze (10 g) and stirred at rt for 17 h. The Cu 

bronze was separated off and washed with hot CHCl 3 (4 ” 50 mL). The filtrate and washings 

were then washed with aq 1 M HCl (2 ” 100 mL), and H 2O (2 ” 100 mL), then dried. 

The solvent was removed under reduced pressure and the crude product was triturated 

with petroleum ether (bp 60–80 8C; 30 mL). The product was collected by filtration, washed 

with petroleum ether (bp 60–80 8C; 2 ” 15 mL), and then dried at 80 8C, to give 80; yield: 

4.04 g (63%); mp 178–1808C. 

Bipyrrole Synthesis Using the Modified Ullmann Reaction; General Procedure: [62] 

The 2-iodo-1H-pyrrole (81; 0.01 mol) and DMAP (0.10 equiv) were mixed with di-tert-butyl 

dicarbonate (1.2 equiv) in dry CH 2Cl 2 (50 mL). The mixture was then passed through a 

short plug of silica gel, eluting with CH 2Cl 2. After evaporation, the residual oil 82 was dissolved 

in DMF (20 mL) under N 2 and then treated with Cu powder (4.7 equiv); after heating 

at 110 8C in an oil bath until iodopyrrole could no longer be detected (TLC monitoring), 

the mixture was cooled to rt, and filtered through Celite (to remove Cu residues). The Celite 

was washed with hot CHCl 3 until eluates were clear, and the combined organic phases 

were washed with 10% aq HCl (” 3), 10% aq Na 2S 2O 3 (” 3), sat. aq NaHCO 3, and then with 

sat. aq NaCl. The organic phase was dried (Na 2SO 4) and concentrated to give the bipyrrole 



a83. This solid was heated under an inert atmosphere at 1808C until gas evolution ceased. 

The cooled solidified glass was recrystallized (hot EtOH or hexanes) to give 84; yield: 65– 

83%. 

17.8.1.1.2 Tripyrroles 


Vol. E 9d, pp 588–590. 

The tripyrroles most often used in porphyrin syntheses are the so-called tripyrranes 

86, which possess three pyrrole rings joined by two methylene groups (Scheme 19); tripyrrenes 

85 are non-nucleophilic on the dipyrromethene side. Tripyrranes have been obtained 

from tripyrrenes by reduction. 

Scheme 19 Unsymmetrical Tripyrranes 

R 5 

R 6 

R 4 R 3 

R 7 

NH HN 

X − 

+ 

NH 

R 8 

85 

R 1 

R 2 

reduction 

17.8.1.1.2.1 Method 1: 

The [2+1] Approach to Tripyrranes 

NH HN 


R 5 

R 6 

R 4 R 3 

Tripyrrane 88 is obtained in 35% yield by treatment of a dipyrromethane 87 (R 1 = H) with a 

2-(acetoxymethyl)-1H-pyrrole 42 (Scheme 20). [35,63] The tripyrrene 91 was employed as an 

intermediate in the synthesis of tripyrrane 92; this was subsequently used in the synthesis 

of a pentapyrrolic sapphyrin. [64] Treatment of the dipyrromethane 89 [35] with the 2formyl-1H-pyrrole 

90 afforded the tripyrrene dibenzyl diester 91 in excellent yield. Catalytic 

hydrogenation to tripyrrane caused debenzylation of the esters as well as reduction 

of the dipyrromethene link. The unstable tripyrrane 92, however, was not characterized 

(Scheme 20). [64] Reduction of the methene link has also been achieved by MacDonald and 

co-workers using sodium borohydride. [37] The route used to prepare tripyrrane 88 is also 

capable of yielding tripyrranes with an unsymmetrical array of substituents, as is the approach 

to 92. 

R 7 

NH 

R 8 

86 

R 1 

R 2


aScheme 20 Unsymmetrical Tripyrranes by the [2 +1] Approach [35,63,64] 

MeO 2C 

MeO2C 

NH 

NH 

87 R 1 = H, CO 2t-Bu 

NH 

NH 

89 

CO2Bn 

+ 

R 1 

CO 2Bn 

OHC 

+ 

N 

H 

90 

MeO 2C 

AcO 

CO2Bn 

MeOH, TsOH (cat.) 

NH HN 


N 

H 

42 

CO 2Bn 

MeO2C 

MeO2C 

HCl 

H 2, Pd/C 

35% 

NH 

88 

CO2Bn 

NH HN 

Cl − + 

NH 

CO2Bn 

91 

NH HN 

NH 

CO 2H 

92 

CO 2Me 

CO 2Bn 

CO 2Bn 

Dibenzyl 3,7,12-Tris[2-(methoxycarbonyl)ethyl]-2,8,13-trimethyltripyrrane-1,14-dicarboxylate 


Benzyl 9-tert-(butoxycarbonyl)-3,7-bis[2-(methoxycarbonyl)ethyl]-2,8-dimethyldipyrromethane-1-carboxylate 

(87, R 1 =CO 2t-Bu; 290 mg, 0.498 mmol) was dissolved in TFA 

(4 mL) and the soln was set aside at rt for 30 min while a stream of N 2 was passed through 

it. The solvent was removed under reduced pressure and the residual oil was dissolved in 

CH 2Cl 2, washed with sat. aq NaHCO 3, and dried (Na 2SO 4). The solvent was removed under 

reduced pressure to leave 87 (R 1 = H) as an oil. This was treated with benzyl 5-(acetoxymethyl)-4-[2-(methoxycarbonyl)ethyl]-3-methyl-1H-pyrrole-2-carboxylate 

(42; 186 mg, 

0.498 mmol) and TsOH (9 mg) in MeOH (4 mL). This mixture was warmed at 358C with stirring 

for 5 h before being cooled to rt and then neutralized with a few crystals of 

CO2H 



aNaOAc•3H 2O. The tripyrrane was collected by filtration and recrystallized (Et 2O/hexanes) 

to give 88; yield: 140 mg (35%); mp 97–99 8C. 

17.8.1.1.2.2 Method 2: 

The [1]+[1] 2 Approach to Symmetrical Tripyrranes 

The classical route to tripyrranes is that discovered by Sessler and co-workers. [65,66] In its 

present state of development it only yields symmetrically substituted tripyrranes, but the 

ease with which tripyrranes can be synthesized using this method far outweighs the apparent 

symmetry limitation. In a typical example, treatment of electron-rich 3,4-diethyl- 

1H-pyrrole with 2 equivalents of a 2-(acetoxymethyl)-1H-pyrrole 93 affords tripyrrane 94 

in excellent yield, presumably via an intermediate dipyrromethane (Scheme 21). Catalytic 

debenzylation then affords the tripyrrane-1,14-dicarboxylic acid 95 (R 1 =CO 2H), which is 

chemically equivalent to the corresponding 1,14-di-unsubstituted derivative 95 (R 1 =H). 

Scheme 21 Unsymmetrical Tripyrranes by the [1]+[1] 2 Approach [65,66] 

Et Et 

N 

H 

93 

82% 

+ 

AcO 

Et 

Et 

Et 

N 

H 

93 

NH HN 

NH 

CO 2Bn 

Et Et 

CO 2Bn 

94 

CO2Bn 

TsOH, EtOH 

60 oC, 8 h 

H 2, Pd/C, THF 

R 1 = CO2H 100% 

NH HN 


Et 

Et 

Et 

Et Et 

NH HN 

NH 

CO 2Bn 

Et Et 

R 1 

95 R 1 = H, CO 2H 

Dibenzyl 3,7,8,12-Tetraethyl-2,13-dimethyltripyrrane-1,14-dicarboxylate (94); Typical 


3,4-Diethyl-1H-pyrrole (0.6 g, 4.9 mmol), benzyl 5-(acetoxymethyl)-4-ethyl-3-methyl-1Hpyrrole-2-carboxylate 

(93; 2.5 g, 7.9 mmol), and TsOH (0.15 g) were dissolved in abs EtOH 

(60 mL) and heated at 608C for 8 h under N 2. The resulting suspension was reduced in volume 

to 30 mL and then placed in a freezer for several hours. The product was collected by 

filtration, washed with a small amount of cold EtOH, and recrystallized (CH 2Cl 2/EtOH) to 

give 94 as a white powder; yield: 2.07 g (82%); mp 211 8C. 

3,7,8,12-Tetraethyl-2,13-dimethyltripyrrane-1,14-dicarboxylic Acid (95,R 1 =CO 2H); Typical 


Dibenzyl 3,7,8,12-tetraethyl-2,13-dimethyltripyrrane-1,14-dicarboxylate (94; 4.5g, 

7.1 mmol) in THF (500 mL) containing Et 3N (1 drop) was hydrogenated over 5% Pd/C 

(250 mg) at 1 atm of H 2 until TLC indicated completion of the reaction. The catalyst was 

separated by filtration and the filtrate was concentrated to dryness on a rotary evaporator. 

The residue was crystallized (CH 2Cl 2/hexanes) to give 95 (R 1 =CO 2H) as an unstable 

white powder; yield: 3.2 g (100%); mp 111–1158C. 

R 1


a17.8.1.1.3 Open-Chain Tetrapyrrolic Intermediates 


Vol. E 9d, pp 590–596. 

Open-chain tetrapyrrole intermediates for use in porphyrin syntheses can potentially 

exist in a variety of different forms; these are bilanes 96, a-bilenes 97 and b-bilenes 98, 

a,b-biladienes 99 and a,c-biladienes 100, and a,b,c-bilatrienes 101 (Scheme 22). However, 

not all open-chain tetrapyrroles can be employed effectively. Among the bilane group, 

only the a-oxo- and b-oxobilanes (102 and 103, respectively) are useful. The only types of 

bilene to be used for syntheses of pure porphyrins are the b-bilenes 98; a,c-biladienes 100 

have been shown to be the only useful biladienes (and in fact have been the most useful of 

all open-chain tetrapyrroles). a,b,c-Bilatrienes 101, though proposed to be intermediates 

in the syntheses of porphyrins via b-bilenes and a,c-biladienes, have not been used routinely 

as intermediates in porphyrin synthesis. 

Scheme 22 Open-Chain Tetrapyrroles 

R 2 

R 3 

R 2 

R 3 

R 2 

O 

R 3 

R 1 R 8 

R 4 

NH HN 

a c 

NH HN 

b 

96 

R 5 

R 1 R 8 

R 4 

N HN 

NH N 

99 

R 5 

R 1 R 8 

R 4 

NH HN 

NH HN 

102 

R 5 

R 7 

R 6 

R 7 

R 6 

R 7 

R 6 

R 2 

R 3 

R 2 

R 3 

R 2 

R 3 

R 1 R 8 

R 4 

NH HN 

N HN 


97 

N HN 

NH N 

R 5 

R 1 R 8 

R 4 

100 

R 5 

R 1 R 8 

R 4 

NH HN 

NH HN 

O 

103 

R 5 

R 7 

R 2 

R 1 R 8 

NH HN 

R 7 

N HN 

R3 R6 R6 R 7 

R 2 

R 4 

98 

NH N 

R 5 

R 1 R 8 

R 7 

N N 

R3 R6 R6 R 7 

R 6 

R 4 

101 

R 5 



a17.8.1.1.3.1 Method 1: 

Oxobilanes 

17.8.1.1.3.1.1 Variation 1: 

a-Oxobilanes 

Making use of one of the dipyrromethane syntheses mentioned earlier (Section 

17.8.1.1.1.2.1), reaction between the pyridinium salt 104 of a 1-(chloromethyl)dipyrroketone 

and the lithium salt 105 of a dipyrromethane-5-carboxylic acid gives a good yield of 

a-oxobilane-1,19-dibenzyl ester 106 (Scheme 23). [67,68] These compounds are easily isolated, 

crystallized, and characterized. 

Scheme 23 Synthesis of a-Oxobilanes [67,68] 

MeO 2C 

N + Cl − 

O 

NH HN 

104 

CO 2Me 

CO2Bn 

MeO 2C 

NH HN 

HCONH2, py, heat CO2Bn 35% 

CO2Bn NH HN 


+ 

− 

O2C CO2Bn Li NH HN 

+ 

MeO 2C CO 2Me 

105 

O 

106 

CO 2Me 

MeO2C CO2Me 

Dibenzyl 3,8,13,17-Tetrakis[2-(methoxycarbonyl)ethyl]-2,7,12,18-tetramethyl-b-oxobilane-1,19-dicarboxylate 


Benzyl 9-(chloromethyl)-3,8-bis[2-(methoxycarbonyl)ethyl]-2,7-dimethyl-5-dipyrroketone- 

1-carboxylate (6.4 g, 11.79 mmol) was dissolved in pyridine (12 mL) with gentle warming 

on a water bath to give 104. 9-(Benzyloxycarbonyl)-3,7-bis[2-(methoxycarbonyl)ethyl]-2,8dimethyldipyrromethane-2-carboxylic 

acid (6.92 g, 13.19 mmol) was suspended in 

HCONH 2 (200 mL), LiOMe (502 mg, 13.21 mmol) was added, and the suspension was shaken 

until the solid had dissolved to give 105. The reactants were combined and the resulting 

clear amber soln was heated at 50 8C under N 2 for 18 h. An oil slowly deposited during 

heating to form a viscous lower layer. After a further 17 h at rt under N 2, the oil had partially 

solidified and the supernatant liquid was decanted. The gummy deposit was washed 

with H 2O and dissolved in CH 2Cl 2. The soln was washed with H 2O, dried (MgSO 4), and concentrated 

in vacuo. Reconcentration of the residue with Et 2O (50 mL) under reduced pressure 

yielded a brown foam, which was redissolved in Et 2O (100 mL) and set aside overnight 

under N 2. The crystallized material was collected by filtration, and washed with a 

little ice-cold Et 2O to give 106; yield: 4.07 g (35%); mp 123–1248C.

a17.8.1.1.3.1.2 Variation 2: 

b-Oxobilanes 


b-Oxobilanes can be readily synthesized from dipyrromethane precursors using the Vilsmeier–Haack 

procedure, as was described earlier for the synthesis of simple dipyrroketones 

(Section 17.8.1.2.1). Thus, the phosphoryl chloride complex of a 1-[(dimethylamino)carbonyl]dipyrromethane 

107 reacts with a 1-unsubstituted dipyrromethane 87 (R 1 =H) 

to give a good yield of tetrapyrrolic imine salt 108; column chromatography at this stage 

enables the polar imine salt to be obtained in fairly pure form. Hydrolysis then gives the 

b-oxobilane-1,19-dibenzyl ester 109 (Scheme 24). [69] Catalytic debenzylation of 109 then 

gives a quantitative yield of the corresponding 1,19-dicarboxylic acid 110. 

Scheme 24 Synthesis of b-Oxobilanes [69] 

Et 

Me2N 

POCl 3 

CH 2Cl 2 

O 

NH HN 

107 

Et 

Me2N + 

Cl − 

Et 

CO2Bn 

+ 

NH HN 

NH HN 

108 

NH HN 

MeO 2C CO 2Me 

Et 

CO 2Bn 

CO 2Bn 

MeO2C CO 2Me 

87 R 1 = H 

aq Na 2CO 3 

H2, Pd/C 

CO 2Bn 

NH HN 

NH HN 


CH 2Cl 2 

86% 

Et 

O 

Et 

O 

NH HN 

NH HN 

109 45% 

110 

Et 

MeO 2C CO 2Me 

Et 

CO 2Bn 

CO 2Bn 

CO 2H 

CO 2H 

MeO2C CO2Me 

Dibenzyl 3,8-Diethyl-13,17-bis[2-(methoxycarbonyl)ethyl]-2,7,12,18-tetramethyl-b-oxobilane-1,19-dicarboxylate 


Benzyl 3,8-diethyl-9-[(dimethylamino)carbonyl]-2,7-dimethyldipyrromethane-1-carboxylate 

(107; 4.35 g, 9.99 mmol) was dissolved in POCl 3 (40 mL) and kept at 50 8C for 15 min. 

The excess of POCl 3 was removed by distillation under reduced pressure and dry 1,2-dibromoethane 

(10 mL) was added and distilled off to remove the POCl 3. The residual orange-brown 

oil was dissolved in CH 2Cl 2 and mixed with a soln of benzyl 3,7-bis[2-(meth- 



aoxycarbonyl)ethyl]-2,8-dimethyldipyrromethane-1-carboxylate [87, R 1 = H (obtained by 

decarboxylation of the corresponding 1-carboxylic acid); 5.5 g, 11.44 mmol]. The mixture 

was refluxed and a slow stream of N 2 gas was bubbled through it until spectrophotometry 

showed maximal intensity of a peak at 412 nm (e ca. 17,000 after 20–24 h). The mixture 

was washed with H 2O, dried (MgSO 4), and concentrated to dryness, and the residual 

brown oil (containing 108) was chromatographed (neutral alumina, 0–100% EtOAc in toluene). 

The column was finally stripped with MeOH and evaporation of the MeOH eluates 

gave 108 as a yellow oil. The oil was taken up in CH 2Cl 2 (50 mL) and hydrolyzed by vigorous 

refluxing (with stirring) with aq Na 2CO 3 (10%, 50 mL) for 90 min. The organic layer 

was separated and the aqueous phase was washed with CH 2Cl 2 (30 mL). The combined organic 

phases were washed with H 2O and dried (MgSO 4) before evaporation to dryness in 

vacuo. The residual oil, after chromatography [neutral alumina (Brockmann Grade III), 

toluene/EtOAc 4:1] was taken up in boiling MeOH (ca. 20 mL) and on cooling and standing 

overnight at rt, the b-oxobilane 109 was obtained; yield: 3.88 g (45%); mp 167–1698C. 

3,8-Diethyl-13,17-bis[2-(methoxycarbonyl)ethyl]-2,7,12,18-tetramethyl-b-oxobilane-1,19dicarboxylic 

Acid (110); Typical Procedure: [69] 

Dibenzyl 3,8-diethyl-13,17-bis[2-(methoxycarbonyl)ethyl]-2,7,12,18-tetramethyl-b-oxobilane-1,19-dicarboxylate 

(109; 1.0 g, 1.14 mmol) in THF (250 mL) containing Et 3N (0.05 mL) 

was hydrogenated at rt and atmospheric pressure over 10% Pd/C (250 mg) until uptake of 

H 2 had ceased. The catalyst was filtered off and after evaporation of the solvent, the residual 

yellow oil was taken up in warm THF (5 mL), and Et 2O (50 mL) was added. The dicarboxylic 

acid 110 separated as small needles; yield: 700 mg (86%); mp 178–1808C. 

17.8.1.1.3.2 Method 2: 

b-Bilenes 

17.8.1.1.3.2.1 Variation 1: 

1,19-Dimethyl-b-bilenes 

1,19-Dimethyl-b-bilenes can be prepared by two general methods (Scheme 25). The first is 

suited to the synthesis of fully alkylated bilenes, but gives low yields when bilenes bearing 

electron-withdrawing substituents are required; condensation of 2 equivalents of a 

2,3,4-trialkyl-1H-pyrrole (e.g., 74) with one of a 1,9-bis(methoxymethyl)dipyrromethene 

111 affords a b-bilene salt 112, which is usually symmetrical about the 10-carbon 

atom. [70–73] Better is the route in which a 1-formyldipyrromethane 113 is treated with a 1unsubstituted 

dipyrromethane (or with the corresponding 1-carboxylic acid) 114; [74] in 

this way unsymmetrically substituted b-bilenes 115 can be obtained in high yield, but it 

is advisable [75] to have an electronegative group on the terminal rings of the b-bilene in 

order to prevent acid-promoted side reactions which result in mixtures of porphyrins. 

Scheme 25 Syntheses of 1,19-Dimethyl-b-bilenes [70–74] 

Et 

Et 

NH 

+ 

NH 

111 

OMe 

Br − 

OMe 

N 

H 

74 

(2 equiv), HBr, benzene 

84% 

NH HN 

+ 

NH HN 


Et 

Et 

112 

Br −


OHC 

NH HN 

113 

a1. TFA, MeOH 

2. HBr, AcOH 

3. Et3N, CHCl3 Ac 

+ 

R 1 

NH HN 

114 R 1 = H, CO2H 


Ac 

NH HN 

N HN 

7,13-Diethyl-1,2,3,8,12,17,18,19-octamethyl-b-bilene Hydrobromide (112); Typical 


2,8-Diethyl-1,9-bis(methoxymethyl)-3,7-dimethyldipyrromethene hydrobromide (111; 

3.0 g, 7.55 mmol) in benzene (30 mL) (CAUTION: carcinogen) and 2,3,4-trimethyl-1H-pyrrole 

(74; 1.9 g, 17.40 mmol) were refluxed for 30 min. Hot petroleum ether (10 mL) was 

then added and the soln was cooled. The hydrobromide precipitated, was washed with 

petroleum ether, and was then recrystallized (CHCl 3/petroleum ether) to give 112; yield: 

3.5 g (84%); mp 187 8C (dec). 

2,18-Diacetyl-1,3,7,8,12,13,17,19-octamethyl-b-bilene (115); Typical Procedure: [74] 

A soln of 8-acetyl-2,3,7,9-tetramethyldipyrromethane-1-carboxylic acid (114 R 1 =CO 2H; 

1 g, 3.47 mmol) and 2-acetyl-9-formyl-1,3,7,8-tetramethyldipyrromethane (113; 1g, 

3.67 mmol) in TFA (5 mL) was added to MeOH (50 mL). The mixture was stirred for 

10 min, a soln of HBr in AcOH (40%, 3 mL) was added dropwise, and the precipitate 

(115•HBr) was collected by filtration after 2 h and washed with MeOH. A portion of the 

product was dissolved in CHCl 3 and treated with an excess of Et 3N. The residue obtained 

by concentration of the soln was crystallized (pyridine/CHCl 3) to give the b-bilene 115 as 

yellow needles; mp 2018C (dec). 

17.8.1.1.3.2.2 Variation 2: 

b-Bilene-1,19-dicarboxylates 

A very useful approach [76,77] to b-bilene-1,19-dicarboxylates involves the condensation of a 

1-unsubstituted dipyrromethane 116 (R 1 = H) [or the corresponding dipyrromethane-1carboxylic 

acid, 116 (R 1 =CO 2H)] with a 1-formyldipyrromethane, e.g. 117, and provides 

high yields of b-bilene-1,19-di-tert-butyl esters 118 as highly crystalline hydrochloride 

salts (Scheme 26). b-Bilene-1,19-dicarboxylic acids are also transient intermediates in the 

synthesis of porphyrins from a-oxobilanes. 

115 

Ac 

Ac 



aScheme 26 Synthesis of b-Bilene-1,19-dicarboxylates [76] 

Et 

NH HN 

R 1 CO 2Bu t 

116 R 1 = H, CO 2H 

CO 2Me 

+ 

NH HN 

NH HN 

+ 

NH HN 


OHC 

Et 

1. TsOH, MeOH, rt, 30 min 

2. HCl (g), CH2Cl2 85% 

117 

CO2Bu t 

Et 

Et 

CO2Me 

118 

CO 2Bu t 

CO 2Bu t 

CO 2Me 

CO2Me 

Di-tert-butyl 7,13-Diethyl-2,18-bis[2-(methoxycarbonyl)ethyl]-3,8,12,17-tetramethyl-b-bilene-1,19-dicarboxylate 

Hydrochloride (118); Typical Procedure: [76] 

tert-Butyl 7-ethyl-9-formyl-2-[2-(methoxycarbonyl)ethyl]-3,8-dimethyldipyrromethane-1carboxylate 

(117; 312 mg, 0.75 mmol) and 9-(tert-butoxycarbonyl)-3-ethyl-8-[2-(methoxycarbonyl)ethyl]-2,7-dimethyldipyrromethane-1-carboxylic 

acid (116, R 1 =CO 2H; 324 mg, 

0.75 mmol) in CH 2Cl 2 (80 mL) were treated with TsOH (600 mg) in MeOH (20 mL). After stirring 

at rt for 30 min the orange-red soln was washed with 2% aq Na 2CO 3 (100 mL) and then 

with H 2O. The soln was dried (MgSO 4) and concentrated to dryness to give a yellow-brown 

oil. Dry benzene (CAUTION: carcinogen) was added and removed under reduced pressure 

and then CH 2Cl 2 (30 mL) was added. Dry HCl gas was passed through the soln for a few 

seconds and dry benzene was quickly added to the deep red soln and then removed under 

reduced pressure. More dry benzene was added and the soln was concentrated to give a 

foam which was taken up in a small amount of Et 2O and refrigerated overnight. The b-bilene 

hydrochloride 118 was collected by filtration; yield: 512 mg (85%); mp 188–1898C. 

17.8.1.1.3.3 Method 3: 

a,c-Biladienes 

17.8.1.1.3.3.1 Variation 1: 

Symmetrical 1,19-Dimethyl-a,c-biladiene Salts 

Using the dipyrromethene synthetic methodology developed by Fischer (see earlier), [26] it 

has been shown that reaction of 1 equivalent of a dipyrromethane 119 with 2 equivalents 

of a 2-formyl-5-methyl-1H-pyrrole 120, in the presence of hydrogen bromide, gives a very 

high yield of the corresponding symmetrical a,c-biladiene dihydrobromide 121 (Scheme 

27). [71] Such salts crystallize readily from the reaction mixtures. Because of the stoichiometry 

used, it follows that rings A and D on the a,c-biladiene must be identical, and this introduces 

a symmetry restriction to the generalization of this approach. In fact, these a,cbiladienes 

are often completely symmetrical (e.g., 123) about the 10- (i.e., b) carbon atom 

because the starting dipyrromethane (e.g., 59) is also symmetrically substituted. 

Cl −


aScheme 27 Synthesis of Symmetrical 1,19-Dimethyl-a,c-biladiene Salts [47,71] 

A 

B B 

N 

H 

57 

NH HN 

119 

CO2Bn 

NH HN 

BnO2C CO2Bn 

59 

A 

N 

H 

122 

C D 

N 

H 

120 

H2, Pd/C, THF, Et 3N 

85% 

H2, Pd/C 

THF, Et3N 100% 

(2 equiv), HBr 

CHO 

(2 equiv), HBr, TFA, MeOH 

CHO 

76% 

NH HN 

+ 

+ 

NH HN 


N 

H 

A 

D 

CO2H 

B B 

C 

121 

NH HN 

HO2C CO2H 

BzCl, DMF 

82% 

NH HN 

+ 

+ 

NH HN 

2-Formyl-3,4,5-trimethyl-1H-pyrrole (122); Typical Procedure: [47] 

Benzyl 3,4,5-trimethyl-1H-pyrrole-2-carboxylate (57; 5.0 g, 20.55 mmol) in THF (200 mL) 

containing Pd/C (500 mg) and Et 3N (0.1 mL) was hydrogenated at rt and atmospheric pressure 

until uptake of H 2 ceased (3 h). The soln was filtered through a bed of Celite, which 

was washed with THF (50 mL) and the combined filtrates were concentrated to dryness to 

give 3,4,5-trimethyl-1H-pyrrole-2-carboxylic acid; yield: 2.66 g (85%). This material (1.92 g, 

123 

C 

N 

H 

122 

A 

D 

2Br − 

CHO 

2Br − 



a12.53 mmol) was dissolved under N 2 in DMF (6 mL) and refluxed for 3 h before cooling to 

08C and addition of BzCl (3 mL). The mixture was stirred for an additional 2 h, after which 

toluene (15 mL) was added and the soln was stirred for 30 min at rt. A brown-yellow precipitate 

was collected by filtration, air dried, and suspended in sat. Na 2CO 3 (100 mL). The 

mixture was stirred for 3 h at 608C, and a yellow precipitate was collected. The product 

was recrystallized (CH 2Cl 2/hexanes) to give the formylpyrrole 122; yield: 1.42 g (82%); mp 

102–1048C. 

1,2,3,7,8,12,13,17,18,19-Decamethyl-a,c-biladiene Dihydrobromide (123); Typical 


Dibenzyl 2,3,7,8-tetramethyldipyrromethane-1,9-dicarboxylate (59; 480 mg, 1.02 mmol) 

and 10% Pd/C (50 mg) were added to THF (100 mL) containing Et 3N (0.1 mL) and the resulting 

soln was hydrogenated at rt and atmospheric pressure for 6 h. Filtration through a 2cm 

pad of Celite, followed by evaporation of the solvent, afforded 2,3,7,8-tetramethyldipyrromethane-1,9-dicarboxylic 

acid as a white solid which was used directly without further 

purification; yield: 297 mg. To the dicarboxylic acid (297 mg, 1.02 mmol) was added 

TFA (4 mL) and the mixture was stirred for 5 min before addition of a soln of 2-formyl- 

3,4,5-trimethylpyrrole (122; 297 mg, 2.16 mmol) in MeOH (20 mL). Upon addition of 122, 

the soln immediately became orange and to this was added 33% HBr in AcOH (1 mL). Et 2O 

(50 mL) was slowly added to the soln and the mixture was left in a refrigerator overnight. 

Dark orange crystals of 123 were collected by filtration; yield: 473 mg (76%), mp >300 8C. 

17.8.1.1.3.3.2 Variation 2: 

Unsymmetrical 1,19-Dimethyl-a,c-biladiene Salts 

The symmetry restrictions in the above a,c-biladiene approach were solved by the development 

of stepwise methods for the synthesis of unsymmetrically substituted a,c-biladiene 

salts. [78–80] Two complementary methods are now available, known as the “clockwise” 

and “counterclockwise” routes (Scheme 28). In the counterclockwise route, [78,79] catalytic 

debenzylation of a benzyl tert-butyl dipyrromethane-1,9-dicarboxylate 124 provides 

the corresponding monocarboxylic acid 116 (R 1 =CO 2H), which can then be treated 

under mild conditions (4-toluenesulfonic acid/methanol) with a 2-formyl-5-methyl-1Hpyrrole 

125 to provide a high yield of a moderately stable tripyrrene salt 126 after anion 

exchange with hydrogen bromide (which, if not done very carefully, might cause cleavage 

of the tert-butyl ester on the tripyrrene). After treatment with trifluoroacetic acid (to 

cleave the tert-butyl ester) and then with a second 2-formyl-1H-pyrrole 127, a high yield 

of a fully unsymmetrical 1,19-dimethyl-a,c-biladiene salt 128 is obtained. 



aScheme 28 Synthesis of Unsymmetrical 1,19-Dimethyl-a,c-biladiene Salts via “Clockwise” 

and “Counterclockwise” Routes [78–80] 

counterclockwise 

BnO2C 

Et 

NH HN 

124 

MeO2C 

CO2Bu t 

N 

H 

125 

1. TFA 

MeO2C 2. 

OHC 

CO 2Me 

80% 

H2, Pd/C 

, TsOH, MeOH, CH2Cl2 CHO 

N 

H 

127 

then HBr, AcOH 

89% 

NH HN 


95% 

CO2Me 

, MeOH 

HO2C 

Et 

Et 

Et 

MeO2C 

CO 2Me 

NH 

+ 

NH 

CO2Bu t 

116 R 1 = CO 2H 

HN 

NH HN 

+ 

+ 

NH HN 

OTs − 

126 

128 

CO 2Bu t 

CO 2Me 

CO2Me 

CO 2Me 

CO 2Me 

CO 2Me 

2Br − 



clockwise 

aNH HN 

BnO2C 

Et 

124 

MeO2C 

OHC 

CO 2Bu t 

N 

H 

127 

CO 2Me 

CO 2Me 

1. H2SO4, HBr 

MeO2C 2. 

, HBr 

N 

H 

125 


TFA 

CHO 

BnO 2C 

BnO2C 

Et 

Et 

NH HN 

Et 

CO2Me 

NH HN 

+ 

HN 

MeO2C 

NH HN 

+ 

+ 

NH HN 

128 

CO 2Me 

Br − 

CO 2Me 

CO 2Me 

CO 2Me 

CO 2Me 

CO 2Me 

In the alternative (more recent) “clockwise” approach (shown in Scheme 29), [80] the benzyl 

tert-butyl dipyrromethane-1,9-dicarboxylate 129 is treated with trifluoroacetic acid 

and a 2-formyl-1H-pyrrole 125 to give the very stable tripyrrene benzyl ester 130, after 

anion exchange using hydrogen bromide gas. Catalytic hydrogenation could not be used 

to cleave the benzyl ester because this would concomitantly reduce the tripyrrene to a 

tripyrrane, thereby causing it to be sensitive to pyrrole ring scrambling in acid. This problem 

is avoided by effecting acidic cleavage (TFA/HBr in AcOH) of the benzyl ester. [80,81] Subsequent 

treatment with pyrrole 131 gave the a,c-biladiene dihydrobromide 132 in good 

yield. 

2Br −


aScheme 29 Synthesis of Unsymmetrical 1,19-Dimethyl-a,c-biladiene Salts via a 

“Clockwise” Route [80,81] 

BnO 2C 

Et 

NH HN 

129 

MeO 2C 

Et 

CO2Bu t 

1. AcOH, HBr, TFA 

Cl 

2. 

TFA 

1. , MeOH, 90 min 

N 

H 

CHO 

125 

2. HBr, AcOH, Et2O, 15 min 

N 

H 

131 

BnO2C 

NH HN 

NH HN 

+ 

+ 

NH HN 


73% 

CHO 

BnO2C 

, MeOH 

Et 

NH HN 

Et 

Cl 

Et 

+ 

HN 

130 83% 

Et 

132 

Et 

Br − 

CO 2Me 

Et 

2Br − 

CO2Me 

Engel and Gossauer have also reported the synthesis of an a,c-biladiene by way of a tertbutyl 

tripyrrenecarboxylate; this is then converted into a porphyrin, as well as into metal 

tetradehydrocorrinate salts. [82] 

Tripyrrenes can apparently be obtained without the need for differential protection 

of the two (1,9) ends of the initial dipyrromethane (Scheme 30). [83] Thus, condensation of a 

1,9-di-unsubstituted dipyrromethane 133 with a 2-formyl-5-methyl-1H-pyrrole, such as 

125, gives very high yields of the corresponding tripyrrene salt 134; quite unexpectedly, 

these are apparently uncontaminated with byproducts due to reaction of the formylpyrrole 

125 at both ends of 133. The tripyrrene intermediates can then be treated with a different 

formylpyrrole 135 to give high yields of the appropriate a,c-biladiene 136 in a manner 

which accomplishes the same objectives as the “clockwise” and “counterclockwise” 

a,c-biladiene approaches reported previously, but with symmetry restrictions which the 

other methods do not have. 



aScheme 30 Symmetry-Restricted Unsymmetrical a,c-Biladiene Synthesis [83] 

A 

B B 

R 1 = I, H, CO 2H 

NH HN 

133 

A 

MeO 2C 

R 1 

MeO2C 

N 

H 

135 

NH HN 

+ 

+ 

NH HN 


N 

H 

125 

, HBr 

CHO 

, HBr 

CHO 

A 

A 

MeO 2C 

B B 

NH HN 

+ 

HN 

134 

B B 

R 1 

136 

A 

Br − 

CO 2Me 

A 

2Br − 

CO2Me 

tert-Butyl 8-Ethyl-2,13-bis[2-(methoxycarbonyl)ethyl]-1,3,7,12-tetramethyl-5-tripyrrene- 

14-carboxylate 4-Toluenesulfonate (126) and Hydrobromide Salts; Typical Procedure: [79] 

Benzyl 9-(tert-butoxycarbonyl)-3-ethyl-8-[2-(methoxycarbonyl)ethyl]-2,7-dimethyldipyrromethane-1-carboxylate 

(124; 2.0 g, 3.83 mmol) in THF (70 mL) containing Et 3N (0.2 mL) 

and 10% Pd/C (270 mg) was hydrogenated at rt and atmospheric pressure until uptake of 

H 2 ceased. After filtration through Celite the solvent was removed under reduced pressure 

to give, after crystallization (THF/hexanes), the dipyrromethane-1-carboxylic acid 

116; yield: 1.6 g (95%); mp dec. Compound 116 (788 mg, 1.82 mmol) and 2-formyl-4-[2- 

(methoxycarbonyl)ethyl]-3,5-dimethyl-1H-pyrrole (125; 381 mg, 2.10 mmol) in CH 2Cl 2 

(100 mL) were stirred with a soln of TsOH (800 mg) in MeOH (10 mL) over a period of 

30 min (monitoring by spectrophotometry, observing maximization of the 492-nm absorption 

band). The soln was washed with aq Na 2CO 3 (150 mL) and then dried (Na 2SO 4) 

and concentrated to dryness. Crystallization (CH 2Cl 2/Et 2O) gave the tripyrrene 4-toluenesulfonate 

126; yield: 1.09 g (80%); mp >1358C (dec). Tripyrrene salts are best isolated as 

the hydrobromide salts by brief treatment of the 4-toluenesulfonate in CH 2Cl 2 with sat. 

aq Na 2CO 3, evaporation, and then brief treatment of a CH 2Cl 2 soln of the tripyrrene freebase 

with dry HBr gas, followed by rapid evaporation, azeotropic removal of HBr gas and 

moisture with benzene (CAUTION: carcinogen), and crystallization from CH 2Cl 2/Et 2O. 

8-Ethyl-2,13,17-tris[2-(methoxycarbonyl)ethyl]-18-[(methoxycarbonyl)methyl]-1,3,7,12,19pentamethyl-a,c-biladiene 

Dihydrobromide (128); Typical Procedure: [81] 

tert-Butyl 8-ethyl-2,13-bis[2-(methoxycarbonyl)ethyl]-1,3,7,12-tetramethyl-5-tripyrrene-14carboxylate 

4-toluenesulfonate (126; 500 mg, 0.665 mmol) in TFA (5 mL) was stirred before 

addition of 2-formyl-3-[2-(methoxycarbonyl)ethyl]-4-[(methoxycarbonyl)methyl]-5methyl-1H-pyrrole 

(127; 217 mg, 0.812 mmol) in MeOH (7 mL) and then 45% HBr/AcOH 

(2 mL). After stirring for 30 min, Et 2O (100 mL) was added dropwise with continued stir-


aring. The a,c-biladiene dihydrobromide was collected by filtration and washed thoroughly 

with Et 2O to give 128 as red-brown crystals; yield: 525 mg (89%); mp >150 8C (dec). 

Benzyl 7,12-Diethyl-2-[2-(methoxycarbonyl)ethyl]-1,3,8,13-tetramethyl-5-tripyrrene-14carboxylate 

Hydrobromide (130); Typical Procedure: [80] 

Benzyl 9-(tert-butoxycarbonyl)-3,8-diethyl-2,7-dimethyldipyrromethane-1-carboxylate 

(129; 400 mg, 0.86 mmol) was treated with TFA (3 mL) with stirring under N 2 at rt for 

5 min. Then, 2-formyl-4-[2-(methoxycarbonyl)ethyl]-3,5-dimethyl-1H-pyrrole (125; 

180 mg, 0.87 mmol) in MeOH (20 mL) was added all at once. The red soln was stirred for 

90 min then 30% HBr/AcOH (3 drops) and Et 2O (25 mL) were added. After stirring for another 

15 min reddish-orange crystals appeared. These were collected by filtration and washed 

thoroughly with Et 2O to give the tripyrrene hydrobromide 130; yield: 461 mg (83%); mp 

115–1168C. 

2-(2-Chloroethyl)-8,13-diethyl-18-[2-(methoxycarbonyl)ethyl]-1,3,7,12,17,19-hexamethyla,c-biladiene 

Dihydrobromide (132); Typical Procedure: [80] 

Benzyl 7,12-diethyl-2-[2-(methoxycarbonyl)ethyl]-1,3,8,13-tetramethyl-5-tripyrrene-14carboxylate 

hydrobromide (130; 107 mg, 0.17 mmol) was treated with a mixture of 30% 

HBr/AcOH (0.5 mL) and TFA (2.5 mL) with stirring under N 2 at rt for 6 h. Then, 4-(2-chloroethyl)-2-formyl-3,5-dimethyl-1H-pyrrole 

(131; 33 mg, 0.18 mmol) in MeOH (10 mL) was 

added all at once. The orange soln immediately turned dark red in color. After stirring 

for 30 min, Et 2O (30 mL) was added rapidly but dropwise to form red crystals. Collection 

by filtration and washing thoroughly with Et 2O gave the a,c-biladiene dihydrobromide 

132; yield: 92 mg (73%); mp 195–1968C. 

17.8.1.1.3.3.3 Variation 3: 

1-Bromo-19-methyl-a,c-biladiene Salts 

1-Bromo-19-methyl-a,c-biladienes 139 have been shown by Johnson and co-workers to be 

very useful precursors in porphyrin syntheses. [84] They are prepared, as shown in Scheme 

31, by treatment of 1-bromo-9-(bromomethyl)dipyrromethene salts (e.g., 137) with 9-unsubstituted 

1-methyldipyrromethenes 138 in the presence of a Friedel–Crafts catalyst 

[usually tin(IV) chloride]; this reaction gives very high yields of the biladiene after removal 

of a templating tin ion [inserted by the tin(IV) chloride] with hydrobromic acid. 

Scheme 31 Unsymmetrical 1-Bromo-19-methyl-a,c-biladiene Synthesis [84] 

Et 

Br 

NH HN 

+ 

137 

Br 

CO 2Me 

Br − 


+ 

Et 

+ 

NH HN 

138 

Et 

1. SnCl 4, CH 2Cl 2, rt, 2 h 

2. HBr, MeOH Br 

81% 

Et 

NH 

+ 

NH 

139 

HN 

+ 

HN 

CO2Me 

Br − 

CO2Me 

2Br − 

CO 2Me 



a1-Bromo-2,17-diethyl-8,12-bis[2-(methoxycarbonyl)ethyl]-3,7,13,18,19-pentamethyl-a,cbiladiene 

Dihydrobromide (139); General Procedure: [84] 

Millimolar proportions of the 1-bromo-9-(bromomethyl)dipyrromethene hydrobromide 

{1-bromo-9-(bromomethyl)-2-ethyl-8-[2-(methoxycarbonyl)ethyl]-3,7-dimethyldipyrromethene 

hydrobromide (137)} and 1-unsubstituted 9-methyldipyrromethene hydrobromide 

{7-ethyl-2-[2-(methoxycarbonyl)ethyl]-3,8,9-trimethyldipyrromethene hydrobromide 

(138)} were suspended in CH 2Cl 2 (50 mL) and SnCl 4 (1 mL) was added. The dry orange 

soln was kept at rt for 2 h before the solvent was removed under reduced pressure. The 

residue was treated with 20% HBr/MeOH (50 mL) and after standing for 15 min the a,c-biladiene 

dihydrobromide was separated and washed with a little MeOH containing a few 

drops of HBr. It was then washed with Et 2O and dried to give the a,c-biladiene dihydrobromide 

139; yield: 81%; mp >300 8C. 

17.8.1.2 Syntheses of Porphyrins 

17.8.1.2.1 Method 1: 

From Monopyrrole Tetramerization 


Vol. E 9d, p 581. 

The stoichiometry of this reaction is as shown in Scheme 7, case A. The best known 

and most used monopyrrole polymerization route to porphyrins yields 5,10,15,20-tetraphenylporphyrin 

(TPP, 22; Scheme 32) as the product. The original method, due to Rothemund, 

[85,86] employed a high-temperature reaction between pyrrole and benzaldehyde in 

pyridine, in a sealed tube. This reaction was modified by Adler, Longo, and colleagues, [87] 

by using hot propanoic acid as a solvent for the pyrrole and benzaldehyde (at atmospheric 

pressure). The reaction was finally optimized by Lindsey s group, [19,88] and in their hands 

involves a two-step reaction, (i) an acid-catalyzed macrocyclization to give tetraarylporphyrinogen, 

followed by (ii) an oxidation step usually using a high-potential quinone 

such as 2,3-dichloro-5,6-dicyanobenzo-1,4-quinone (DDQ). 

The crude product from the Rothemund and Adler/Longo approach usually contains 

[89] between 2 and 5% of meso-tetraphenylchlorin 140, which is best dealt with by 

brief treatment [90,91] of the crude product with 2,3-dichloro-5,6-dicyanobenzo-1,4-quinone; 

this accomplishes transformation of the chlorin into 5,10,15,20-tetraphenylporphyrin 

(22) and is much easier than attempting to chromatographically separate one 

from the other. The newer modifications to the Rothemund reaction enable a large variety 

of 5,10,15,20-tetraarylporphyrins to be prepared, [19] and also permit syntheses of highly 

non-planar dodecasubstituted porphyrins. [92–96] 

Scheme 32 Synthesis of Chlorin-Free 5,10,15,20-Tetraphenylporphyrin [91] 

N 

H 

PhCHO, EtCO2H 

heat 

26% 

Ph 

NH N 

N HN 


Ph 

Ph 

22 

Ph 

+ 

Ph 

DDQ, CHCl 3, benzene 

94−96% 

Ph 

NH N 

N HN 

Ph 

140 

Ph


aSince it involves some demanding pyrrole chemistry, the approach to octaalkyl-type porphyrins 

by tetramerization (or similar chemistry) of monopyrroles is more complicated. 

To ensure that only one porphyrin product is obtained, the substituents at the 3- and 4positions 

of the monopyrrole must be identical. In this way, symmetrical porphyrins 

such as 2,3,7,8,12,13,17,18-octaethylporphyrin (OEP, 21) can be prepared. 

Two primary approaches have been developed. The first (Scheme 33) involves polymerization 

of 2,5-di-unsubstituted 1H-pyrroles in the presence of agents which will provide 

the four carbons required for the meso-methine carbons of the product; this stoichiometry 

is as shown in Scheme 7, case A. Macrocyclization of such -free pyrroles with formic 

acid [97] is a viable method; an improved synthesis of 3,4-diethyl-1H-pyrrole has been 

reported, and this has been coupled with a formic acid method for the synthesis of 

2,3,7,8,12,13,17,18-octaethylporphyrin (21) to give yields between 55–75%, depending 

upon the scale. [98] 

The second approach (Scheme 33) is the tetramerization of pyrroles bearing 2-CH 2R 1 

substituents, the methylene carbon of which will eventually be the source of the 5,10,15 

and 20-carbons of the desired porphyrin; this is an example of the mode shown in 

Scheme 7, case B. Tetramerization of monopyrroles bearing an appropriately modified 

2-methyl substituent (which can provide the porphyrin interpyrrolic carbons), followed 

by aerial oxidation, often affords good yields of symmetrical porphyrins. This approach 

is also best illustrated by syntheses of 2,3,7,8,12,13,17,18-octaethylporphyrin (21). A typical 

example is the Mannich reaction of 3,4-diethyl-1H-pyrrole with dimethylamine and 

formaldehyde [or with commercially available (N,N-dimethylmethylene)ammonium iodide 

(Eschenmoser s reagent) [99,100] ] to give the 2-[(dimethylamino)methyl]-1H-pyrrole 

141; when this is heated in refluxing acetic acid a 52% yield of 21 is obtained. [101] Alternatively, 

hydrolysis of the pyrrole 142 gives pyrrole 143 which can be converted into 

2,3,7,8,12,13,17,18-octaethylporphyrin (21) in 44% yield by heating in acetic acid in the 

presence of potassium ferricyanide. [102] The introduction of the Barton–Zard pyrrole synthesis 

[103,104] has enabled ready access to monopyrroles of the type 62 in high yield; reduction, 

followed by acid-catalyzed cyclotetramerization of the resulting 1H-pyrrole-2-carbinol 

144 affords excellent yields of 2,3,7,8,12,13,17,18-octaethylporphyrin (21); [105,106] a potentially 

troublesome cleavage of the 2-CH 2OH group is circumvented by addition of dimethoxymethane 

(“methalal”). 

Scheme 33 Syntheses of 2,3,7,8,12,13,17,18-Octaethylporphyrin [98,101,102,104,105] 

Et Et 

N 

H 

HCO 2H 

55−75% 

Et 

Et 

Et Et 

NH N 

N HN 


Et 

21 

Et 

Et 

Et 



Et Et 

Et 

aNH N 

H2C NMe2 I 

N HN 

Et 

− 

Et Et 

Et Et 

+ 

AcOH, heat 

NMe2 100% 

52% 

N 

N 

H 

H 

AcO 

Et Et 

N 

H 

62 

Et Et 

N 

H 

142 

CO 2Et 

CO2Et 

LiAlH4 

THF 

141 

KOH, MeOH 

reflux, 4 h 

96% 

Et Et 


N 

H 

144 

HO 

Et Et 

44% 

N 

H 

AcOH 

K3[Fe(CN) 6] 

heat 

OH 

143 

CO 2H 

Et 

Et 

Et 

Et 

21 

NH N 

N HN 

Et 

Et Et 

Et 

MeO OMe 

TsOH, CH2Cl2, rt, 12 h 

Et 

21 

NH N 

N HN 

Et 

Et Et 

Et 

21 55% 

If the substituents at the pyrrole 3- and 4-positions are not identical, then mixtures can 

result. It is not immediately obvious why this should happen, since one might expect 

that a stepwise polymerization of four pyrroles should maintain the ordering of the peripheral 

substituents. Indeed, self-condensations of pyrroles such as 145 proceed through 

dipyrromethanes (e.g., 146), tripyrranes 147, bilanes 148, even higher oligomers, and 

porphyrinogens 149 (Scheme 34). Unfortunately, all these species, under the acid conditions 

essential for the reaction, can scramble to give statistical mixtures of porphyrins 

such as (for the specific case of pyrrole 145) the four “primary type-isomers” (7–10, 

Scheme 3) of the etioporphyrins. The porphyrinogen scrambling process was investigated 

in an early paper by Mauzerall. [107] However, it should be pointed out that the enzymemediated 

tetramerization of porphobilinogen (150) to give uroporphyrinogen III (151) 

(Scheme 34) is uniquely regiospecific under normal circumstances. [108–112] 

Et 

Et 

Et 

Et 

Et 

Et 

Et


aScheme 34 Monopyrrole Oligomerization 

2 

HO 2C 

N 

H 

145 

Et 

N 

H 

150 

X 

Et 

CO 2H 

− HX 

NH HN 

X 

NH 2 

147 

HN 

Et 

enzymes 

Et 

Et 

NH HN 

NH HN 

NH HN 


146 

N 

H 

145 

Et 

X 

HO2C HO2C 

X 

, − HX 

− HX 

Et 

NH HN 

NH HN 

Et 

X 

Et 

N 

H 

145 

Et 

Et 

Et 

X 

CO 2H 

, − HX 

NH HN 

NH HN 

148 

CO 2H 

149 

HO2C 

CO2H HO2C CO2H 151 

Some ingenious methods have been developed to enable the type-I isomer of a porphyrin 

to be obtained by rational acid-catalyzed tetramerization of a monopyrrole. For example, 

when perfluoroalkyl-1H-pyrrole-2-carbinols are tetramerized, exclusively the type-I isomer 

is formed. [106] Large steric hindrance by one of the two b-substituents on a pyrrole 

(e.g., 152) has also been shown to result in the formation of only the type-I porphyrin 

153 (Scheme 35). [113] 

A more general solution to the acid-catalyzed pyrrole redistribution reaction can be 

achieved simply by avoidance of the acid catalysts usually used in the monopyrrole selfcondensation. 

For example, treatment of 2-[(dialkylamino)methyl]-1H-pyrroles (such as 

155, obtained from pyrroles 154 by catalytic hydrogenation) with iodomethane (to afford 

156) gives a 25% yield of pure etioporphyrin I (7) (Scheme 35); the iodomethane quaterni- 

Et 

Et 

Et 

Et 



azes the amino group to produce an excellent “benzylic” leaving group which can react at 

the unsubstituted pyrrole 5-position to give porphyrinogen 149 under neutral conditions. 

Porphyrin 7 can then be obtained by way of in situ oxidation using potassium ferricyanide. 

[114] 

Scheme 35 Unsymmetrical Monopyrrole Oligomerizations [113,114] 

Pr i 

N 

H 

BnO 2C 

OH 

152 

MeOH, Et3N 

R 1 = Me, Et 

N 

H 

Pr i 

154 

Pr i 

Et 

NR 1 2 

Et 

H2 Pd/C 

THF 

Et 

Pr i 

NH HN 

NH HN 

149 

HO 2C 

NH N 

N HN 


Et 

N 

H 

Pr i 

155 

Et 

Pr i 

Pr i 

Et 

Pr i 

NR 1 2 

Pr i 

Pr i 

153 

MeI 

CH2Cl2 K3[Fe(CN) 6] 

MeOH, Et3N 

Et 

Pr i 

Pr i 

Pr i 

Pr i 

HO 2C 

Et 

N 

H 

156 

Pr i 

NH N 

N HN 

7 36% 

Et 

NR1 + 

2Me 

An interesting one-pot procedure which uses the mode of synthesis illustrated in Scheme 

7, case C, has been reported. [115,116] This induces two different pyrroles to react together, in 

one flask, but to produce only one regiochemically pure porphyrin. For example, treatment 

of the 2,5-bis[(dimethylamino)methyl]-1H-pyrrole (157) with 3,4-dimethyl-1H-pyrrole 

(158) in methanol containing potassium ferricyanide affords the porphyrin 160 

with two pairs of identical pyrrole rings opposite each other (Scheme 36). The avoidance 

of acid catalysis and use of an in situ oxidant [potassium ferricyanide] serves to circumvent 

any pyrrole ring redistribution reactions in the intermediate species 159 prior to formation 

of porphyrin 160. 

Et 

I − 

Et


aScheme 36 One-Pot Porphyrin Synthesis with Two Pyrroles [115,116] 

Et Et 

N 

H 

+ 

H2C NMe2 MeNO2 

86% 

Et 

Et 

I − 

NH HN 

NH HN 

159 

Me 2N 

Et 

Et Et 

N 

H NMe 2 


157 

Et 

N 

H 

158 

Et 

, K 3[Fe(CN) 6], MeOH, heat 

Et 

NH N 

N HN 

160 19.5% 

Chlorin-Free 5,10,15,20-Tetraphenylporphyrin (TPP, 22); Typical Procedure: [91] 

Benzaldehyde (66.5 mL, 0.63 mol) and 1H-pyrrole (46.5 mL, 0.69 mol) were added simultaneously 

to refluxing propanoic acid (2.5 L) and the mixture was refluxed for a further 

30 min before being set aside at rt. The product was collected by filtration, washed with 

hot H 2O and then with MeOH to give crystals of crude 5,10,15,20-tetraphenylporphyrin 

(22); yield: 20.4 g (19.8%). Concentration of the propanoic acid soln afforded another 

crop of crude 5,10,15,20-tetraphenylporphyrin (22); yield: 6.0 g (26% overall). The crude 

5,10,15,20-tetraphenylporphyrin (20 g, 32.5 mmol) in EtOH-free CHCl 3 (2.5 L) was treated 

with DDQ (5 g) in dry benzene (150 mL) (CAUTION: carcinogen). The mixture was refluxed 

for 3 h before filtration of the yellow-red soln under suction through a sintered glass funnel 

(6.4 cm diameter ” 20.4 cm) containing alumina (100–300 g, Brockmann Grade I). The 

alumina was washed with CH 2Cl 2 (200 mL) and the combined filtrates were concentrated 

to ca. 200 mL before addition of MeOH (200 mL). Filtration afforded chlorin-free 

5,10,15,20-tetraphenylporphyrin (22); yield: 19.2 g (96%); mp >300 8C. In a smaller scale 

reaction [5,10,15,20-tetraphenylporphyrin (22; 1g),CH 2Cl 2 (250 mL), DDQ (250 mg), benzene 

(15 mL)], only 30 min reflux was required, to give pure 5,10,15,20-tetraphenylporphyrin 

(22); yield: 940 mg (94%). 

2-[(Dimethylamino)methyl]-3,4-diethyl-1H-pyrrole (141); Typical Procedure: [101] 

3,4-Diethyl-1H-pyrrole (41.7 g, 0.338 mol) in MeOH (325 mL) under N 2 was cooled to –158C 

in an acetone/dry ice bath. A soln of Me 2N•HCl (28.1 g, 0.344 mol), KOAc (33.8 g, 

0.344 mol), and 37% aq HCHO (27.8 g, 0.343 mol) in H 2O (130 mL) was added dropwise 

over 1.75 h, the soln temperature being kept between –15 and –108C. After complete addition, 

the soln was stirred at –10 8C for 30 min and then kept at 08C for 12 h. Cold 5% aq 

HCl (400 mL) was slowly added with stirring and the cold soln was extracted with Et 2O. 

The aqueous layer was made basic by slow addition of 2 N NaOH (500 mL) while stirring 

and cooling in an ice bath. The basic soln was extracted with Et 2O (3 ” 500 mL) and the 

combined Et 2O layers were dried (K 2CO 3) and concentrated under reduced pressure to afford 

141 as a brown oil, pure by 1 H NMR spectroscopy; yield: 61.0 g (100%). 

Et 

Et 



a2,3,7,8,12,13,17,18-Octaethylporphyrin (21) from 2-[(Dimethylamino)methyl]-3,4-diethyl- 

1H-pyrrole (141); Typical Procedure: [101] 

2-[(Dimethylamino)methyl]-3,4-diethyl-1H-pyrrole (141; 61.0 g, 0.338 mol) was taken up in 

pure AcOH (500 mL). The soln was refluxed for 1 h with rapid stirring and with a strong 

stream of O 2 bubbling through it. Within minutes a dark precipitate appeared. The soln 

was cooled, the AcOH was removed under reduced pressure, and MeOH (500 mL) was added 

to the residue. The slurry was stirred and collected by filtration, and the precipitate 

was washed with MeOH until it was no longer brown. After drying, crude 21 was recrystallized 

(toluene); yield: 23.51 g (52%); mp 324–3258C. 

3,4-Diethyl-5-hydroxymethyl-1H-pyrrole-2-carboxylic Acid (143); Typical Procedure: [102] 

A mixture of ethyl 5-(acetoxymethyl)-3,4-diethyl-1H-pyrrole-2-carboxylate (142; 15.2 g, 

56.86 mmol) and KOH (30 g) in MeOH (210 mL) was refluxed for 4 h. The soln was concentrated 

under reduced pressure and H 2O (150 mL) was added. The soln was extracted with 

Et 2O, and the aqueous phase was then acidified with dil aq HCl (350 mL, dropwise with 

cooling and stirring). The product was collected by filtration, washed with aq NaOAc, 

and H 2O, then dried to give the pyrrole 143; yield: 10.7 g (96%); mp 115–1208C. 

2,3,7,8,12,13,17,18-Octaethylporphyrin (21) from 3,4-Diethyl-5-hydroxymethyl-1H-pyrrole-2-carboxylic 

Acid (143); Typical Procedure: [102] 

3,4-Diethyl-5-hydroxymethyl-1H-pyrrole-2-carboxylic acid (143; 10 g, 50.7 mmol) in AcOH 

(40 mL) containing K 3[Fe(CN) 6] (1 g, 3.03 mmol) was heated at 1008C with stirring for 1 h. 

After standing overnight at rt, the product was collected by filtration to give 21 (2 g). The 

filtrate was concentrated under vacuum, and purified by chromatography [alumina 

(Brockmann Grade III), CH 2Cl 2] to give a second crop (1.0 g) of 21; total yield: 3.0 g (44%). 

Ethyl 3,4-Diethyl-1H-pyrrole-2-carboxylate (62); Typical Procedure: [105] 

A mixture of 3-acetoxy-4-nitrohexane (16.3 g, 0.083 mol), ethyl isocyanoacetate (9.8 g, 

0.087 mol), and DBU (26.4 g, 0.17 mole) in THF (100 mL) was stirred at 208C for 12 h. The 

mixture was poured into H 2O containing 1 M HCl and extracted with EtOAc. The extracts 

were washed with H 2O and dried (MgSO 4). Concentration of the solvents under reduced 

pressure gave a residue, which was chromatographed (silica gel, hexanes/CH 2Cl 2). Concentration 

of the eluates gave 62 as an oil; yield: 14.2 g (86%). 

2,3,7,8,12,13,17,18-Octaethylporphyrin (21) from Ethyl 3,4-Diethyl-1H-pyrrole-2-carboxylate 


Ethyl 3,4-diethyl-1H-pyrrole-2-carboxylate (62; 657 mg, 3.2 mmol) was added dropwise at 

0–5 8C to a stirred soln of LiAlH 4 (320 mg, 8.0 mmol) in dry THF (15 mL). The mixture was 

stirred for 2 h at 0–5 8C before the excess of LiAlH 4 was destroyed by addition of EtOAc. It 

was then poured into sat. aq NH 4Cl, extracted with EtOAc (3 ” 10 mL), washed with sat. 

brine, and dried (MgSO 4). The soln was concentrated to dryness in vacuo before addition 

of CH 2Cl 2 (15 mL). To this soln was added dimethoxymethane (methalal; 0.7 mL, 

9.6 mmol) and TsOH (110 mg, 0.65 mmol), and the mixture was stirred for 12 h at rt. Aerial 

oxidation took place under these conditions, but p-chloranil could also be used (without 

any improvement in yield). The mixture was washed with aq NaHCO 3 and the organic layer 

was dried (MgSO 4). Evaporation gave a residue which was chromatographed (silica gel, 

CH 2Cl 2) to give, after evaporation of the eluates and recrystallization of the residue 

(CH 2Cl 2/MeOH), 21; yield: 240 mg (55%). 

Benzyl 4-Ethyl-5-[(dimethylamino)methyl]-3-methyl-1H-pyrrole-2-carboxylate (154, 

R 1 = Me); Typical Procedure: [114] 

DMF (5 mL) was cooled an in an ice bath and then POCl 3 (5 mL) was added. The resulting 

soln was stirred at 0 8C for 20 min before a soln of benzyl 4-ethyl-3-methyl-1H-pyrrole-2- 



acarboxylate (3.0 g, 12.3 mmol) in CH 2Cl 2 (80 mL) was added. The light brown soln was stirred 

at rt under N 2 for 12 h before the solvent was removed to yield a thick brown oil. The 

oil was redissolved in CH 2Cl 2 (50 mL), cooled in an ice bath, and then NaBH 4 (3.32 g, 

87.6 mmol) in MeOH (5 mL) was added slowly. The resulting mixture was stirred at rt for 

5 h. The excess of NaBH 4 was quenched with AcOH, and the mixture was diluted with 

CH 2Cl 2 (50 mL), washed with H 2O, aq NaHCO 3, and brine, and dried (Na 2SO 4). Removal of 

the solvent gave 154 (R 1 = Me) as a light brown oil; yield: 2.6 g (54%). 

Benzyl 4-Ethyl-5-[(diethylamino)methyl]-3-methyl-1H-pyrrole-2-carboxylate (154,R 1 = Et); 


A soln of Br 2 (6.65 g, 42 mmol) in CH 2Cl 2 (25 mL) was added dropwise to a soln of benzyl 4ethyl-3,5-dimethyl-1H-pyrrole-2-carboxylate 

(10.7 g, 42 mmol) and K 2CO 3 (100 mg) in dry 

Et 2O (150 mL). The mixture was stirred at rt for 20 min after the addition of Br 2. A soln of 

Et 2NH (16 mL) in Et 2O (50 mL) was then added (color change; deep red to pale yellow), and 

the mixture was stirred at rt for 30 min before H 2O (200 mL) was added. The organic phase 

was separated and washed with H 2O and then extracted with ice-cold 3.7% HCl (100 mL). 

The aqueous layer was washed rapidly with Et 2O before a soln of 15% NH 4OH (200 mL) was 

added and the resulting mixture was extracted with Et 2O. The combined organic phases 

were washed with H 2O, dried (Na 2SO 4), and concentrated to give 154 (R 1 = Et) as a yellow 

oil, which turned to an amorphous solid upon standing; yield: 11.5 g (86%). 

3,8,13,18-Tetraethyl-2,7,12,17-tetramethylporphyrin (Etioporphyrin I, 7); Typical 


Benzyl 4-ethyl-5-[(dialkylamino)methyl]-3-methyl-1H-pyrrole-2-carboxylate (154; 

6.6 mmol) was dissolved in THF (600 mL), and 10% Pd/C (500 mg) was added. The resulting 

mixture was stirred under H 2 at rt for 12 h before the catalyst was removed and the solvent 

was removed under reduced pressure. Recrystallization from CH 2Cl 2/hexanes afforded 

carboxylic acid 155 as an off-white powder in quantitative yield. Because of spontaneous 

decarboxylation at rt, this was used immediately: The pyrrole carboxylic acid 155 

(6.6 mmol) was stirred briefly with an excess of MeI (1 mL) in CH 2Cl 2 (10 mL) to give 156. 

Solvents were evaporated at rt and the residue was dissolved in a soln of MeOH (200 mL) 

and Et 3N (2 mL) and refluxed for 15 min. K 3[Fe(CN) 6] (3.8 g, 11.6 mmol) was added and the 

mixture was then refluxed for 10 h. The solvent was removed and the residue was redissolved 

in CHCl 3. Some insoluble material was filtered off and the red soln was passed 

through a plug of silica gel (CHCl 3). The solvent was removed under reduced pressure 

and the residual porphyrin was crystallized (CH 2Cl 2/MeOH) to afford etioporphyrin I (7); 

yield: 284 mg (36%); mp >300 8C. 

2,5-Bis[(dimethylamino)methyl]-3,4-diethyl-1H-pyrrole (157); Typical Procedure: [116] 

3,4-Diethyl-1H-pyrrole (2.22 g, 18.02 mmol) and Eschenmoser s reagent [99] (4.48 g, 

46.90 mmol) were dissolved in dry MeNO 2 (200 mL) and stirred at rt under N 2 for 12 h before 

the solvent was removed. The residue was redissolved in CH 2Cl 2 and the soln washed 

with sat. Na 2CO 3, dried (Na 2SO 4), and the solvent was removed under reduced pressure to 

afford 157 as a crude dark brown solid, pure enough (by NMR analysis) for subsequent reactions 

without further purification; yield: 3.67 g (86%). 

2,3,12,13-Tetraethyl-7,8,17,18-tetramethylporphyrin (160); Typical Procedure: [116] 

Pyrrole 157 (0.84 g, 3.55 mmol) and 3,4-dimethyl-1H-pyrrole (158; 0.34 g, 3.56 mmol) were 

added to a soln of K 3[Fe(CN) 6] (3.80 g, 11.54 mmol) in MeOH (75 mL). The mixture was refluxed 

for 4 h before the solvent was removed. The residue was dissolved in CH 2Cl 2 and 

washed with H 2O, 5% NH 4OH (” 2), H 2O, and brine, and then dried (Na 2SO 4). The solvent 

was removed under reduced pressure and the crude product was chromatographed (silica 




agel, 10% petroleum ether/CH 2Cl 2). Recrystallization (CH 2Cl 2/cyclohexane) afforded the 

porphyrin 160; yield: 162 mg (19.5%); mp >3008C. 

17.8.1.2.2 Method 2: 

From Dipyrrolic Intermediates: The [2+2] Routes 


Vol. E 9d, p 585. 

The dipyrrolic intermediates most often used for porphyrin synthesis are dipyrromethenes 

and dipyrromethanes. Because dipyrromethanes are sensitive to cleavage by 

acidic reagents if they are not substituted with electron-withdrawing groups, most of 

the Fischer-era developments in porphyrin synthesis depended upon dipyrromethenes 

as the intermediates. In those times, Fischer did not always concern himself with avoidance 

of mixtures due to ambiguities related to symmetry limitations; there were occasions 

when access to a particular porphyrin was so important that preparation of a mixture 

followed by chromatographic separation was perfectly acceptable. However, this still 

required an extra layer of tactical planning; for example, if a hypothetical [2 +2] dipyrromethene 

condensation reaction was to be used (Scheme 37), the two halves would be 

chosen so that one half, 162, possessed polar groups while the other, 161, did not. If the 

required product was mesoporphyrin IX, then this molecule (163, bearing two carboxylate 

groups) could be readily separated from the two other porphyrin products, etioporphyrin 

I (7, bearing no polar carboxylate groups) and coproporphyrin II (164, bearing 

four carboxylates). 

Scheme 37 Strategy for Porphyrin Synthesis Using Side-Chain Polarity of Dipyrromethenes 

Br 

Et 

Et 

NH HN 

+ 

161 

NH N 

N HN 

163 

Et 

Br − 

Et 

CO2H CO2H 

+ 

+ 

Br − 

Et 

Br Br 

+ 

NH HN 

CO 2H 

NH N 

N HN 


Et 

7 

162 

Et 

Et 

CO 2H 

+ 

heat 

CO 2H CO2H 

CO2H 

NH N 

N HN 

Obvious symmetry problems will be associated with all [2 +2] approaches to porphyrins 

whether dipyrromethenes or dipyrromethanes are used. In the absence of methodology 

to prevent equal reactivity at both ends of each dipyrrole component, mixtures will result 

if two different dipyrroles are used. For example, condensation of dipyrromethenes 165 

and 166, presumably intended to give 167 will also result in the production of porphyrin 

168; there is no simple way that the second porphyrin can be avoided (Scheme 38). One 

must therefore carefully strategize symmetry considerations if a single pure porphyrin is 

164 

CO2H


arequired, and a mixture is to be avoided. This is not difficult to do; in simple terms, as long 

as one of the two dipyrroles is symmetrically substituted about its 5-carbon, a mixture 

will not result. This analysis applies to Scheme 7, mode E. Thus, porphyrins (e.g., 170) 

which possess symmetry in one or both precursor halves (165, 169) of the molecule can 

be targeted through this approach. As it happens this is not a significant hardship because 

many natural porphyrins, for example protoporphyrin IX (2), coproporphyrin III (3), and 

uroporphyrin III (171) do have “lower-hemisphere” symmetry either side of meso-carbon- 

15. These complex natural molecules can therefore be synthesized by the [2 +2] approach 

provided that the strategy involves condensation of an A–B dipyrrole unit with a C–D dipyrrole 

in which either the A–B or C–D hemisphere is symmetrical about its interpyrrolic 

carbon atom. Alternatively, as in the case shown in Scheme 7, mode F, the route can be 

limited to the synthesis of porphyrins (e.g., 173) which are centrosymmetrically substituted 

(i.e., produced by self-condensation of a dipyrrolic compound 172). 

Scheme 38 Strategy for Porphyrin Synthesis Using Side-Chain Symmetry 

A 

A 

B C 

NH HN 

+ 

D 

X 

Br Br 

− 

165 

+ 

X 

− 

H 

+ 

NH HN 

G 

A 

H 

B C 

NH N 

N HN 


166 

G 

F 

167 

B 

NH 

C 

HN 

+ 

D 

X 

+ 

X 

− 

E 

+ 

NH HN 

Br Br 

F 

F 

− 

A B D C 

165 169 

E 

F 

E 

D 

E 

heat 

+ 

heat 

A 

E 

A 

E 

B C 

F 

NH N 

N HN 

168 

A B 

NH N 

N HN 

D C 

G 

B C 

F 

170 

F 

D 

H 

D 

E 



HO 2C 

aNH N 

HO2C 

2 

HO 2C 

HO 2C 

A 

Br 

N HN 

171 

B C 

NH HN 

+ 

172 

X − 

CO2H 

CO2H D 

CO2H 

CO2H 

heat 

NH N 

N HN 


A 

D 

B C 

Application of mode D shown in Scheme 7 almost invariably involves the use of dipyrromethanes. 

Dipyrromethenes are simply not nucleophilic enough (particularly in the presence 

of acid, which produces the non-nucleophilic cationic salts) to react with the necessary 

one-carbon linking units (formaldehyde or orthoformate equivalents, or benzaldehyde). 

17.8.1.2.2.1 Variation 1: 

Using Dipyrromethenes 

Most porphyrin syntheses from dipyrromethenes were developed by Hans Fischer s 

group in Munich. The case illustrated in Scheme 7 mode F is achieved by self-condensation 

of 1-bromo-9-methyldipyrromethenes [e.g., 174 R 1 = Et, (CH 2) 2CO 2H; R 2 = Me] in boiling 

formic acid or in organic acid melts (succinic, tartaric, etc.) at temperatures up to 

and exceeding 200 8C to give, for example, etioporphyrin I (176, R 1 = Et) or coproporphyrin 

I (176)[R 1 = (CH 2) 2CO 2H, usually isolated as the tetramethyl ester 178] (Scheme 39). [117– 

119] Fischer s collaborators determined which organic acid to use by trial and error, the 

choice simply relating to the temperature at which the best yield of porphyrin was obtained. 

It is also possible to heat 1-bromo-9-(bromomethyl)dipyrromethene hydrobromides 

[e.g., 174 (R 2 =CH 2Br)] [120] or 1-bromo-9-methyldipyrromethene perbromides, (e.g., 

175) [30] or even a mixture of both [121,122] in formic acid to give very good yields of centrosymmetrically 

substituted porphyrins, such as etioporphyrin I (176, R 1 = Et), coproporphyrin 

I tetramethyl ester (178) [via acid 177], 2,3,7,8,12,13,17,18-octaethylporphyrin 

(21), or more recently the opp-dibenzoporphyrin 180 (from the dipyrromethene 179) 

(Scheme 39). [123] (See also Scheme 7, case F.) 

C 

173 

B 

D 

A


aScheme 39 Synthesis of Porphyrins from Dipyrromethenes [30,117–122] 

R 1 

R 

NH HN 

1 

Br R2 + 

Br − 

174 

R 1 = Et, (CH 2) 2CO 2H; R 2 = Me, CH 2Br 

HO 2C 

2 

Br 

Cl 

NH HN 

+ 

Br − 

177 

NH HN 

+ 

Br − 

179 

Et 

and/or 

CO2H 

NH HN 

+ 

Br 

− 

3 


Br 

R 1 

1,2-Cl2C6H4 

heat 

175 

heat 

1. Br2, HCO2H heat 

2. MeOH, H2SO4 19% 

MeO 2C 

MeO 2C 

Et 

R 1 

R 1 

R 1 

NH N 

N HN 

178 

NH N 

N HN 

180 

NH N 

N HN 

Et 

176 

CO2Me 

R 1 

CO 2Me 

These kinds of dipyrromethene approach can be adapted to the synthesis of fairly complex 

porphyrins (e.g., natural type-III systems) by heating of 1,9-dibromodipyrromethenes 

182 with 1,9-dimethyl- or 1,9-bis(bromomethyl)dipyrromethenes 181 in organic acid 

melts; this is an example of the mode shown in Scheme 7, case E. A notable example of 

this approach is Fischer s synthesis of deuteroporphyrin IX (183), an intermediate in the 

Munich total synthesis of hemin (184) (Scheme 40). [124] The formation of a mixture of por- 

R 1 



aphyrins is avoided by selection of one dipyrromethene (i.e., 182) which is symmetrically 

substituted about its 5-(meso)-carbon atom. 

Scheme 40 Hemin Synthesis from Dipyrromethenes [124] 

NH HN 

R1 R1 Br 

+ 

− 

+ 

Br Br 

+ 

NH HN 

181 R1 CO2H CO2H = Me, CH2Br 182 

CO 2H 

NH N 

N HN 

183 

N Cl N 

N N 

3,8,13,18-Tetraethyl-2,7,12,17-tetramethylporphyrin (Etioporphyrin I, 176,R 1 = Et); Typical 


Brominated kryptodipyrromethene hydrobromide (36; 10 g, 24.86 mmol) in HCO 2H 

(20 mL) was heated on a boiling water bath with regular shaking for 4 h. After cooling 

the soln was diluted with H 2O and treated with aq NaOH until alkaline. The precipitate 

was subjected to Soxhlet extraction, initially using MeOH, until the solvents were weakly 

brown. Then the extraction was performed with CHCl 3 (ca. 20 mL) until the percolating 

solvent was colorless. The CHCl 3 soln was separated, treated with MeOH, and the crystals 

were collected by filtration. Recrystallization (CHCl 3/MeOH) gave 176 (R 1 = Et); yield: 2 g; 

mp >300 8C. 

3,8,13,18-Tetrakis[2-(methoxycarbonyl)ethyl]-2,7,12,17-tetramethylporphyrin (Coproporphyrin 

I Tetramethyl Ester, 178); Typical Procedure: [30] 

1-Bromo-3,8-bis(2-carboxyethyl)-2,7,9-trimethyldipyrromethene hydrobromide (177; 1g, 

2.04 mmol) was suspended in HCO 2H (10 mL) and refluxed for 2 h before the solvent was 

removed by distillation at atmospheric pressure. The residue was dissolved in H 2SO 4/ 

MeOH [5% (v/v), 100 mL] and left at rt in the dark for 12 h. The soln was poured into H 2O 

and extracted with CH 2Cl 2; this soln was then washed with H 2O, dried (MgSO 4), and concentrated 

to dryness. The purple residue was chromatographed [alumina (Brockmann 

Grade III), CH 2Cl 2], the red eluates were concentrated and the residue was crystallized 

(CH 2Cl 2/MeOH) to give the porphyrin 178; yield: 140 mg (19%); mp 255–2568C. 

In an improvement designed to simulate use of the perbromide 175 [R 1 =(CH 2)CO 2H] 

instead of the hydrobromide 174, compound 174 [R 1 =(CH 2)CO 2H, R 2 =Me; 2g, 

4.07 mmol] in HCO 2H (20 mL) was treated with Br 2 (0.65 g, 4.07 mmol) and refluxed for 

2 h. After a workup as above, coproporphyrin I tetramethyl ester (178) was isolated; yield: 

733 mg (50%). 


CO 2H 

Br − 

CO 2H 

Fe 

184 

CO2H


a17.8.1.2.2.2 Variation 2: 

Using Dipyrromethanes 

Fischer s almost exclusive use of dipyrromethenes overshadowed the development of 

porphyrin syntheses using other dipyrroles; even in those days it was known that dipyrromethanes 

were so unstable toward acidic reagents (and most certainly to those used by 

Fischer) that they might not be useful as porphyrin precursors. This is indeed true for 

one of Fischer s procedures, [125] for which it has been shown that the self-condensation 

of dipyrromethane-1,9-dicarboxylic acids (e.g., 185) in formic acid gives a mixture of 

porphyrin type-isomers rather than pure etioporphyrin II (186,R 1 = Et) or coproporphyrin 

II [186,R 1 =(CH 2) 2CO 2H] (Scheme 41). [126,127] 

Scheme 41 Synthesis of Porphyrins from Dipyrromethanes [25,48,126–128] 

R 1 R 1 

NH HN 

HO 2C CO 2H 

185 

R 1 = Et, (CH 2) 2CO 2H 

MeO 2C 

MeO2C 

HCO 2H, heat 

R 1 R 1 

NH N 

N HN 

OHC CHO 

NH HN 

+ 

NH HN 

1 R R1 

187 R1 CO2Me CO2Me MeO2C CO2Me 

MeO2C CO2Me 

= H, CO2H 188 

HI, [O] 


R 1 

MeO 2C 

MeO 2C 

MeO 2C 

186 

R 1 

NH N 

N HN 

MeO2C CO2Me 

189 

CO2Me 

CO2Me CO2Me 



MeO 2C 

OHC CHO 

aNH HN 

CO2Me 

+ 

NH HN 

1 R R2 

190 R 1 = H, CO 2H, CO 2Bn; R 2 = H, CO 2-t-Bu 

CO 2Me 

NH HN 

R1 CHO 

193 R 1 = H, CO 2H 

CO2Me 

TsOH, [O] 

MeO 2C CO 2Me 

MeO2C 

MeO 2C 

MeO 2C 

MeO 2C 


191 

NH N 

N HN 

192 41% 

NH N 

N HN 

178 

CO 2Me 

CO2Me 

CO2Me 

CO 2Me 

A critically important development in the art and science of porphyrin synthesis occurred 

with the discovery by MacDonald and his group [25] that a 1,9-diformyldipyrromethane 

(e.g., 188) can be treated with a 1,9-di-unsubstituted dipyrromethane 187 (R 1 = H, or its 

chemically equivalent 1,9-dicarboxylic acid R 1 =CO 2H) in the presence of an acid catalyst 

to afford a pure porphyrin [e.g., uroporphyrin III octamethyl ester (189)] in yields often as 

high as 60% (Scheme 41). MacDonald s key publications employed hydriodic acid (which 

is not easy to handle or to purify), and the high yields achieved by his group appear to be 

limited to sterically encumbered porphyrins such as those of the uroporphyrin series. Recently, 

4-toluenesulfonic acid has been shown [48,128] to be a much more convenient alternative 

to hydriodic acid as the important acid catalyst; in this way, for example, coproporphyrin 

III tetramethyl ester (192) is obtained from the dipyrromethanes 190 (R 1 =CO 2Bn, 

R 2 =CO 2t-Bu, via R 1 =CO 2H and R 1 ,R 2 = H) and 191. 

The MacDonald [2 +2] route is probably the most widely used pathway to synthetic 

porphyrins, even though it suffers the same symmetry restrictions apparent in Fischer s 

syntheses from dipyrromethenes. Thus, one of the two dipyrromethanes (e.g., compounds 

188 and 191 in Scheme 41) must be symmetrical about its interpyrrolic 5-carbon 

atom; this is an example of mode E illustrated in Scheme 7. The approach can also be 

modified (Scheme 7, mode F) to include the preparation of centrosymmetrically substitut-


aed porphyrins 178 by self-condensation of a 9-unsubstituted 1-formyldipyrromethane 

193 (Scheme 41). 

5,10,15,20-Tetraarylporphyrins, such as 5,10,15,20-tetraphenylporphyrin (22), are 

prepared by reaction of an arylaldehyde with pyrrole, but if a tetraarylporphyrin is required 

that has different aryl groups at the each of the meso positions some major synthetic 

problems need to be overcome. Such porphyrins are usually synthesized by the condensation 

of pyrrole with a mixture of arylaldehydes, [130,131] but are obtained in poor yields after 

lengthy chromatographic separation and purification. If pyrrole were to be condensed 

with a mixture of four arylaldehydes there is only a minor possibility that a porphyrin 

with one each of the aryl groups in it would be obtained, and even then one would not 

know the spatial relationship of each of the aryl groups to the others (i.e., which is at position 

5, 10, 15, 20, etc.). However, a synthetic route has been developed which, for example, 

can yield the totally unsymmetrical porphyrin 195. [132] It is based on the MacDonald [2+2] 

route, using 5-aryl-1,9-diaroyldipyrromethanes 194 rather than 1,9-diformyldipyrromethanes. 

Scheme 42 shows such a route to porphyrin 195. This is an example of mode E 

outlined in Scheme 7. A very similar approach was subsequently reported by Lindsey 

and co-workers. [133] 

Scheme 42 Unsymmetrical Tetraarylporphyrins by the MacDonald Approach [132] 

MeO 

MeO 

O 

O 

N 

H 

N 

H 

LiAlH4 

POCl3 

DMF 

4-TolMgBr 

44% 

O 

N 

H 

CHO 

71% 

OH 

4-Tol 

MeO 

N 

H O 

K-10 clay 

NH N 

N HN 


45% 

MeO 

Ph 

MeO 

4-Tol 

NH HN 

OH HO 

MeO 

Ph 

4-Tol 

NH HN 

O O 

194 

4-Tol 

F 

195 

NH HN 

F 

EtCO2H, heat 

12% 

Ph 

Ph 



aAround the same time (1960) that MacDonald published his general [2 +2] approach using 

dipyrromethanes, R. B. Woodward published his synthesis of chlorophyll a. [44,134,135] 

Woodward also used a bisdipyrromethane [2 +2] mode, but characteristically, designed 

his approach so that the normal requirement that there be symmetry about one of the 

dipyrromethane 5-carbon atoms was circumvented; though mode E, Scheme 7, was employed, 

enhanced reactivity of one of the terminal positions of the 1,9-di(“carbonyl”)dipyrromethane 

196 (Scheme 43) allowed exquisitely regioselective condensation with 56, 

by way of the tethered tetrapyrrole (see arrow in 197) to give only one b-bilene 198 and 

finally only one porphyrin 199. The transient involvement of the b-bilene prompted later 

researchers to investigate approaches to unsymmetrical porphyrin syntheses via openchain 

tetrapyrrole precursors such as 198 and particularly of biladienes. 

Scheme 43 Woodward s Version of the [2 +2] Dipyrromethane Approach [44,134,135] 

CO2Me 

NH 2 

NH 

NH 

+ 

S 

O 

H 

HN 

HN 

CO 2Me 

56 196 

+ NH3 Et 

CO2Me 

MeO 2C 

NH N 

N HN 


AcOH 

CO2Me 

Et 

HCl, MeOH 

NH HN 

+ 

I2/Ac2O 48% 

NH HN 

CO 2Me 

O 

198 

CO 2Me 

CO2Me 

2Cl − 

N 

NH N 

NH HN 

O 

197 

CO2Me 

NH 2 

Et 

CO 2Me 

CO2Me 

199 

Et 

CO2Me 

The MacDonald procedure, through dipyrromethanes, fully mirrors the Fischer routes 

through dipyrromethenes, each method having its relative advantages and disadvantages. 

An obvious disadvantage of the Fischer route is the vigorous thermal and acidic 

conditions required; these often cause destruction of the sensitive side chains which are 

available and essential in modern porphyrin syntheses. The advantage of the MacDonald 

approach is that dipyrromethanes with complex substituents tend to be more readily prepared 

than the corresponding dipyrromethene analogues, and once synthesized these intermediates 

can be transformed into porphyrins using very mild reaction conditions. 

Thus, in recent times, the MacDonald approach has even been modified to afford a very 

useful [3+1] analogue (see Section 17.8.1.2.3). [116,136–143] 

Scheme 7, mode D illustrates a procedure in which two 1,9-di-unsubstituted dipyrroles 

are joined together by use of two identical one-carbon (formaldehyde, ortho-


aformate, or arylaldehyde) units. This approach only works well for dipyrromethanes due 

to the non-nucleophilicity of the corresponding dipyrromethene analogues. This mode of 

synthesis is demonstrated in the synthesis of coproporphyrin II tetramethyl ester (201)by 

treatment of the dipyrromethane 200 in dichloromethane with trimethyl orthoformate 

in the presence of trichloroacetic acid catalyst (Scheme 44). [68] A 24% yield of coproporphyrin 

II tetramethyl ester is obtained in this way. 

Methodology has also been developed which allows the synthesis of 5,15-diaryl- or 

5,15-dialkylporphyrins from a dipyrromethane and a one-carbon linker unit (formaldehyde, 

orthoformate equivalent, or alkyl/aryl aldehyde). [52] Conditions are similar to those 

employed in the MacDonald route. Scheme 44 shows typical examples, e.g. porphyrin 203 

produced from the 5-mesityldipyrromethane 202 and 4-iodobenzaldehyde. 

Scheme 44 Synthesis of Porphyrins from Dipyrromethanes [52,68] 

MeO 2C 

NH HN 

HO2C CO 2H 

Mes 

200 

NH HN 

202 

CO2Me 

CHO 

I 

BF3 OEt2, DDQ, CHCl3 32% 

Cl3CCO2H, HC(OMe)3, CH2Cl2, O2 

24% 

MeO2C 

MeO 2C 

NH N 

N HN 

NH N 

N HN 


Mes 

Mes 

203 

201 

CO 2Me 

CO2Me 

I I 



Mes 

NH HN 

a202 

CHO 

TMS 

TMS 

, H + 

NH N 

N HN 

A mixed dipyrromethane/dipyrromethene synthesis has also been reported by MacDonald 

s group (Scheme 45). Condensation of a 1,9-bis(bromomethyl)dipyrromethene 205 

with a 1,9-di-unsubstituted dipyrromethane 204 affords a good yield of the isomerically 

pure porphyrin 206. [25] 

Scheme 45 Synthesis of Porphyrin from Dipyrromethane and Dipyrromethene [25] 

HO2C HO2C NH HN 

CO2H 

CO2H 


+ 

Mes 

Mes 

Br Br 

+ 

NH HN 

204 205 

HO2C HO2C NH N 

N HN 

206 

Br − 

TMS 

HO2C CO 2H 

CO2H 

CO2H 

HO2C CO 2H 


III Tetramethyl Ester, 192); Typical Procedure: [129] 

Benzyl 9-(tert-butoxycarbonyl)-3,8-bis[2-(methoxycarbonyl)ethyl]-2,7-dimethyldipyrromethane-1-carboxylate 

(190, R 1 =CO 2Bn; R 2 =CO 2t-Bu; 456 mg, 0.79 mmol) in THF 

(100 mL) containing Et 3N (2 drops) and 10% Pd/C (46 mg) was hydrogenated at rt and atmospheric 

pressure until uptake of H 2 ceased. The catalyst was filtered off through Celite 

and the filtrate was concentrated to dryness to give 190 (R 1 =CO 2H; R 2 =CO 2t-Bu); the residue 

was dissolved in TFA (25 mL) and kept under N 2 for 45 min before concentration under 

reduced pressure. CH 2Cl 2 and H 2O were added and the organic phase was washed with 

aq NaHCO 3 and then H 2O to give 190 (R 1 =R 2 = H) before being dried (Na 2SO 4) and made up 

to a total volume of 150 mL with CH 2Cl 2. This soln was added to a darkened flask (alumi-


anum foil) containing 1,9-diformyl-3,7-bis[2-(methoxycarbonyl)ethyl]-2,8-dimethyldipyrromethane 

(191; 250 mg, 0.62 mmol) in CH 2Cl 2 (100 mL), and then treated with a soln of 

TsOH (900 mg, 4.7 mmol) in MeOH (12.5 mL). After stirring for 6 h in the dark, the soln 

was treated with a sat. soln of Zn(OAc) 2 in MeOH (12.5 mL) and set aside overnight. The 

mixture was washed with H 2O, aq NaHCO 3,H 2O, and then dried (Na 2SO 4). After concentration 

to dryness, the residue was dissolved in H 2SO 4/MeOH (5%, 20 mL) and set aside overnight 

at rt in the dark. The soln was poured into CH 2Cl 2/H 2O, and the organic phase was 

collected and washed with H 2O, aq NaHCO 3,H 2O, and then dried (Na 2SO 4). Concentration 

gave a red residue, which was chromatographed [neutral alumina (Brockmann Grade III), 

CH 2Cl 2]. The red eluates were concentrated and recrystallization of the residue (CH 2Cl 2/ 

MeOH) gave 192; yield: 180 mg (41%); mp 150–1538C, remelting at 179–1828C. 

3,7,13,17-Tetrakis[2-(methoxycarbonyl)ethyl]-2,8,12,18-tetramethylporphyrin 

(Coproporphyrin II Tetramethyl Ester, 201); Typical Procedure: [68] 

3,7-Bis[2-(methoxycarbonyl)ethyl]-2,8-dimethyldipyrromethane-1,9-dicarboxylic acid 

(200; 550 mg, 1.27 mmol) [obtained by catalytic hydrogenation (in THF, over 5% Pd/C) of 

dibenzyl 3,7-bis[2-(methoxycarbonyl)ethyl]-2,8-dimethyldipyrromethane-1,9-dicarboxylate] 

was treated with 1 M trichloroacetic acid in CH 2Cl 2 (72 mL) and an excess of 

HC(OMe) 3 (2.5 g, 23.6 mmol) in CH 2Cl 2 (408 mL). The soln was stirred in the presence of 

O 2 overnight at rt in the dark, monitored by observation of the Soret absorption band 

(410 nm, dication salt). The soln was washed with 10% aq Na 2SO 4 (200 mL), H 2O 

(2 ” 200 mL), dried (MgSO 4), and concentrated to dryness. The residue was chromatographed 

[neutral alumina (Brockmann Grade III), CH 2Cl 2] and the red eluates were collected. 

Concentration and crystallization (CH 2Cl 2/MeOH) gave 201; yield: 104 mg (24%); mp 285– 

2888C. 

5,15-Bis(4-iodophenyl)-10,20-di(mesityl)porphyrin (203); Typical Procedure: [52] 

A soln of 4-iodobenzaldehyde (58 mg, 0.25 mmol) and 5-mesityldipyrromethane (202; 

66 mg, 0.25 mmol) in CHCl 3 (25 mL) was purged with argon for 10 min before addition of 

2.5 M BF 3•OEt 2 in CHCl 3 (33 mL, 3.3 mM). The soln was stirred for 1 h at rt and then DDQ 

(43 mg, 0.19 mmol) was added. The mixture was stirred at rt for 1 h and the solvent was 

removed. Column chromatography (silica gel, CH 2Cl 2) afforded the porphyrin 203 as the 

first moving band; yield: 38 mg (32%); mp >300 8C. Comparable yields were obtained using 

TFA (0.01–0.05 M) as the catalyst. 

17.8.1.2.2.3 Variation 3: 

Using Dipyrroketones 

The carbonyl group in dipyrroketones is a bis-vinylogous amide, and therefore does not 

chemically behave like a regular ketone; reagents such as diborane are required to accomplish 

the reduction to methylene. It cannot, therefore, be reduced simply by the addition 

of sodium borohydride to the dipyrroketone. Porphyrins per se cannot be synthesized directly 

from dipyrroketones using a [2 +2] protocol (e.g., Scheme 7, modes D, E, and F) because 

the 5-carbonyl function in the dipyrroketone will remain in the final cyclization 

product to yield species known as oxophlorins. However, oxophlorins (e.g., 209) which 

can be readily converted into the corresponding porphyrins, can be prepared in good 

yield [144] by a MacDonald-type condensation of 1,9-diformyldipyrroketones 207 with 1,9di-unsubstituted 

dipyrromethanes 208 (R 1 = H) or the corresponding 1,9-dicarboxylic 

acids 208 (R 1 =CO 2H) (Scheme 46). 1-Formyl-9-(hydroxymethyl)dipyrroketones (e.g., 210) 

can be used in place of 207. [145] The diformyldipyrroketones 207 are best obtained by direct 

oxidation of readily available 1,9-diformyldipyrromethanes 211 (Scheme 39; see also 

Section 17.8.1.1.1.3). [146] However, the formyl groups, which eventually form the bridging 

carbon atoms between the two dipyrrolic halves, must be placed on the dipyrroketone 




amoiety because 1,9-di-unsubstituted dipyrroketones (e.g., 212) are not nucleophilic 

enough to react with 1,9-diformyldipyrromethanes (e.g., 211). 

As might be anticipated, the same symmetry considerations that restrict the Fischer 

syntheses from dipyrromethenes, and the standard MacDonald syntheses from dipyrromethanes, 

are also applicable to [2+2]-type syntheses of 5-oxophlorins. 

Scheme 46 Synthesis of Oxophlorin from Dipyrroketones [144,145] 

MeO 2C 

A 

OHC 

O 

NH HN 

OHC CHO 

207 

B O C 

NH HN 

210 

D 

OH 

CO 2Me 

A 

+ 

MeO2C 

B C 

NH HN 

R 1 R 1 

NH HN 

208 R 1 = H, CO 2H 

MeO2C 

MeO2C 

CO 2Me 

NH HN 

N HN 


D 

OHC CHO 

211 

A 

O 

209 

1. TFA 

2. NH3, MeOH 

B O C 

NH HN 

212 

CO 2Me 

CO2Me 

Transformation of oxophlorins 213 into porphyrins 215 is possible using several different 

routes (Scheme 47). [147] The oxophlorin oxo-group can be removed by: (i) sodium amalgam 

reduction followed by re-oxidation of an intermediate porphyrinogen 214, usually 

with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, to porphyrin 215; or (ii) catalytic hydrogenation 

of the oxophlorin to give the macrocyclic tetrapyrroketone 217, followed by reduction 

with diborane to give the porphyrinogen 214 and re-oxidation to porphyrin 215; 

or (iii) treatment of the oxophlorin with acetic anhydride in pyridine to give the enol-acetate 

5-acetoxyporphyrin 216, followed by catalytic hydrogenation to the porphyrinogen 

214 (or possibly intermediate 218) and re-oxidation with 2,3-dichloro-5,6-dicyanobenzo- 

1,4-quinone to give the meso-unsubstituted porphyrin, mesoporphyrin IX dimethyl ester 

(215). Method (iii), via the readily isolated 5-acetoxyporphyrin 216, is the method of 

choice, and yields of porphyrin 215 from 216 are often as high as 85%. The yield of 5-acetoxyporphyrin 

216 from oxophlorin 213 is usually excellent (see Section 17.8.1.2.4.2). 

D


aScheme 47 Porphyrin Syntheses from Oxophlorins [147] 

Et 

CO 2Me 

MeO2C 

NH HN 

N HN 

Ac2O py 

213 

MeO2C 

Et 

Et 

NH HN 

NH HN 

217 

Et 

O 

CO 2Me 

Na/Hg 

NH N 

N HN 

216 

Et 

Et 

CO2Me 

Et 

OAc 

CO 2Me 

NH HN 

NH HN 


214 

H 2 

Pd/C 

MeO2C 

Et 

Et 

DDQ 

CO 2Me 

NH HN 

NH HN 

218 

Et 

CO 2Me 

O OAc 

CO2Me 

Et 

NH N 

N HN 

CO2Me 

215 

Et 

CO 2Me 

3,7,13,17-Tetrakis[2-(methoxycarbonyl)ethyl]-2,8,12,18-tetramethyl-5-oxophlorin (209); 


1,9-Diformyl-3,7-bis[2-(methoxycarbonyl)ethyl]-2,8-dimethyl-5-dipyrroketone (207; 

830 mg, 1.99 mmol) was added in portions over 15 min to a stirred soln of 3,7-bis[2-(methoxycarbonyl)ethyl]-2,8-dimethyldipyrromethane-1,9-dicarboxylic 

acid (208, R 1 =CO 2H; 

900 mg, 2.07 mmol) in TFA (8.0 mL). After 2 h, the violet soln was poured into cold MeOH 

(40 mL) and the stirred mixture was kept at 108C while 3 M aq NH 3 was added dropwise 

until the pH was slightly alkaline. The green precipitate was collected, washed with aq 

MeOH (90%), and recrystallized (CHCl 3/MeOH) to give the oxophlorin 209; yield: 1.2 g 

(83%); mp 232–2348C. 

3,8-Diethyl-13,17-bis[2-(methoxycarbonyl)ethyl]-2,7,12,18-tetramethylporphyrin (Mesoporphyrin 

IX Dimethyl Ester, 215); Typical Procedure: [69] 

5-Acetoxy-3,18-diethyl-8,12-bis[2-(methoxycarbonyl)ethyl]-2,7,13,17-tetramethylporphyrin 

(216; 50 mg, 0.078 mmol) in THF (40 mL) containing Et 3N (1 drop) was hydrogenated 

over 10% Pd/C (50 mg) until uptake of H 2 ceased (7 h). The catalyst was filtered off and 

the solvent was removed under vacuum to give a yellow gum, which was dissolved in 



aCH 2Cl 2 (300 mL) and oxidized by addition of portions (12 ” 100 mL) of 0.005% I 2 in 3% aq 

NaOAc. [Note: addition of an excess of DDQ in toluene is more convenient and gives a 

higher yield]. The mixture was shaken after each addition and the final organic layer 

was separated, washed with H 2O, and dried (MgSO 4). After concentration to dryness, the 

residual red gum was chromatographed [neutral alumina (Brockmann Grade III), eluting 

with CH 2Cl 2] to give, after recrystallization (CH 2Cl 2/MeOH), mesoporphyrin IX dimethyl 

ester (215); yield: 29 mg (64%); mp 216–2178C. 

5-Acetoxy-3,18-diethyl-8,12-bis[2-(methoxycarbonyl)ethyl]-2,7,13,17-tetramethylporphyrin 


Crude 3,18-diethyl-8,12-bis[2-(methoxycarbonyl)ethyl]-5-oxo-2,7,13,17-tetramethylphlorin 

[213; obtained from cyclization of 3,8-diethyl-13,17-bis[2-(methoxycarbonyl)ethyl]- 

2,7,12,18-tetramethyl-b-oxobilane-1,19-dicarboxylic acid (110; 345 mg, 0,45 mmol)] was 

taken up in pyridine (30 mL) and Ac 2O (8 mL). After stirring at rt for 10 min, the deep red 

soln was concentrated under reduced pressure to give an oil, which was chromatographed 

twice [neutral alumina (Brockmann Grade III), CH 2Cl 2]. The red eluates were concentrated 

to give a residue, which was crystallized from CH 2Cl 2/MeOH to give the 5-acetoxyporphyrin 

216; yield: 245 mg (70%); mp 236–2378C. 

17.8.1.2.3 Method 3: 

From Tripyrrolic Intermediates: The [3+1] Route 


Vol. E 9d, p 588. 

The protocol involving cyclization of an open-chain tripyrrole with a 2,5-difunctionalized 

monopyrrole to produce a porphyrin (Scheme 48) utilizes the mode of attachment 

G shown in Scheme 7, and has a number of useful applications. Porphyrin models are being 

increasingly used as mimics for natural systems and for commercial applications, the 

objective of a particular approach often being the attachment of some biological moiety 

to the porphyrin system; access to porphyrins in which one pyrrole subunit might be 

functionalized uniquely for that attachment is made possible by the [3+1] approach. For 

example, if a porphyrin attached at one point to a peptide was the synthetic target, using 

the [3 +1] protocol it would be possible to quickly synthesize a porphyrin bearing, for example, 

one carboxylic acid group (on the monopyrrole component). Less sophisticated 

monopyrrole polymerization methods would obviously yield a porphyrin with one carboxylic 

acid group on each of the four porphyrin subunits. For usefulness in such biological 

applications, the [3 +1] protocol must be simple, and almost as easy to operate as a 

monopyrrole tetramerization. Such simplicity has been facilitated by recent advances in 

tripyrrane syntheses (see Section 17.8.1.1.2.2) and in the accompanying monopyrrole activation 

[either by formylation (see Variation 1, 17.8.1.2.3.1) or (dimethylamino)methylation 

using Eschenmoser s reagent, (dimethylmethylidene)ammonium iodide (Variation 2, 

17.8.1.2.3.2)]. 

Scheme 48 Porphyrin Syntheses from Tripyrranes 

R 4 

R 5 

R 3 R 2 

R 6 

NH HN 

NH 

HN 

R 7 

R 1 

R 8 

NH N 

N HN 


R 4 

R 5 

R 3 R 2 

R 6 

R 7 

R 1 

R 8


aFor the [3+1] approach to be used successfully, the tripyrrole component is always a tripyrrane 

(i.e., a tripyrrole linked by two methylene groups). To date, tripyrrenes have not 

been used in this approach because of the lack of nucleophilicity (in acid) of the “methene” 

end of the tripyrrole. The [3 +1] route is not without symmetry limitations. The Sessler 

approach used for the tripyrrane synthesis requires that the terminal rings of the tripyrrane 

be identical (i.e., R 1 =R 6 ,R 2 =R 5 , Scheme 48) , though it should not take much effort 

to develop a rational route to unsymmetrically substituted tripyrranes if one was required. 

However, even if unsymmetrical tripyrranes were readily available, one would 

need to use a 2,5-diformyl-1H-pyrrole in which both the 3- and 4-substituents are identical 

(i.e., R 7 =R 8 , Scheme 48); otherwise, two porphyrins would result. 

17.8.1.2.3.1 Variation 1: 

Using a Tripyrrane and a 2,5-Diformyl-1H-pyrrole 

Johnson and co-workers used a [3+1] method for synthesis of monoheteroporphyrins, but 

not for porphyrins themselves. [148] Boudif and Momenteau were the first to apply the 

[3+1] approach (Scheme 7, mode G) for the synthesis of porphyrins, using a 2,5-diformyl-1H-pyrrole 

and a tripyrrane; [136,137] using this route they chose to synthesize only bisacrylic 

or bis-propanoic porphyrins (e.g., 221) from the tripyrrane 219 and diformylpyrroles 

220. Lash and co-workers demonstrated the generality of the approach, and have 

completed a number of syntheses of porphyrins such as 224 and 225 (Scheme 49). [138–142] 

For the synthesis of 224, the tripyrrane-1,14-dicarboxylic acid 222 is synthesized from 2 

equivalents of the 2-(acetoxymethyl)-1H-pyrrole 92 and one of 4,5,6,7-tetrahydro-2H-isoindole, 

followed by catalytic debenzylation. The tripyrrane 222 is then treated with the 2,5diformyl-1H-pyrrole 

223 to give porphyrin 224. Sessler and co-workers have also shown 

the applicability of the approach and accomplished syntheses of porphyrins such as 226 

and 227 through similar methodology. [143] A one-step route for synthesis of 2,5-diformyl- 

1H-pyrroles is available, which makes the [3+1] approach even more attractive. [149] 




aScheme 49 Porphyrin Syntheses Using the [3+1] Approach [136–143] 

EtO2C 

EtO 2C 

Et 

NH 

219 

NH HN 

NH 

CO2H 

AcO 

1. 

Et 

Et 

2. H2, Pd/C 

CO 2H 

N 

H 

92 

1. 

OHC 

2. DDQ 

+ 

EtO 2C 

EtO 2C 

NH N 

N HN 


OHC 

HN 

CO (2 equiv), H 

2Bn 

+ 

Et Et 

N 

H 

223 

47% 

CHO 

CHO 

220 

CO2Et 

Et 

, TFA, CH 2Cl2 

Et 

CO 2Et 

Et 

221 

NH HN 

NH 

CO2H 

222 

Et 

Et 

CO2Et 

NH N 

N HN 

224 

CO 2H 

Et 

Et 

CO2Et 

Et

aNH N 


Et 

Et 

MeO 2C 

Et 

N HN 

225 

NH N 

N HN 

227 

Et 

Et 

Et 

Et 

Et 

CO2Me 

NH N 

N HN 


Et 

Et 

Et 

226 

Et 

CO 2Me 

2:3-Butano-7,12,13,18-tetraethyl-8,17-dimethylporphyrin (224); Typical Procedure: [141] 

7:8-Butano-3,12-diethyl-2,13-dimethyltripyrrane-1,14-dicarboxylic acid (222; 100 mg, 

0.22 mmol) was stirred in TFA under a N 2 atmosphere for 10 min before being diluted 

with CH 2Cl 2 (19 mL) and treated with 3,4-diethyl-2,5-diformyl-1H-pyrrole (223; 40mg, 

0.223 mmol). The mixture was stirred for 2 h under N 2, and then neutralized by dropwise 

addition of Et 3N. DDQ (53 mg, 0.23 mmol) was then added and the mixture was stirred at 

rt for 2 h under N 2. The soln was washed with H 2O, concentrated under reduced pressure, 

and the residue was chromatographed [neutral alumina (Brockmann Grade III), CH 2Cl 2]. 

The porphyrin fraction was collected and concentrated under vacuum to give a residue 

which was crystallized (CHCl 3/MeOH) to give 224; yield: 47 mg (47%); mp >300 8C. 

17.8.1.2.3.2 Variation 2: 

Using a Tripyrrane and a 2,5-Bis[(dimethylamino)methyl]-1H-pyrrole 

While in the process of developing “acid-free” porphyrin macrocyclization techniques 

(e.g., Scheme 35), [114,115] a [3 +1] protocol for porphyrin synthesis was devised [116] which, 

though not a MacDonald approach, is nevertheless an example of mode G illustrated in 

Scheme 7. Treatment of the tripyrrane 229 with, for example, the 2,5-bis[(dimethylamino)methyl]-1H-pyrrole 

230 in methanol containing ferricyanide, gives the porphyrin 

231 in 16% yield (Scheme 50). The starting tripyrrane 228 is synthesized from 2 equivalents 

of the 2-(acetoxymethyl)-1H-pyrrole 42 and 3,4-diethyl-1H-pyrrole, and then subjected 

to catalytic debenzylation to give 229; the 2,5-bis[(dimethylamino)methyl]-1H-pyrrole 

230 is obtained by treatment of 3,4-diphenyl-1H-pyrrole with an excess of Eschenmoser s 

salt. 



aScheme 50 Porphyrin Syntheses Using the [3+1] Approach [116] 

Et Et N 

H 

42 

N 

H 

Ph Ph 

N 

H 

MeO2C 

AcO 

H2, Pd/C, THF 

100% 

(2 equiv), MeOH, TsOH 

CO2Bn MeO 2C 

84% 

Et 

H2C NMe2 I − + 

, MeNO2 83% 

MeO 2C 

MeO2C 

NH N 

N HN 


Et 

NH HN 

NH 

CO2H 

229 

CO 2H 

Et 

CO 2Me 

Ph Ph 

Et 

Me2N NMe 2 

N 

H 

230 

Et 

Et 

NH HN 

NH 

CO2Bn 

228 

Ph Ph 

231 

N 

H 

Ph 

CO 2Me 

CO 2Bn 

Me 2N NMe2 

230 

MeOH, K3[Fe(CN)6] 

16% 

CO 2Me 

Dibenzyl 7,8-Diethyl-3,12-bis[2-(methoxycarbonyl)ethyl]-2,13-dimethyltripyrrane-1,14-dicarboxylate 


3,4-Diethyl-1H-pyrrole (0.37 g, 3.00 mmol) and benzyl 5-(acetoxymethyl)-4-[2-(methoxycarbonyl)ethyl]-3-methyl-1H-pyrrole-2-carboxylate 

(42; 2.02 g, 5.41 mmol) were dissolved in 

MeOH (35 mL) and TsOH (0.10 g, 0.5 mmol) was added. The mixture was heated at 608C 

under N 2 for 12 h before the volume was reduced to about 20 mL. The resulting suspension 

was stored at 0 8C for several hours, then the solid was collected by filtration and 

washed with cold MeOH to afford 228 as an off-white powder; yield: 1.72 g (84%); mp 

163–1648C. 

2,5-Bis[(dimethylamino)methyl]-3,4-diphenyl-1H-pyrrole (230); Typical Procedure: [116] 

3,4-Diphenyl-1H-pyrrole (2.60 g, 11.90 mmol) and Eschenmoser s reagent (6.61 g, 

35.62 mmol) were dissolved in dry MeNO 2 (250 mL) and stirred at rt under N 2 for 12 h. Further 

Eschenmoser s salt (another 1.52 g, 8.19 mmol) was added and the mixture was re- 

Ph


afluxed for 15 min before the solvent was removed. Workup gave 230; yield: 3.97 g (83%); 

mp dec. 

7,8-Diethyl-3,12-bis[2-(methoxycarbonyl)ethyl]-2,13-dimethyl-17,18-diphenylporphyrin 


Tripyrrane 228 (0.33 g, 0.45 mmol) was dissolved in THF (80 mL), and 10% Pd/C (70 mg) and 

one drop of Et 3N were added. The resulting mixture was stirred under H 2 at rt for 10 h. The 

catalyst was removed by filtration and the solvent was removed from the filtrate to leave 

a residue. Crystallization (CH 2Cl 2/hexanes) afforded tripyrrane-1,14-dicarboxylic acid 229 

as a white powder in quantitative yield; because of spontaneous decarboxylation at room 

temperature, this was used immediately. Tripyrrane diacid 229 (0.26 g, 0.45 mmol) was 

dissolved in MeOH (100 mL) and refluxed for 15 min before pyrrole 230 (0.28 g, 

0.45 mmol) and K 3[Fe(CN) 6] (0.96 g, 2.93 mmol) were added. The resulting mixture was refluxed 

for 6 h. The MeOH was removed and the residue was redissolved in CH 2Cl 2. Some 

insoluble material was filtered off and the filtrate was washed with H 2O, 5% NH 4OH, H 2O, 

and brine, and then dried (Na 2SO 4). The solvent was removed and the crude mixture was 

chromatographed (silica gel, CH 2Cl 2). Recrystallization (CH 2Cl 2/cyclohexane) afforded the 

porphyrin 231 as a purple crystalline solid; yield: 52 mg (16%); mp 195–1968C. 

17.8.1.2.4 Method 4: 

From Open-Chain Tetrapyrrolic Intermediates 


Vol. E 9d, pp 590–596. 

Truly general porphyrin syntheses proceed in a stepwise manner from monopyrroles, 

eventually through unique open-chain tetrapyrrolic intermediates. In this way, 

the synthesis of a porphyrin with a completely asymmetric array of peripheral substituents 

is possible. Once constructed, with modern spectroscopic methods it is possible to 

verify that the intended array of substituents is present on the open-chain intermediate, 

and it must also be verified that the array remains intact during and after the cyclization 

step; this is particularly so with intermediates such as bilanes and bilenes, which have saturated 

methylene linkages, because cyclizations invariably require acidic reagents. The 

success and efficiency of a newly developed synthetic porphyrin approach is demonstrated 

definitively by choosing a target porphyrin which has been well-characterized by earlier 

workers; in this way, comparisons can be made with literature data and presumably 

by comparison with an authentic sample. Additionally, if the potential for acid-catalyzed 

pyrrole ring redistribution reactions is apparent, the target porphyrin should have pyrrole 

ring subunits that are differently substituted, for example, with pyrroles bearing 

methyl/ethyl and methyl/propanoate pairs of substituents. If acid-catalyzed scrambling 

of the pyrrole subunits in the open-chain tetrapyrrole occurs, the product will consist of 

a mixture of porphyrins containing, for example, from one to four propanoic ester 

groups. This complication is readily observable, even by simple thin-layer chromatography 

monitoring of the reaction mixture. If, on the other hand, the target molecule contains 

identical rings with only methyl/ethyl (or with only methyl/propanoate) substituent 

pairs, as in the etioporphyrins (or coproporphyrins), then more refined techniques are required 

to check for the presence of only one isomer. If conditions for cyclization of the 

open-chain tetrapyrrole are not mild, or if electron-withdrawing groups have not been 

strategically placed within the molecule, the synthesis may yield a mixture of several different 

porphyrins from a single, pure open-chain tetrapyrrole. 

The earliest attempt [150] to synthesize a porphyrin from a bilane targeted etioporphyrin 

II (8), a porphyrin in which each ring has one ethyl and one methyl substituent, the 

worst possible choice for a target. Only recently, for example, has it been possible to identify 

individual etioporphyrin type-isomers. [151] There is little doubt that this first attempt 




ato use a bilane resulted in the formation of a mixture of etioporphyrins. [150] Only after the 

publication of this synthesis was the lability of bilanes [67] and porphyrinogens [107,152] toward 

s redistribution reactions in acidic solution, understood. The dipyrromethane methylene 

linkage, particularly when it lacks stabilizing electronegative substituents on adjacent 

pyrrole rings, is extremely unstable toward pyrrole ring redistribution reactions 

(Scheme 51). Protonation of a dipyrromethane 232 bearing two different rings, X and Y, 

at either the 4- or 6-positions, can give either 233 or 234. All steps shown in Scheme 51 are 

acid–base reactions, and are therefore reversible; deprotonation will reform 232, but fragmentation, 

as shown in structure 234, can give two species, 237 and 238. Similarly, protonated 

species 233 can afford 235 and 236; once again, these pairs of intermediates can 

react together to afford eventually 232. However, pyrrole cation 237 can react with 235 to 

afford the X–X dipyrromethane 239. Likewise, the Y–Y dipyrromethane 240 can be produced 

from a reaction between 238 and 236. Thus, treatment of the X–Y dipyrromethane 

232 with acid eventually results in formation of an equilibrium mixture of the X–X, X–Y, 

Y–X, and Y–Y dipyrromethanes. There are additional factors that can affect the position of 

the equilibrium; placement of electron-withdrawing groups on the X and Y pyrrole rings 

will inhibit protonation of that pyrrole subunit, and thus inhibit the overall redistribution 

reaction. 

Scheme 51 Acid Scrambling of Pyrroles in Dipyrromethanes 

H 

X 

NH 

+ 

X 

N 

H 

233 

+ 

HN 

Y 

N+ 

H 

235 236 

X 

NH 

239 

X 

HN 

X Y 

NH HN 


232 

X 

N 

H 

+ 

NH 

234 

+ 

H 

Y 

HN 

+ 

Y 

N 

H 

237 238 

Y 

NH 

240 

Y 

HN


aSyntheses of compounds which can be used as porphyrin intermediates have been outlined 

in earlier sections of this chapter. As was mentioned above, bilanes 96 without electron-withdrawing 

functionalities are so sensitive to acidic conditions that they cannot be 

used with success; with the exception of the transient intermediacy of a bilane in the aoxobilane 

approach (Variation 1; Section 17.8.1.2.4.1); attempts to use them have always 

failed to give pure porphyrins. [150] Likewise, a-bilenes, a,c-biladienes, and a,b,c-bilatrienes 

have not found any useful application in porphyrin syntheses, mostly because of acid 

scrambling at the dipyrromethane linkages and lack of nucleophilicity due to the dipyrromethene 

link(s). 

17.8.1.2.4.1 Variation 1: 

Using a-Oxobilanes 

This approach employs mode H shown in Scheme 7. The oxo function at the a-position 

exerts a stabilizing influence on the pyrrole rings on either side of it, but the highly electronegative 

nature of this carbonyl group reduces the nucleophilicity of the terminal ring 

such that it will not react with an electrophilic one-carbon linking unit. In order to effect 

macrocyclization, it is, therefore, necessary to remove the oxo function; diborane reduction 

of 106 (Scheme 23) gives the dibenzyl bilane-1,19-dicarboxylate, which is then catalytically 

debenzylated to give the bilane-1,19-dicarboxylic acid 241 (Scheme 52). As mentioned 

above, acid-catalyzed cyclization using a one-carbon equivalent produces a complex 

mixture of porphyrins due to the use of acid, so the bilane must be pre-stabilized by 

transformation into the b-bilene 242 by oxidation with tert-butyl hypochlorite; use of this 

reagent predominantly causes oxidation at the central (“b”) methylene rather than at “a” 

or “c”. Since bilenes are readily protonated in acid (similarly to dipyrromethenes), the bilene 

moiety has the effect of placing a conjugated, positively charged (and hence highly 

electronegative) function in the middle of the tetrapyrrole. Cyclization of the b-bilene 

242 in the presence of trichloroacetic acid and trimethyl orthoformate (as the one-carbon 

linking unit) affords pure porphyrin, coproporphyrin III tetramethyl ester (192), in 23% 

yield from 106 (Scheme 52). [67,68] 




aScheme 52 Porphyrin Synthesis through a-Oxobilanes [67,68] 

MeO 2C 

MeO2C 

O 

NH HN 

NH HN 

106 

241 

CO 2Me 

MeO2C CO 2Me 

NH HN 

NH HN 

CO 2Bn 

CO2Bn 

CO 2Me 

CO 2H 

CO2H 

MeO2C CO2Me 

H + , HC(OMe)3, CH2Cl2 

1. B2H6, THF, EtOAc 

2. H2, Pd/C, THF 

t-BuOCl 

THF, Et2O MeO 2C 

MeO2C 

Cl 

MeO2C CO2Me 

242 

− 

MeO 2C 

NH HN 

+ 

NH HN 


NH 

N 

N 

HN 

192 23% 

CO 2Me 

CO 2H 

CO2H 

CO2Me 

CO2Me 

The a-oxobilane porphyrin synthesis can be used to prepare a variety of unsymmetrically 

substituted porphyrins, and the intermediates are readily synthesized from easily accessible 

dipyrromethanes. Nevertheless, this route has been somewhat ignored because it is 

complex and lengthy, and requires excellent experimental technique. After some initial 

examples were published by the inventors [67,68] it moved into obscurity, being passed over 

in favor of the b-oxobilane and a,c-biladiene routes (discussed in Sections 17.8.1.2.4.2– 

17.8.1.2.4.8 inclusive). 


III Tetramethyl Ester, 192); Typical Procedure: [68] 

Dibenzyl 3,8,13,17-tetrakis[2-(methoxycarbonyl)ethyl]-2,7,12,18-tetramethyl-a-oxobilane- 

1,19-dicarboxylate (106; 1.18 g, 1.2 mmol) in dry THF (35.2 mL) and dry EtOAc (35.2 mL)


awas reduced with diborane [generated from NaBH 4 (580 mg) in bis(2-methoxyethyl) ether 

(21 mL) and BF 3•OEt 2 (5.8 mL) in bis(2-methoxyethyl) ether (16 mL)] over a period of 5 min. 

The diborane was swept into the reaction vessel with a slow stream of N 2. After about 

90 min the absorption due to the dipyrroketone (at 360 nm) had disappeared. The resulting 

colorless soln was concentrated to dryness under a reduced pressure of N 2, treated 

with MeOH (26 mL) and set aside under N 2 until the oil had dissolved. THF (26 mL) was 

then added, together with 10% Pd/C (520 mg) and a soln of Et 3N in THF (3%, 8 drops). The 

soln was then hydrogenated at rt and atmospheric pressure for 17 h. The mixture was filtered 

through Hiflosupercel under N 2 and then concentrated under reduced pressure. It 

was then reconcentrated from Et 2O to remove traces of THF and MeOH to give 241 as a 

buff-colored gummy solid. This material was dissolved in THF (140 mL) and the soln diluted 

to 280 mL with Et 2O. The vessel was flushed with N 2 and the soln was cooled, under N 2, 

to –15 8C. tert-Butyl hypochlorite (0.144 mL) in dry Et 2O (50 mL), cooled to 08C, was then 

added over a period of 1 h in the dark. After 15 min, a starch/KI test was negative and so 

the b-bilene 242 was allowed to warm to rt. The suspension was concentrated to dryness 

and the residue was triturated with Et 2O to give the solid b-bilene [l max (CH 2Cl 2) 505 nm]. 

This bilene (assumed 1200 mmol), dissolved in CH 2Cl 2 (240 mL) containing HC(OMe) 3 

(2.56 mL), was added to dry trichloroacetic acid (12.3 g, 75.3 mmol) in CH 2Cl 2 (240 mL), 

and then stirred overnight under O 2 in the dark. The soln was then washed with aq 1 N 

Na 2CO 3 (4 ” 100 mL), H 2O (5 ” 100 mL), dried (MgSO 4), and concentrated. The residue, in a 

little CH 2Cl 2, was filtered through a plug of neutral alumina (Brockmann Grade III), and 

then chromatographed [neutral alumina (Brockmann Grade III), toluene/CH 2Cl 2 1:1]. The 

red eluates gave a purple solid (262 mg), which was triturated with Et 2O to give 192; yield: 

198 mg (23%); mp 150–155 8C and then again at 179–1828C. 

17.8.1.2.4.2 Variation 2: 

Using b-Oxobilanes 

This approach, through b-oxobilanes, is another example of the pyrrole ring connection 

mode H shown in Scheme 7. Unlike the a-oxobilane case, it is not necessary to remove the 

b-oxo function before proceeding to the porphyrin because it is too distant to affect the 

nucleophilicity of the bilane termini; in fact, the presence of the electronegative carbonyl 

group is a bonus because it provides protection against acid-promoted pyrrole subunit redistribution 

reactions in the B/C-portion of the bilane. The A and D rings, of course, are 

already protected from protonation by the electronegative benzyl esters. Thus, direct catalytic 

hydrogenation of 109 gives the dicarboxylic acid 110 (see Scheme 24), which can 

then be cyclized (as for a-oxobilanes) by treatment with trichloroacetic acid and trimethyl 

orthoformate, to give the oxophlorin 213 after air oxidation and chromatographic purification; 

yields from dipyrromethanes are usually quite high (Scheme 53). However, the 

blue oxophlorin product must first be transformed into a red porphyrin by reduction of 

the meso-carbonyl group. Methods for carrying out this transformation were discussed 

earlier (see Section 17.8.1.2.2.3, Scheme 47), and as mentioned then, the best method involves 

firstly the preparation of the enol-acetate 216 of the oxophlorin by treatment with 

acetic anhydride in pyridine. This is followed by catalytic hydrogenation and re-oxidation 

of the resulting porphyrinogen with 2,3-dichloro-5,6-dicyanobenzo-1,4-quinone, to give 

mesoporphyrin IX dimethyl ester (215) (see Scheme 47). [69] 




aScheme 53 Porphyrin Synthesis through b-Oxobilanes [69] 

Et 

O 

B A 

NH HN 

NH HN 

C D 

110 

Et 

CO 2H 

CO2H 

MeO2C CO 2Me 

H + , HC(OMe) 3, CH 2Cl 2 


70% 

Et 

O 

MeO 2C 

NH 

NH 

213 

N 

HN 

Et 

CO2Me 

The b-oxobilane approach has experienced much more success than the a-oxobilane 

route, and has been used for the synthesis of several unsymmetrical porphyrins. [48,153,154] 

The route involves a large number of steps, and for this reason has been superceded by 

the various a,c-biladiene routes, and also by the MacDonald [2 +2] pathway. Nevertheless, 

it can be used for the synthesis of a wide variety of porphyrins, and has the significant 

advantage that it affords the biologically interesting oxophlorins as intermediates. The 

dipyrromethane starting materials are available in large amounts, and unlike the corresponding 

dipyrromethenes, are easy to purify by chromatography or by recrystallization. 

3,18-Diethyl-8,12-bis[2-(methoxycarbonyl)ethyl]-10-oxo-2,7,13,17-tetramethylphlorin 


3,8-Diethyl-13,17-bis[2-(methoxycarbonyl)ethyl]-2,7,12,18-tetramethyl-b-oxobilane-1,19dicarboxylic 

acid (110; 368 mg, 0.53 mmol) in CH 2Cl 2 (50 mL) was treated successively 

with 1 M trichloroacetic acid in CH 2Cl 2 (30 mL) and HC(OMe) 3 (1.16 mL) in CH 2Cl 2 

(130 mL). The deep red soln was stirred for 2 h in the dark before addition of pyridine 

(2.4 mL), and the mixture was stirred exposed to the air overnight. The resulting green 

soln was concentrated to dryness under reduced pressure, toluene (20 mL) was added 

and the pyridinium trichloroacetate was filtered off and washed with a little toluene. 

The combined organic phases were concentrated to give a green oil, which was chromatographed 

twice [neutral alumina (Brockmann Grade III), CH 2Cl 2]. The blue eluates were 

concentrated to a small volume and on being kept at 0 8C the oxophlorin 213 crystallized 

as deep blue prisms; yield: 227 mg (70%); mp 186–1878C. 

17.8.1.2.4.3 Variation 3: 

Using 1,19-Dimethyl-b-bilenes 

As mentioned earlier, cyclization reactions of a-bilenes do not give pure porphyrins. [155] 

However, use of b-bilenes has resulted in good success. The various synthetic uses of b-bilenes 

have been summarized by Clezy, [21] who has been the major proponent for the use 

of b-bilenes in porphyrin synthesis since A. W. Johnson s time. Clezy has pointed out that 

the b-bilene method works best when electron-withdrawing substituents are present on 

the b-bilene. [21] 

b-Bilenes 115 (see Scheme 25) bearing 1- and 19-methyl groups readily undergo oxidative 

cyclization to give copper(II) porphyrinates 243 by using copper(II) salts in pyridine 

or in dimethylformamide (Scheme 54). [71–73] The copper porphyrinates can be demetalated 

with concentrated sulfuric acid, or better, with concentrated sulfuric acid in trifluoroacetic 

acid, to give metal-free porphyrin 244. [79,80] This procedure has also been used successfully 

[21,74,156–159] for the cyclization of b-bilenes bearing electron-withdrawing groups. The 

mechanism of the cyclization of 1,19-dimethyl-b-bilenes and of a,c-biladienes to give porphyrins 

has been extensively investigated. It appears that both b-bilenes and a,c-bila-


adienes are transformed into the same a,b,c-bilatriene species in the first steps of the 

mechanism. Since most of the definitive isotope labeling and other work was carried 

out using a,c-biladienes, the mechanism will be discussed in full in that section of this 

chapter (Section 17.8.1.2.4.6). 

Scheme 54 Porphyrin Synthesis Using 1,19-Dimethyl-b-bilenes [71–73] 

NH 

N 

115 

HN 

HN 

Ac 

Ac 

Cu(II), DMF 

heat or py 

H2SO4 or 

H2SO4, TFA 

N N 

N N 

The b-bilene general method for porphyrin synthesis has many advantages, mostly related 

to its simplicity and to the way it can be used to prepare relatively large quantities of 

porphyrins. Its disadvantages relate to substituent limitations associated with the bilene 

intermediates, and difficulty in purification of the b-bilenes if they do not happen to crystallize 

spontaneously. 

3,7-Diacetyl-2,8,12,13,17,18-hexamethylporphyrin (244); Typical Procedure: [74] 

2,18-Diacetyl-1,3,7,8,12,13,17,19-octamethyl-b-bilene (115; all of the material isolated 

from the preparation described in Section 17.8.1.1.3.2.1) in pyridine (40 mL) was treated 

with Cu(OAc) 2 (2 g) and the mixture was stirred for 10 min at 408C. AcOH (5 mL) and 

more Cu(OAc) 2 (3 g) were then added and the mixture was stirred for 2 h at 608C before 

being diluted with EtOH (50 mL). The precipitate was collected by filtration after 4 h, and 

washed with EtOH to give the copper(II) complex 243 (400 mg), mp >3008C. A soln of the 

copper(II) complex (200 mg) in concd H 2SO 4 (10 mL) was poured onto ice (100 g) and the 

mixture was stirred for 4 h. The precipitate was collected to give 244; yield: 150 mg; mp 

>350 8C. 

17.8.1.2.4.4 Variation 4: 

Using b-Bilene-1,19-diesters 

The synthesis of mesoporphyrin XIII dimethyl ester 245 is shown in Scheme 55. [76] Treatment 

of the di(tert-butyl) b-bilene-1,19-diester 117 with trifluoroacetic acid, followed by 

cyclization in the presence of trichloroacetic acid and trimethyl orthoformate (as the 

one-carbon linking unit) and then oxidation with air gives a 57% yield of porphyrin. The 

b-bilenes can be conveniently prepared from a tert-butyl 9-formyldipyrromethane-1-carboxylate 

and a tert-butyl 9-unsubstituted dipyrromethane-1-carboxylate (see Section 

17.8.1.1.1.2.1). This method is simple, direct, and yields crystalline intermediates at all 


Cu 

243 

Ac 

Ac 

NH 

N 

244 

N 

HN 

Ac 

Ac 



astages. However, it can be erratic and occasionally yields mixtures, particularly when 

electron-withdrawing substituents are sited on the B–C portion of the b-bilene. 

Scheme 55 Porphyrin Synthesis Using b-Bilene-1,19-diesters [76] 

Et 

MeO 2C 

NH 

+ 

NH 

HN 

HN 

Bu t O 2C CO 2Bu t 

Et 

Cl − 

1. TFA 

2. HC(OMe)3 

H + , O2 

N HN 

NH N 

CO2Me 

MeO2C CO2Me 118 245 

2,8-Diethyl-13,17-bis[2-(methoxycarbonyl)ethyl]-3,7,12,18-tetramethylporphyrin (Mesoporphyrin 

XIII Dimethyl Ester, 245); Typical Procedure: [76] 

Di-tert-butyl 7,13-diethyl-2,18-bis[2-(methoxycarbonyl)ethyl]-3,8,12,17-tetramethyl-b-bilene-1,19-dicarboxylate 

(118; 247 mg, 0.284 mmol) in TFA (15 mL) was purged with N 2 for 

20 min. The TFA was removed under reduced pressure, dry benzene (CAUTION: carcinogen) 

was added and removed under vacuum, and the resulting red oil was taken up in 

CH 2Cl 2 (50 mL). It was washed with H 2O, aq Na 2CO 3, and then H 2O again. The deep yellow 

soln was dried (MgSO 4), concentrated to dryness under reduced pressure, and the residue 

was dissolved in CH 2Cl 2 (57 mL) containing HC(OMe) 3 (0.65 mL) before addition of 1 M trichloroacetic 

acid in CH 2Cl 2 (42 mL). Spectrophotometry showed porphyrin formation to 

be almost instantaneous, but the soln was stirred in air overnight in the dark at rt. It was 

washed with aq Na 2CO 3 and then H 2O. After drying (MgSO 4), the soln was concentrated to 

dryness under reduced pressure to give a red-brown oil which was separated from the 

nonvolatile liquid by heating at 508C and 0.2 Torr for 30 min. Chromatography (2 ”) (alumina, 

CH 2Cl 2) separated a red band. These fractions were concentrated to dryness to give 

a red residue, which was crystallized (CH 2Cl 2/MeOH) to give mesoporphyrin XIII dimethyl 

ester (245); yield: 102 mg (57%); mp 2178C. 

17.8.1.2.4.5 Variation 5: 

Using Other b-Bilenes 

As mentioned earlier, a b-bilene 198 (Scheme 43) is a transient intermediate in Woodward 

s synthesis of chlorophyll a [44] and provides an elegant way of circumventing the 

symmetry limitations normally apparent using the MacDonald [2+2] route. Deoxophylloerythroetioporphyrin 

247 is also synthesized [160] in low yield from b-bilene 246 (Scheme 

56). tert-Butyl 19-methyl-b-bilene-1-carboxylates have been prepared, [161] but they are not 

easy to cyclize to porphyrins. A synthesis [156–159] of porphyrins using the condensation of 1formyl-9-methyldipyrromethanes 

with 1-unsubstituted 9-(N,N-dimethylformimino)dipyrromethane 

salts in methanol/acetic acid, proceeds by way of a b-bilene intermediate. 


57% 

Et 

Et


aScheme 56 Porphyrin Synthesis Using Other b-Bilenes [160] 

Et 

Et 

NH 

NH 

R 1 

R 2 

+ 

HN 

HN 

Et 

Cl − 

NH N 

N HN 

246 247 

R 1 = 4-MeOC6H4CH2CO2; R 2 = CHO 

17.8.1.2.4.6 Variation 6: 

Using 1,19-Dimethyl-a,c-biladienes 

The synthesis and subsequent oxidative cyclization of a,c-biladienes, and particularly 

1,19-dimethyl-a,c-biladienes 248, to give metal porphyrinates 249 has been thoroughly 

reviewed recently. [20] 

Johnson and Kay [71] have shown that oxidative cyclization of 1,19-dimethyl-a,c-biladiene 

and 1,19-dimethyl-b-bilene salts with copper(II) acetate in methanol gives porphyrins 

in overall yields as high as 30% (Scheme 57). Use of boiling dimethylformamide for 

brief periods, rather than extended periods of refluxing in methanol, [162] or cyclization at 

room temperature with copper(II) chloride, results in improved yields. Treatment of the 

zinc(II) complex of the a,c-biladiene with a variety of oxidizing agents [163] affords yields 

similar to those obtained by the copper(II) salt method in hot dimethylformamide. Cyclization 

of 1,19-dimethyl-a,c-biladienes 248 via metal porphyrinates [usually copper(II) 

complexes, 249] to give porphyrins (e.g., 8) must involve loss of at least one of the 1-/19methyl 

groups in the first step. It is possible that both methyl groups are lost, and that a 

one-carbon unit from the solvent (usually dimethylformamide) is inserted. However, 

much more likely, one methyl group is lost in a manner similar to the way in which one 

of the pyrrole -carbons is lost in the synthesis of symmetrical dipyrromethanes from 2- 

(bromomethyl)- or 2-(acetoxymethyl)-1H-pyrroles (see Section 17.8.1.1.1.2.3). 


Et 

Et 

Et 



aScheme 57 Porphyrin Synthesis from 1,19-Dimethyl-a,c-biladienes [162] 

Et 

Et 

NH 

+ 

NH 

248 

HN 

1 

+ 19 

HN 

Et 

Et 

2Br − 

CuCl2 2H2O 

DMF, heat 

H2SO4 or 

H2SO4, TFA 

N N 

N N 

Et Et 

Et Et 

NH N 

In the simplest terms, 1,19-dimethyl-a,c-biladiene salts can be oxidatively cyclized to give 

porphyrins using a copper(II) oxidant in hot dimethylformamide. The copper salt is usually 

copper(II) acetate; copper(II) chloride has been used but this can result in the production 

of chlorinated porphyrins as byproducts. [164] The product from the copper cyclization 

is invariably the copper complex of the porphyrin, but this can be demetalated to give 

metal-free porphyrin using acid (usually 5–20% sulfuric acid in trifluoroacetic acid). Interestingly, 

if a chromium(III) salt is used in the oxidative cyclization, metal-free porphyrins 

are produced, and this can be extremely advantageous if the product porphyrin is sensitive 

to strong acids. Metal-free porphyrins can also be obtained when 1,19-dimethyl-a,cbiladiene 

salts are subjected to cyclization using anodic oxidation. [47,165] 

The Oxidant: It was long believed that the metal salt used in the oxidative cyclization 

played a dual role: (a) as a one-electron oxidizing agent and therefore the reagent driving 

the chemistry of the reaction, and (b) as a chelating or templating agent which arranged 

the a,c-biladiene ligand into a cyclic conformation, thus ensuring that its terminal methyl 

groups were close enough to facilitate macrocyclization. However, it has been shown that 

copper(II) is not uniquely qualified to perform this reaction, and recent results appear to 

show that chelation is not a critically important factor; when a,c-biladienes were treated 

with a known non-chelating oxidant in place of, for example, a copper(II) salt, the lack of 

importance of templation became obvious. [166] 

In 1986, a study using 20 oxidants was reported. [163] In some of the reactions, zinc(II) 

was used as a separate chelating salt, but it was also hoped that the zinc would prevent 

other metals, more difficult to remove than zinc, from ending up in the center of the 

product porphyrin. Optimal yields of porphyrin were obtained with potassium dichromate 

or silver iodate, and other oxidants, such as lead(IV) oxide, potassium iodide, mercury(II) 

acetate, silver(I) oxide, and silver(I) acetate, gave only moderate yields of porphyrin; 

others gave only a trace of porphyrin, or none at all. 

Boschi and co-workers [167] demonstrated that chromium(III) salts promote very efficient 

cyclizations of a,c-biladienes 248 to directly afford metal-free porphyrins 8. The 

chromium methodology has also been extended to the use of chromium(III) hydroxy acetate 

[Cr 3(OAc) 7(OH) 2] instead of chromium(III) acetate. [168,169] This reagent also affords good 

yields of metal-free porphyrins, but dimethylformamide at 1008C is chosen as the prefer- 


61% 

Et 

Et 

Cu 

249 

N 

8 

Et 

HN 

Et


ared solvent, rather than hot ethanol buffered with sodium acetate (as preferred by Boschi 

and co-workers). 

The mechanism of the cyclization of a,c-biladienes to give porphyrins using the copper(II) 

salt method, or using chromium(III), or electrochemical oxidation, has been extensively 

investigated, and will be discussed in the mechanism section. It should be mentioned 

that since the first step in both the a,c-biladiene and b-bilene cyclizations has 

been postulated to be formation of an a,b,c-bilatriene, it is very likely that after that first 

step, the mechanisms of the a,c-biladiene and b-bilene cyclizations are identical. 

The Mechanism – Origin of the Bridging Meso-Carbon Atom: As mentioned earlier, at 

least one of the 1- or 19-methyl groups must be lost in the macrocyclization reaction. It 

is possible that both carbons are lost, since dimethylformamide has been shown to provide 

the meso-carbon in certain cyclizations of a,c-biladienes to give porphyrins. [162] As early 

as 1969, however, Grigg and co-workers [162] postulated a free-radical mechanism for the 

cyclization, in which one of the two a,c-biladiene terminal methyl groups is incorporated 

into the newly formed porphyrin at a meso position. More support for this idea was published 

in 1971, when it was shown [170] that oxidative cyclization of the 2,18-di-unsubstituted 

1,19-dimethyl-a,c-biladiene 250 using copper(II)/lead(IV) oxide gives the 13-formylporphyrin 

251, this suggesting that the “second” methyl group is somehow oxidized and has 

migrated to the b-position of the product porphyrin 251 as indicated in Scheme 58. 13C studies have eventually confirmed definitively that one of the a,c-biladiene terminal 

methyl groups finishes up as a bridging meso-carbon; the 13C enriched a,c-biladiene dihydrobromide 

252 is synthesized using the methodology described above. Cyclization using 

copper(II) chloride in dimethylformamide affords porphyrin 253 in which the new mesocarbon 

is enriched with 13C. [171] 

Scheme 58 Studies Showing the Origin of the Bridging meso-Carbon Atom [170,171] 

MeO2C 

MeO 2C 

+ 

NH HN 

2Br N N 

− 

CuCl2/PbO2 250 

+ 

NH 

+ 

NH 

252 

HN 

+ 

HN 

13CH3 

13 CH3 

2Br − 

Cu(II), DMF 

MeO 2C 

MeO2C 


− Cu 

Cu 

251 

CHO 

NH 

N 

253 

N 

HN 

13 C 



aIt has been shown subsequently [172] that copper(II)-mediated cyclization of the 2-unsubstituted 

1,19-dimethyl-a,c-biladiene 254 (R 1 ,R 2 = Me) affords the expected porphyrin 259, 

along with the 15-methyl- (256), 15-dimethylamino- (255), 13-formyl- (257), and 15-formyl- 

(258) porphyrins (Scheme 59), depending upon the conditions used. Isolation of compound 

257 directly complements the earlier Russian results (Scheme 58), [170] and compounds 

256 and 258 also provide further information on the fate of the “missing” a,c-biladiene 

terminal carbon after it is cleaved during the cyclization. 

Scheme 59 Products of Cyclization of 2-Unsubstituted 1,19-Dimethyl-a,c-biladiene [172] 

Et 

Et 

Et 

Et 

N N 

Cu 

N N 

NMe2 

255 

N N 

Cu 

N N 

259 

Et 

Et 

CuCl2, PbO2 Cu(OAc) 2 

DMF 

DMF 

9.1% 9.3% 

CuSO4 

DMF 

23% 

Et 

Et 

Et 

Et 

N N 

N N 

N N 

N N 


NH 

+ 

NH 

R 1 

Cu 

HN 

+ 

R 2 

CHO 

258 

HN 

254 R 1 = R 2 = Me, 13 CH 3 

3.7% Cu(NH4) 2Cl 4 

DMF 

Et 

Et 

2Br − 

Et 

Et 

CuCl 2, PbO 2 

DMF 

Et 

Et 

Cu 

256 

N N 

Cu 

N N 

The doubly and singly 13 C-labeled a,c-biladienes 254 (R 1 ,R 2 = 13 CH 3 and R 1 = 13 CH 3,R 2 =Me, 

respectively) have been prepared using standard methods and then cyclized. [172] Using either 

doubly or singly 13 C-labeled a,c-biladiene 254 (Scheme 59), the 15-dimethylaminoporphyrin 

255 contains no 13 C enrichment, confirming that the dimethylamino 

group and the bridging meso-carbon are derived from the dimethylformamide solvent. 

The labeled a,c-biladienes 254 afford porphyrins that show that terminal methyls migrate 

only across the pyrrole ring to which they were originally attached (in the a,c-biladiene), 

and confirm in all respects the mechanisms proposed [166,172] to account for the cyclization. 

The Mechanism – An Intermediate in the Cyclization Reaction: An important result was 

obtained upon anodic oxidation of 1,19-dimethyl-a,c-biladienes (e.g., 123, Scheme 60). 

This methodology was investigated as a means of promoting 1,19-dimethyl-a,c-biladiene 

9.2% 

257 

CHO 

Et 

Et


acyclizations without the troublesome chelation of, for example, copper. It was argued 

that the cleanest of all oxidative cyclizations might simply involve an anode, from which 

the cyclized product could readily be retrieved without contamination. This approach 

was successful, and provided vital information on the mechanism of the cyclization; it 

also enables the isolation of macrocyclic intermediates, which allowed conclusions to be 

drawn for both the anodic oxidation approach and the standard copper(II) procedure. Cyclic 

voltammetry showed that a,c-biladienes, such as 123, are subject to clean and reversible 

one-electron oxidations. [47,165] Bulk electrolyses (using an “H” cell) were carried out at 

800 mV and gave spectrophotometric evidence (Soret absorption band at 400–410 nm) of 

porphyrin formation. Larger scale electro-oxidations at 800 mV produced a large quantity 

of a blue-green intermediate 260 with a very simple 1 H NMR spectrum. This demonstrated 

that the 1-methyl macrocycle 260 is an intermediate on the pathway from the a,c-biladiene 

123 to the porphyrin 262, and after spectroelectrochemistry, also provided definitive 

evidence for formation of a fully oxidized tetrapyrrole 261 prior to the loss of the 1methyl 

group to afford porphyrin 262. Metal-free 1-substituted macrocycles (such as 260) 

can be further transformed to produce porphyrins using electrochemistry. [47,165] The 1methyl 

intermediate 260 can also be obtained chemically by oxidative cyclization of the 

decamethyl-a,c-biladiene 123 with, for example, potassium ferricyanide. [166] 

Scheme 60 Intermediates in the a,c-Biladiene Cyclization [47,165] 

NH 

+ 

HN 

NH N 

NH 

+ 

HN 

2Br 63% 

N HN 

− 

K3[Fe(CN) 6] 

DMF 

123 260 

[O] 

NH N 

N N 

261 

NH N 

N HN 

a,c-Biladienes (e.g., 263) substituted at their 1- and 19-positions with groups other than 

methyl (e.g., acetic and propanoic ester, arylmethyl) also undergo ring cyclization using 

copper(II) or chromium(III) reagents (Scheme 61). However, since these bulky 1,19-substituents 

are not as easily eliminated as methyl, stable macrocycles, such as 264, are 

formed, and at high temperatures these can be induced to undergo intramolecular migrations 

to give chlorins (such as 265 and 266) and even novel meso-functionalized porphyrins 

(e.g., 267). [168,169,173] 


262 



aScheme 61 Cyclizations of Novel a,c-Biladiene Salts [168,169,173] 

NH 

+ 

NH 

EtO2C 

heat 

263 

HN 

+ Cu 2+ 

2Br − 

HN 

4-Tol 

N 

N 

Cu 

EtO2C 

265 

N 

N 

4-Tol 


heat 

heat 

N 

N 

Cu 

EtO2C 

264 

N 

N 

N 

N 

4-Tol 

Cu 

N 

N 

CO 2Et 

266 

N 

N 

Cu 

N 

N 

CO2Et 267 

The mechanism proposed [166] for formation of a porphyrin from 1,19-dimethyl-a,c-biladienes 

through oxidative cyclization is outlined in Scheme 62. Deprotonation of the a,cbiladiene 

268 affords the conjugated a,b,c-bilatriene-type molecule 269 (a step also proposed 

[21] as the first in the cyclization of b-bilenes, see Scheme 63). This is then oxidized 

(chemically or electrochemically) to give the 1-alkyl radical 270; loss of another electron 

and proton produces an intermediate 271 with an exocyclic double bond. This compound 

then undergoes electrocyclic ring closure to form the isolated 1-methyl intermediate 272 

(cf. 260), which then undergoes metalation and oxidation to give 273 (cf. macrocycle 261) 

followed by nucleophilic displacement of the 1-methyl group to give metal porphyrinate 

274. 

4-Tol 

4-Tol


aScheme 62 Proposed Mechanism of the Cyclization of a,c-Biladiene Salts To Give 

Porphyrins [166] 

R 7 

R 6 

− e − , − H + 

R 5 

NH 

HN 

+ + 

NH HN 

R 4 

R 8 R 1 

electrocyclic 

ring closure 

R 7 

268 

R 6 

R 5 

NH 

NH 

R 3 

R 2 

2Br − 

HN 

N 

R 4 

R 8 R 1 

270 


R 3 

− 2H + 

R 2 

R 

NH N 

6 R3 R 7 

R 5 

R 8 

N 

272 

HN 

R 4 

R 1 

R 2 

R 7 

− e − , − H + 

R 6 

1. metalation 

2. [O] 

R 5 

NH 

NH 

R 6 

R 7 

R 5 R 4 

R 8 

HN 

N 

N 

N 

R 4 

R 8 R 1 

R 7 

R 6 

269 

R 5 

N 

NH 

+ 

M 

273 

N 

HN 

N 

N 

R 3 

R 2 

R 4 

R 8 R 1 

R 6 

271 

N 

N 

Nu − 

M 

N 

N 

R 1 

R 5 R 4 

As mentioned above, a mechanism has also been proposed for the cyclization of b-bilenes 

(e.g., 275), which is presented in Scheme 63. [21] It is similar in many respects to the mechanism 

for a,c-biladiene cyclizations, since the first proposed intermediate in Scheme 63 is 

the same compound that is proposed in Scheme 62 (cf. 269). [166] The main differences between 

the a,c-biladiene and b-bilene proposals are: (i) the proposed involvement of radical 

processes in the a,c-biladiene mechanism, and (ii) the intermediacy of a metalloporphodimethene 

276 in the latter pathway. 

R 7 

R 8 

274 

R 1 

R 3 

R 2 

R 3 

R 2 

R 3 

R 2 



aScheme 63 Proposed Mechanism of Cyclization of b-Bilene Salts To Give Porphyrins [21] 

R 7 

R 6 

R 5 

NH 

NH 

HN 

+ 

HN 

R 4 

R 8 R 1 

R 7 

R 6 

275 

R 5 

NH 

NH 

R 3 

R 2 

HN 

HN 

R 4 

R 8 R 1 

R 6 

R 7 

[O] 


R 3 

R 2 

R 5 R 4 

R 8 

N N 

Cu 

N 

276 

N 

R 7 

R 6 

R 5 

N 

NH 

1. electrocyclization 

2. oxidation 

3. copper insertion 

R 1 

R 3 

R 2 

HN 

HN 

R 4 

R 8 R 1 

[O] 

R 6 

R 7 

R 6 

R 3 

N 

R 2 

R5 R4 H + 

R 8 

Nu − 

N N 

Cu 

N 

N 

N N 

Cu 

N 

R 1 

R 5 R 4 

(2,8,12,18-Tetraethyl-3,7,13,17-tetramethylporphyrinato)copper(II) [Copper(II) Etioporphyrin 

II, 249]; Typical Procedure: [162] 

A soln of CuCl 2•2H 2O (6.2 g, 20 equiv) in DMF (62 mL) was added to 2,8,12,18-tetraethyl- 

1,3,7,13,17,19-hexamethyl-a,c-biladiene dihydrobromide (248; 1.2 g, 1 equiv) and the mixture 

was refluxed gently for 2 min. After cooling, the crystalline copper(II) porphyrinate 

was collected on Celite, washed with H 2O and MeOH (20 mL), and extracted with CHCl 3 

(400 mL) using a Soxhlet apparatus. The extract was reduced in volume to ca. 10 mL and 

hot MeOH was added. The copper(II) porphyrinate 249 crystallized; yield: 598 mg (61%); 

mp >300 8C. Demetalation was accomplished with concd H 2SO 4 to give etioporphyrin II 

(8). 

Cyclization of 1,2,3,7,8,12,13,17,18,19-Decamethyl-a,c-biladiene Dihydrobromide (123) 

To Give 1,2,3,7,8,12,13,17,18-Nonamethyl-20-dihydroporphyrin (260); Typical 


DMF (25 mL) was purged with dry argon for 15 min before a,c-biladiene dihydrobromide 

123 (56 mg, 0.093 mmol), K 3[Fe(CN) 6] (260 mg, 0.93 mmol), and Et 3N (1–2 mL) were added. 

The temperature was increased to 1008C for 60 min. The soln was poured into ice water 

and extracted with CH 2Cl 2 (3 ” 150 mL). The combined organic layers were then washed 

with deionized H 2O (2 ” 100 mL) and sat. NaCl soln (100 mL), dried (Na 2SO 4), filtered, and 

concentrated. Residual DMF was removed in vacuo. The residue was then chromatograph- 

R 7 

R 8 

R 1 

R 3 

R 2 

R 3 

R 2


aed (alumina, CH 2Cl 2/petroleum ether 1:1), to afford the 1-methyl intermediate 260; yield: 

26 mg (63%); mp >300 8C. 

17.8.1.2.4.7 Variation 7: 

Using 1-Bromo-19-methyl-a,c-biladienes 

1-Bromo-19-methyl-a,c-biladiene dihydrobromides 139 can be cyclized to give the corresponding 

porphyrin, e.g. mesoporphyrin IX dimethyl ester (215) in very high yield by 

heating in 1,2-dichlorobenzene [84] (Scheme 64) or at room temperature in dimethyl sulfoxide 

and pyridine. [174] These a,c-biladienes 139 can also be cyclized to produce porphyrins 

by treatment with copper(II) salts and other one-electron oxidizing agents. [162] In a certain 

sense, this procedure developed by Johnson and co-workers can be considered to be an 

ingenious two-stage version of Fischer s dipyrromethene approach. Use of the two stages 

eliminates the symmetry restrictions of the [2 +2] dipyrromethene approach. The route 

affords good yields at all of its intermediate and final stages, is amenable to large-scale 

preparations and has been used to prepare a large variety of unsymmetrically substituted 

porphyrins. Its main disadvantage is that the dipyrromethene starting materials 137 and 

138 (Scheme 31) are often difficult to obtain and purify in more complex cases. 

Scheme 64 Preparation of Porphyrins from 1-Bromo-19-methyl-a,c-biladienes [84] 

Et 

Br 

Et 

NH 

+ 

NH 

HN 

+ 

HN 

CO 2Me 

2Br − 

CO 2Me 

1,2-Cl2C6H4 heat 

69−93% 

139 215 


Et 

Et 

NH 

N 

N 

HN 

CO 2Me 

CO2Me 

Cyclization of 1-Bromo-19-methyl-a,c-biladiene Salts (e.g., 139) To Give Porphyrins (e.g., 

215); General Procedure: [84] 

The 1-bromo-19-methyl-a,c-biladiene dihydrobromide (200 mg) was suspended in redistilled 

dry 1,2-dichlorobenzene (50 mL) and then refluxed for 15 min. The solvent was removed 

under reduced pressure. When the product contained free-acid substituents, these 

were (re)esterified by dissolving the crude residue in 5% H 2SO 4 in MeOH, and leaving for 

several hours at rt. The soln was then diluted with H 2O, the porphyrin ester was extracted 

into CHCl 3, and this soln was washed with dil aq NH 4OH, then with H 2O, and dried 

(MgSO 4). After concentration to ca. 15 mL the soln was chromatographed [alumina 

(Spence type H), CHCl 3]. Concentration of the eluates, followed by crystallization of the 

residue, gave the porphyrin; yield: 69–93%. When the porphyrin contained no free-acid 

substituents the crude residue was extracted with CHCl 3 and the extract was then chromatographed 

as above. 

17.8.1.2.4.8 Variation 8: 

Using Other a,c-Biladienes 

1,19-Di-unsubstituted a,c-biladiene salts are most often used for synthesis of corroles (see 

Section 17.8.3.2.3). [175,176] Heating of 1-unsubstituted 19-methyl-a,c-biladienes furnishes 

porphyrins, and these compounds are more often used as intermediates in the synthesis 

of tetradehydrocorrins, [176] but a number of such a,c-biladienes have been transformed 

into porphyrins, such as 277 (Scheme 65). [83] In related studies, 1-methyl-a,c-biladiene-19- 



acarboxylic acids (e.g., 278) can be cyclized very efficiently to give porphyrins 279 by heating 

in 1,2-dichlorobenzene in the presence of iodine, [177,178] or iodine and bromine. [179] 

1,19-Di-unsubstituted a,c-biladienes and a,c-biladiene-1,19-dicarboxylic acids 280 have 

been efficiently converted into porphyrins 281 under acidic conditions by using aldehydes 

to provide the new meso-carbon atom (Scheme 65). [71,180–182] 

Scheme 65 Preparation of Porphyrins by Cyclization of Other a,c-Biladienes [71,83,177–182] 

MeO2C 

A 

R 1 = H, CO2H, I 

AcO 

R 5 

R 6 

R 4 

R 7 

R 1 = H, Ph 

B 

NH 

+ 

NH 

NH 

+ 

NH 

NH 

+ 

NH 

R 1 

HN 

+ 

HN 

CO2H 

HN 

+ 

HN 

B 

A 

2Br − 

CO 2Me 

OAc 

[O], heat 

I2, 1,2-Cl2C6H4 heat 

38% 

CO2Me 

278 279 

280 

HN 

+ 

HN 

R 3 

R 8 

R 2 

CO2H 

CO 2H 

R 9 

2Cl − 

2X − 

B B 

NH N 

N HN 


R 1 CHO 

R 5 

R 6 

A 

MeO 2C CO2Me 

277 

AcO 

NH N 

N HN 

R 4 R 3 

NH N 

N HN 

R 7 R 8 

281 

R 2 

R 1 

R 9 

A 

CO2Me 

3,8-Bis(2-acetoxyethyl)-13-[2-(methoxycarbonyl)ethyl]-2,7,12,18-tetramethylporphyrin 


8,13-Bis(2-acetoxyethyl)-18-[2-(methoxycarbonyl)ethyl]-1,3,7,12,15-pentamethyl-a,c-biladiene-19-carboxylic 

acid dihydrochloride (278; 539 mg, 0.72 mmol) in 1,2-dichlorobenzene 

(130 mL) was treated with I 2 (1.11 g, 4.37 mmol) and then stirred under reflux for 

20 min. After cooling to rt, Et 3N (0.5 mL) was added dropwise and the mixture was applied 

to a flash chromatography column [alumina (Brockmann Grade V), hexanes (3 column 

volumes) then 5% THF in CH 2Cl 2]. A second purification using flash column chromatogra- 

OAc

17.8.2 Reduced Porphyrins 1161 

aphy was carried out (silica gel, 5% THF in CH 2Cl 2) and the red eluates were collected and 

concentrated to dryness. The residue was crystallized (CH 2Cl 2/cyclohexane) to give 279; 

yield: 150 mg (38%); mp 211–2148C. 

17.8.2 Product Subclass 2: 

Reduced Porphyrins 


Vol. E 9d, p 600; further reactions: Vol. E 9d, pp 597–613. 

17.8.2.1 Chlorins (b,b¢-Dihydroporphyrins) 


Vol. E 9d, p 614. 

Chlorins, such as 12 (Scheme 4), with adjacent b,b¢-hydrogen atoms on a particular 

pyrrole subunit, are fairly sensitive to re-oxidation to porphyrin under conditions used 

for ring synthesis of porphyrins by most, if not all, of the methodologies discussed above. 

Thus, unless the b,b¢-bond is blocked against re-oxidation, for example with geminal 

methyl substituents, most approaches seem doomed to failure. Indeed, there appeared 

until fairly recently to be no good reason to perform rational syntheses from pyrroles to 

give direct access to chlorins; instead, chlorins were readily accessible simply by reduction 

of the corresponding porphyrins or metal porphyrinates. That situation has changed 

with reports of several direct approaches to chlorins. Since it appeared to be steric factors 

that affected whether or not a porphyrin would be obtained from an attempted chlorin 

synthesis, most new developments have been achieved by paying particular attention to 

steric issues (but not ignoring electronic factors). 

17.8.2.1.1 Method 1: 

By Ring Synthesis 

A stepwise preparation of a chlorin from an open-chain tetrapyrrole has been reported 

(Scheme 66). [183] MacDonald-type [2 +2] condensation of a dipyrromethane 282 with a 

1,9-diformyldipyrromethane 283 gives the porphodimethene intermediate 284, from 

which chlorin 285 is obtained after metalation with zinc(II) and thermolysis. The porphodimethene 

is the normal MacDonald intermediate before oxidation to porphyrin, and 

this procedure is based upon the known equilibria between metalated meso-dihydroporphyrins 

and metallochlorins. [184–186] 




aScheme 66 Chlorin Ring Synthesis by Oxidation of a Porphodimethene Intermediate [183] 

MeO 2C 

HO 2C 

NH 

MeO 2C 

HN 

+ 

OHC 


NH 

Et 

282 283 

NH 

N 

N 

HN 

Et Et 

284 

HN 

Et 

CHO 

Zn(OAc)2, heat 

H + 

MeO 2C 

N N 

Zn 

N N 

Et Et 

Numerous chlorins which, because of the geminal substitution mentioned above, cannot 

adventitiously re-oxidize to porphyrins have been prepared. Chlorin 287 is prepared in a 

stepwise fashion (Scheme 67) from the open-chain precursor 286 (by treatment with 1,8diazabicyclo[5.4.0]undec-7-ene); 

[187,188] oxidation to the porphyrin level during the process 

is prevented by the presence of the geminal dimethyl group in ring A. 

Scheme 67 Chlorin Ring Synthesis by Cyclization of a Geminally Disubstituted Open-Chain 

Precursor [187,188] 

MeO2C 

NC 

Br 

A 

N N 

CN 

Zn 

N N 

286 

base 

MeO2C 

NC 

285 

N N 

Zn 

N N 

Rational syntheses of b-blocked chlorins have also been reported. For example, treatment 

of the reduced dipyrrole 290 with the 3-aryldipyrromethane 289 (obtained from 288 by 

reduction with sodium borohydride) affords the dihydrobilene a 291, which undergoes 

metal-mediated oxidative cyclization [with silver periodate and zinc(II) acetate] to give 

the meso-substituted zinc(II) chlorinate 292 (Scheme 68). [189,190] 

287


aScheme 68 Chlorin Ring Synthesis by Metal-Mediated Oxidative Cyclization of a 

Dihydrobilene Precursor [189,190] 

O 

4-Tol 

4-Tol 

Br 

N 

HN 

N 

N 

288 

4-Tol 

Br 

291 

HN 

N 

I 

NaBH 4 

THF/MeOH 

I 

N N 

N N 


HO 

Br 

AgIO 3 

N 

HN 

Zn(OAc) 2 

toluene 

piperidine 

289 

I 

4-Tol 

Zn 

290 

292 18% 

NH 

N 

, TFA, MeCN 

Some stepwise synthetic approaches to bonellin (a natural chlorin involved in sex differentiation, 

which is obtained from the echurian worm), as its dimethyl ester 297 have 

been described. [191,192] For example, [191] condensation of the two compounds 293 and 294 

gives the open-chain tetrapyrrole 295 (Scheme 69); the selectively differentiated cyanoethyl 

and (methoxycarbonyl)ethyl substituents are used in order to provide access to 

natural amino acid derivatives of bonellin. Photocyclization of 295 then affords the cyano 

derivative 296 from which bonellin dimethyl ester (297) is produced. 

Scheme 69 Chlorin Ring Synthesis by Photocyclization of an Open-Chain Tetrapyrrole 

Precursor [191] 

NH 

N 

293 

hν (580 nm) 

+ 

OHC 

MeO 

N 

HN 

NC CO 2Me 

294 

NH N 

N HN 

NC CO2Me 296 

H + 

NC 

N 

N 

MeO 

295 

HN 

N 

NH N 

N HN 

MeO2C CO2Me 297 

I 

CO 2Me 



aIn connection with studies of the intermediates in vitamin B 12 biosynthesis, and identification 

of siroheme (298) and sirohydrochlorin (299), a number of similar geminally Cmethylated 

chlorins [e.g., faktor-I octamethyl ester (300)] have been synthesized (Scheme 

70). 

Scheme 70 Geminally C-Methylated Chlorins 

HO2C 

HO2C 

MeO 2C 

H 

CO 2H 

N N 

Fe 

N N 

CO 2H 

CO 2H 

HO2C CO 2H 

MeO 2C 

H 

298 

CO2Me 

NH N 

N HN 

MeO 2C CO 2Me 

300 

H 

CO2H 

CO2Me 

CO 2Me 

CO2Me 

N N 

NH HN 


HO2C 

HO2C 

H 

CO 2H 

CO 2H 

CO 2H 

HO2C CO 2H 

[17,18-Dihydro-18,18-dimethyl-5-(4-tolyl)-12-(4-iodophenyl)chlorinato]zinc(II) (292); Typical 


To a soln of 1-bromo-3-(4-iodophenyl)-9-(4-methylbenzoyl)dipyrromethane (288; 110 mg, 

0.20 mmol) in anhyd THF/MeOH (4:1; 7.5 mL) at rt was added an excess of NaBH 4 

(100 mg, 2.6 mmol) in small portions. The reaction was monitored by TLC and upon completion 

was quenched with cold H 2O (10 mL) and extracted with CH 2Cl 2 (3 ” 25 mL). The 

combined organic phases were washed with brine (50 mL), dried (K 2CO 3) for 2–3 min, 

and concentrated at rt under reduced pressure to give 289 in CH 2Cl 2 (ca. 1–2 mL). 1,3,3- 

Trimethyldihydrodipyrromethene (290; 45 mg, 0.24 mmol) in anhyd MeCN (ca. 2–3 mL) 

was combined with 289 (from above) and additional dry MeCN was added to give a total 

volume of 22 mL. The soln was stirred at rt under argon and TFA (20 mL, 0.26 mmol, ca. 11 

mM) was added. The reaction was monitored by TLC (observing disappearance of 290), 

and the mixture was quenched with aq NaHCO 3 (10%) then extracted with CH 2Cl 2 

(3 ” 25 mL). The combined organic phases were washed with H 2O and brine, dried 

(Na 2SO 4), and concentrated under vacuum at rt to give 291. The residue was dissolved in 

anhyd toluene (14 mL) under argon and AgIO 3 (848 mg, 3.0 mmol), piperidine (300 mL, 

3.0 mmol), and Zn(OAc) 2 (550 mg, 3.0 mmol) were added. This mixture was heated at 

808C for 2.5 h, monitoring by TLC and spectrophotometry (new bands at about 410 and 

610 nm). The mixture was cooled and passed through a short column (silica gel, hexanes/CH 

2Cl 2); a major fraction was collected, concentrated, and rechromatographed under 

the same conditions. Concentration of the eluates gave a greenish-blue solid, which 

299 

H 

CO2H


awas taken up in CH 2Cl 2 and precipitated by addition of hexanes to give 292 as a solid; 

yield: 25 mg (18%). 

17.8.2.1.2 Method 2: 

By Reduction of Porphyrins or Metal Porphyrinates 

Porphyrins can be reduced to provide a wide variety of dihydroporphyrins (chlorins 301, 

phlorins 302, and porphodimethenes 303), tetrahydroporphyrins (bacteriochlorins 304, 

isobacteriochlorins 305, and porphomethenes 306), and hexahydroporphyrins (pyrrocorphins 

307 and porphyrinogens 308) (Scheme 71). 

Scheme 71 Hydroporphyrin Types 

R 1 

R 8 

R 1 

R 8 

R 1 

R 8 

R 2 

R 7 

R 2 

R 7 

R 2 

R 7 

N 

NH 

N 

NH 

N 

NH 

301 

304 

307 

HN 

N 

HN 

N 

HN 

N 

R 3 

R 6 

R 3 

R 6 

R 3 

R 6 

R 4 

R 5 

R 4 

R 5 

R 4 

R 5 

R 1 

R 8 

R 1 

R 8 

R 1 

R 8 

trans-Chlorins, such as trans-310 are most often obtained by the reduction of iron(III) bsubstituted 

porphyrins 309 with sodium metal in isopentyl alcohol (Scheme 72). [193–195] 

When the porphyrin is unsymmetrically substituted at the b-positions, mixtures of chlorin 

regioisomers are formed in ratios that are dependent upon electronic and steric factors, 

as pyrrole subunits bearing electron-withdrawing groups and/or an adjacent substituted 

meso position are preferentially reduced. Reduction to cis-chlorins (e.g., cis-310) is 

usually accomplished using the classical diimide approach, [196–199] the diimide being obtained 

from 4-toluenesulfonylhydrazine (Scheme 72). Porphyrins can also be photoreduced 

in the presence of amines, ascorbic acid, and other compounds. [200–205] 

R 2 

R 7 

R 2 

R 7 


NH 

NH 

N 

R 2 

R 7 

NH 

302 

305 

NH 

NH 

HN 

N 

N 

HN 

308 

HN 

HN 

R 3 

R 6 

R 3 

R 6 

R 3 

R 6 

R 4 

R 5 

R 4 

R 5 

R 4 

R 5 

R 1 

R 8 

R 1 

R 8 

R 2 

R 7 

R 2 

R 7 

N 

NH 

NH 

NH 

303 

306 

HN 

N 

N 

HN 

R 3 

R 6 

R 3 

R 6 

R 4 

R 5 

R 4 

R 5 



aScheme 72 Reductions of Porphyrins to Chlorins [193–199] 

Et 

Et 

Et 

Et 

Et 

N Cl N 

Fe 

N N 

Et 

Et Et 

Et 

309 

NH N 

N HN 

Et 

Et Et 

21 

Et 

Et 

Et 

Et 

Na/iPr(CH2)2OH 

− Fe 

N2H2 

NH N 

N HN 


Et 

Et 

Et 

Et 

Et 

Et 

Et 

Et Et 

trans-310 

NH N 

N HN 

Et 

Et Et 

cis-310 

Regioselective photoreductions to provide cis-chlorins have been reported, using ascorbic 

acid in the presence of diazabicyclo[2.2.2]octane (Scheme 73). [204–207] Photoreduction of 

zinc(II) methyl pyropheophorbide a (311) in 8–10% ethanol in pyridine gives initially the 

(vinyl)isobacteriochlorin 312, which undergoes allylic shift of the vinyl double bond to 

afford the E-(ethylidene)isobacteriochlorin 313 (Scheme 73). This pathway has been proposed 

as a chemical model for the reduction of the 8-vinyl to ethyl in chlorophyll biosynthesis, 

and also for the biological formation of bacteriochlorophyll a derivatives from the 

corresponding vinylporphyrin or vinylchlorin. [208,209] Photoreduction to give predominantly 

(vinyl)isobacteriochlorin 312 is achieved by using benzene as the solvent and a 

smaller amount of the diazabicyclo[2.2.2]octane catalyst. 

Et 

Et 

Et 

Et


aScheme 73 Diazabicyclo[2.2.2]octane Reduction of a Vinylchlorin [204–207] 

MeO2C 

N N 

Zn 

N N 

311 

O 

Et 

ascorbic acid 

DABCO 

EtOH, benzene or py, hν 

DABCO 

MeO2C 

MeO2C 

N N 

N N 


Zn 

312 

N N 

Zn 

N N 

Reduction of methyl nickel(II) mesopyropheophorbide a (314) with Raney nickel under 

hydrogen gives isobacteriochlorin 315 (as a mixture of diastereomers), the 13 1 -deoxochlorin 

316, and a minor amount of hexahydroporphyrin 317 (Scheme 74). [210] The isobacteriochlorin 

315 is preferentially formed when acetone is used as solvent, but 13 1 -deoxochlorin 

316 is the major product when methanol is used as solvent. 

Scheme 74 Raney Nickel Reduction of Methyl Nickel(II) Mesopyropheophorbide a [210] 

MeO2C 

Et 

N N 

Ni 

N N 

314 

O 

Et 

H 2 

Raney Ni 

N N 

MeO2C 

+ Ni 

+ 

MeO 2C 

Et 

N N 

316 

Et 

Et 

N N 

Ni 

N N 

315 

MeO2C 

Et 

O 

313 

Et 

N N 

Ni 

N N 

317 

O 

O 

O 

Et 

Et 

Et 



aRaney nickel reduction of the nickel(II) “anhydro”-rhodoporphyrin 318 produces six 

products: deoxo derivative 319, isobacteriochlorins 320 and 321, hexahydroporphyrins 

322 and 323 (as major products), and the octahydroporphyrin 324 (Scheme 75). [211] 

Scheme 75 Raney Nickel Reduction of Nickel(II) “Anhydro”-Rhodoporphyrin [211] 

Et 

Et 

N 

N 

N 

N 

Ni 

318 

Ni 

320 

N 

N 

O 

N 

N 

O 

Et 

CO 2Me 

Et 

CO2Me 

Raney Ni 

Et 

O 

321 


N 

N 

N 

N 

Et 

N 

N 

Et 

Ni 

319 

+ Ni 

+ 

Et 

N 

323 

CO 2Me 

+ Ni 

+ 

N 

N 

N 

O 

Et 

CO2Me 

N 

N 

Et 

CO 2Me 

Et 

Et 

N 

N 

Ni 

322 

N 

N 

+ 

N 

N 

O 

Ni 

324 

Et 

CO 2Me 

N 

N 

O 

Et 

CO 2Me 

Dihydroporphyrins can also be prepared by intramolecular cyclizations, such as in Woodward 

s chlorophyll a synthesis which involves the acid-catalyzed transformation of porphyrin 

325 into the purpurin-type chlorin 326. Intramolecular cyclizations of meso-acrolein- 

and meso-acrylateporphyrins 327 (R 1 = CHO and CO 2Et, respectively), produce the 

corresponding trans-purpurins 328 (Scheme 76). [212–214] As in Woodward s case, formation 

of purpurins 328 occurs in refluxing acetic acid, although base-catalyzed cyclizations (using 

Et 3N or KOH/MeOH in CH 2Cl 2) have been employed for the preparation of 5,15-disubstituted 

purpurins. [215–217] In this case the cyclization reaction is regiospecific, giving only 

one purpurin product from unsymmetrically substituted porphyrins; for example, purpurin 

330 is the preferred product from the cyclization of the etioporphyrin I 5-ethyl 

acrylic ester (329). Bis-cyclization of the 5,15-bis[2-(ethoxycarbonyl)vinyl]porphyrin 331 

produces regiospecifically the air-sensitive bacteriochlorin 332, containing two purpurin 

rings (Scheme 76). [218]


aScheme 76 Formation of Purpurins [212–214,218] 

AcHN 

MeO 2C 

Et 

Et 

Et 

NH 

N 

NH 

N 

325 

N 

HN 

CO2Me 

327 

N 

HN 

Et Et 

R 1 = CHO, CO2Et 

Et 

EtO2C 

Et 

NH 

N 

Et 

Et 

329 

Et 

N 

HN 

Et 

Et 

NH 

N 

Et 

CO 2Me 

Et 

Et 

Et 

N 

HN 

Et 

Et Et 

331 

R 1 

AcOH, heat 

AcOH, heat 

R 1 = CO2Et 68% 

CO2Et AcOH, heat 

Et 

Et 

CO 2Et 

MeO 2C 

AcOH, heat 


AcHN 

Et 

Et 

EtO2C Et 

Et 

Et 

MeO2C 

Et 

Et 

Et 

NH 

N 

NH 

N 

326 

328 

N 

HN 

N 

HN 

Et Et 

NH 

N 

NH 

N 

330 

N 

HN 

N 

HN 

Et 

Et 

Et Et 

332 

Et 

CO2Me 

Et 

Et 

Et 

Et 

Et 

Et 

R 1 

CO 2Et 

CO2Et 



aMontforts and co-workers [219–221] have shown that hematoporphyrins [i.e., (1-hydroxyethyl)porphyrins], 

such as 333, react with N,N-dimethylacetamide dimethyl acetal at high 

temperatures, to give the corresponding (Z)-ethylidenechlorins (e.g., 334) (Scheme 77). 

When subjected to catalytic hydrogenation, these chlorins yield the corresponding alkylchlorins. 

[222] Oxidative cleavage of the exocyclic double bond in the zinc(II) or nickel(II) 

complexes of chlorin 334 gives the oxochlorin 335 after demetalation; oxochlorin 335 

can be hydrolyzed to the ester, and then stereoselectively reduced with lithium tri-tert-butoxyaluminohydride 

to give hydroxychlorin 336. [223,224] The corresponding dioxoisobacteriochlorins 

have also been prepared from the hematoporphyrin IX dimethyl ester 337 

using the same methodology. [225,226] 

In an interesting intramolecular cyclization to give chlorins, treatment of [(2-acetylamino)ethyl]porphyrins 

(e.g., 338) with phosphoryl chloride in pyridine results in the intramolecular 

cyclization of the Vilsmeier-complex substituent with formation of spirochlorin 

339 (Scheme 77). [227,228] 

Scheme 77 Intramolecular Cyclizations To Give Chlorins [219–228] 

HO 

NH 

N 


N 

HN 

1. metalation (Zn or Ni) 

2. oxidative cleavage 

3. demetalation 

O 

Me2N 

MeO OMe 

xylene, 160 o C 




O 

N 

NMe 2 

NH 

N 

HN 

O 

Me 2N 

MeO 2C 

HO 

N 

NH 

N 

HN 

1. hydrolysis 

2. reduction 

N 

NH 


N 

HN


HO 

NH 

MeO2C CO2Me a337 

Et 

NH 

N 

338 

N 

N 

HN 

N HN 

Et Et 

OH 

NHAc 

POCl 3, py 

MeO 2C 


O 

NH 

N 

N 

HN 

CO2Me 

MeO2C CO 2Me 

Et 

NH 

339 

N 

O 

N HN 

Et Et 

Metal porphyrinates are easily reduced to the p-dianions with reductants such as sodium 

in tetrahydrofuran or with sodium anthracenide. [184,229–231] Protonation and alkylation of 

porphyrin p-anions usually occur at the 5-, 10-, 15-, or 20-positions, resulting inthe formation 

of phlorins and porphodimethenes, which can rearrange to chlorins or be oxidized 

to give porphyrins. 

Ethyl 2,3,7,8,12,13,17,18-Octaethylpurpurin-3 1 -carboxylate (328,R 1 =CO 2Et); Typical Procedure: 

[213] 

5-[2-(Ethoxycarbonyl)vinyl]-2,3,7,8,12,13,17,18-octaethylporphyrin (327, R 1 =CO 2Et; 

100 mg, 0.16 mmol) in glacial AcOH (20 mL) was refluxed under N 2 for 24 h. After cooling 

to rt, the solvent was removed under vacuum and replaced with CH 2Cl 2. Chromatography 

(silica gel, CH 2Cl 2) gave a green major fraction, which was concentrated to dryness. The 

residue was crystallized (CH 2Cl 2/MeOH) to give purple microcrystals of 328 (R 1 =CO 2Et); 

yield: 68 mg (68%); mp 135–1388C. 

17.8.2.1.3 Method 3: 

By Oxidation of Porphyrins or Metal Porphyrinates 

Strangely enough, the chlorin chromophore can be obtained by oxidation, as well as the 

more traditional reduction approach. Thus, osmiumtetroxide reacts selectively at the b— 

b¢ double bonds of porphyrins [e.g., 2,3,7,8,12,13,17,18-octaethylporphyrin (21)] to produce 

cis-dihydroxychlorins (e.g., 340). [232–234] Such b,b¢-disubstituted cis-chlorins readily 

undergo pinacol–pinacolone rearrangement in perchloric acid or fuming sulfuric acid to 

give b-oxochlorins (e.g., 341). The regioselectivity in the osmiumtetroxide oxidation reaction 

and the migratory aptitudes of different peripheral substituents in the subsequent 

pinacol–pinacolone rearrangement have been studied extensively. [235–238] The use of hydrogen 

peroxide in concentrated sulfuric acid also achieves direct oxidation of porphyrins 

to oxochlorins, but mixtures of mono-, di- and trioxo derivatives are often obtained. 

[239,240] Benzoyl peroxide reacts with 5,10,15,20-tetraphenylporphyrin (342, R 1 =H) 

to produce a b-benzoyloxyporphyrin, which can be converted into 343 by metalation, hydrolysis, 

and demetalation (Scheme 78). [241] Porphyrin 343 is, however, obtained in higher 

yield from 2-nitro-5,10,15,20-tetraphenylporphyrin 342 (R 1 =NO 2) by nucleophilic dis- 

N 



aplacement of the nitro group with the sodium salt of (E)-benzaldoxime. [242] Oxidation of 

343 to afford the 2,3-dioneporphyrin 344 can be accomplished under a variety of oxidative 

conditions [chromium(VI) oxide/acetic acid, [243] photooxidation or selenium dioxide/ 

dioxane] (Scheme 78). [242] 

Scheme 78 Oxidations of Porphyrins To Give Chlorins [232–234,241,242] 

Et Et 

NH N 

Et 

Ph 

Et 

N 

21 

HN 

Et 

Et Et 

NH 

N 

Ph 

Ph 

N 

HN 

342 R 1 = H, NO 2 

Et 

R 1 

Ph 

OsO4, CH2Cl2, py 

56% 


Et 

Et 

A: 70% HClO4, CH2Cl2 

B: H2SO4 

A: 72% 

B: 72% 

1. BzOOH, PhCl, 100 oC 2. Zn(OAc)2 

3. NaOH, THF, MeOH 

4. H + 

CrO 3, AcOH 

Et 

NH 

N 

340 

N 

HN 

Et 

Et Et 

Et 

Et 

Et 

OH 

OH 

Et 

NH 

N 

Et 

341 

N 

HN 

O 

Et Et 

2,3,7,8,12,13,17,18-Octaethyl-cis-2,3-dihydroxy-22H,24H-chlorin (340); Typical 


2,3,7,8,12,13,17,18-Octaethylporphyrin (21; 700 mg, 1.31 mmol) in CH 2Cl 2 (120 mL) and 

pyridine (0.5 mL) was stirred with OsO 4 (545 mg, 2.14 mmol) under N 2 in the dark for 

90 h. The solvent was removed under reduced pressure and the residue was dissolved in 

MeOH (100 mL) and CH 2Cl 2 (30 mL) and H 2S was passed through the soln for 30 min. The 

Ph 

Ph 

NH 

N 

Ph 

Ph 

343 

N 

HN 

NH 

N 

Ph 

OH 

Ph 

344 

N 

HN 

Ph 

O 

Et 

Et 

Et 

O 

Ph


aprecipitate was filtered off (glass sinter) and the pad was washed with CHCl 3. The total filtrate 

was concentrated to dryness, the residue dissolved in CHCl 3 (5 mL), and MeOH 

(50 mL) was added to precipitate unchanged 21. The soln was filtered, the pad was washed 

with MeOH (100 mL) and the total filtrate was concentrated to dryness. The residue was 

chromatographed [silica gel (300 ” 25 mm diameter), CHCl 3/acetone 98:2]. After elution 

of unchanged 21 (total recovery 20%), the major band afforded diol 340; yield: 420 mg, 

(56%); mp 2138C (dec). The product was recrystallized (CH 2Cl 2/hexanes); mp 219–2208C 

(Et 2O); 218 8C (dec) (MeOH/CHCl 3). 

3,3,7,8,12,13,17,18-Octaethyl-2-oxochlorin (341); Typical Procedure: [233] 

Method A: Using perchloric acid: 2,3,7,8,12,13,17,18-Octaethyl-cis-2,3-dihydroxy-22H,24Hchlorin 

(340; 100 mg, 0.18 mmol) in CH 2Cl 2 (60 mL) was stirred with 70% HClO 4 (1 mL) for 

30 min at 208C. The mixture was washed in turn with H 2O, aq NaHCO 3, and H 2O. The organic 

layer was separated, dried (Na 2SO 4) and concentrated to dryness to give a residue 

which was then purified by chromatography [silica gel (250 ” 35 mm), CH 2Cl 2]. The faster-moving 

band was discarded and the major band was worked up to give 341; yield: 

71 mg (72%); mp 247–2508C. 

Method B: Using sulfuric acid: Concd H 2SO 4 (2.5 mL) and fuming H 2SO 4 (2 mL; 20% SO 3) 

were added to 2,3,7,8,12,13,17,18-octaethyl-cis-2,3-dihydroxy-22H,24H-chlorin (340; 

100 mg, 0.18 mmol) and the resulting green soln was kept at rt for 7 min, then poured 

into a large excess of ice and extracted with CHCl 3. The organic layer was washed with 

H 2O, dried (Na 2SO 4), and concentrated to dryness to give a residue, which was crystallized 

from CHCl 3/hexanes to give 341; yield: 71 mg (72%); mp 247–2508C. 

17.8.2.2 Bacteriochlorins and Isobacteriochlorins (b,b¢,b¢¢,b¢¢¢-Tetrahydroporphyrins) 


Vol. E 9d, pp 636 and 644. 

Bacteriochlorins 13 are tetrapyrroles in which opposite pyrrole subunits are reduced, 

whereas isobacteriochlorins 14 have adjacent pyrrole subunits modified (see 

Scheme 4). Until fairly recently, with the discovery of siroheme (298) and of precorrin intermediates 

on the biosynthetic pathway to vitamin B 12, and of heme d (345) (Scheme 79), 

the only naturally occurring tetrahydroporphyrin-type macrocycles were thought to be 

the bacteriochlorins found as bacteriochlorophyll a and bacteriochlorophyll b (and their 

demetalated/deesterified bacteriopheophorbide derivatives). 

Tetrahydroporphyrins are obtained by further reduction of chlorins under the conditions 

described for the preparation of chlorins (i.e., sodium in alcohols, or diimide); isobacteriochlorins 

(e.g., 346) are formed preferentially by reduction of metal porphyrinates, 

whereas bacteriochlorins (e.g., 347) are usually produced from metal-free porphyrins. 

Likewise, in the oxidation protocol for removal of a peripheral double bond from the 

porphyrin chromophore, metal-free oxochlorins 348 (M = 2 H) react further and regioselectively 

at the opposite pyrrole ring with osmiumtetroxide (see above) to give diol 349, 

whereas the metal derivatives 348 (M = Zn) react preferentially at an adjacent b—b¢ double 

bond to give diol 350 (Scheme 79). [244,245] Thus, the oxidative methodology has been 

extended for the preparation of vic-dihydroxy- and oxobacteriochlorins and isobacteriochlorins. 

[246–248] 




aScheme 79 Typical Structures and Syntheses of Bacteriochlorins and 

Isobacteriochlorins [244–248] 

HO2C 

Ph 

Et 

Et 

O 

N 

N 

Fe 

HO2C CO2H 

345 

NH 

N 

Ph 

Ph 

347 

N 

HN 

Et O 

N 

N 

M 

N 

N 

Et Et 

348 M = 2H, Zn 

N 

N 

Et 

Ph 

Et 

Et 

CO 2H 

O 

OsO4 


M = 2H 

M = Zn 

− Zn 

Ph 

N 

N 

Et 

Ph 

Zn 

Ph 

346 

N 

N 

NH 

349 

Ph 

Et O 

Et 

HO 

N 

HO 

Et 

HO 

Et 

Et 

HO Et 

N 

NH 

350 

N 

HN 

N 

HN 

Et 

O 

Et Et 

Geminally C-methylated isobacteriochlorins have been synthesized in connection with 

the characterization of intermediates on the vitamin B 12 biosynthetic pathway. [249–256] 

17.8.2.3 Syntheses of Benzoporphyrins 


Vol. E 9b, pp 607, 621, 623 and Vol. E 9d, pp 717–833 (phthalocyanines). 

Benzoporphyrins have b,b¢-pyrrole-fused benzene rings and some have been found, 

in trace amounts, in various oil shales and petroleums. The class comprises the classical 

Et 

Et 

Et 

Et 

Et 

Et


atetrabenzoporphyrins (e.g., 351, 352), as well as monobenzoporphyrins (e.g., 353–355), 

dibenzoporphyrins (e.g., 356–358) and the so-called benzoporphyrin derivatives (e.g., 

359) (Scheme 80). 

Scheme 80 Benzoporphyrin Types 

Et 

Et 

MeO 2C 

NH 

N 

NH 

N 

351 

354 

N 

HN 

N 

HN 

Et Et 

356 

MeO 2C 

NH 

N 

Ph 

N 

HN 

NH 

N 

MeO2C Ph 

Ph 

358 

N 

HN 

17.8.2.3.1 Method 1: 

Tetrabenzoporphyrins 

Ph 

CO 2Me 

Ph 


NH 

N 

Ph 

Ph 

352 

MeO2C 

MeO2C 

N 

HN 

Ph 

N 

NH 

HN 

NH 

N 

N 

HN 

Et Et 

353 


Et 

NH 

N 

357 

N 

HN 

MeO 2C 

MeO2C 

Et 

R 1 O2C 

N 

N 

NH 

HN 

N 

359 R 1 = R 2 = H, Me 

CO2R 2 

Compounds of the type 351 (Scheme 80) are porphyrin analogues of the phthalocyanines 

360 (Scheme 81) and are prepared by cyclotetramerization of phthalimidine derivatives, 

isoindoles, or certain pyrrolic intermediates. Derivatives of tetrabenzoporphyrin contain- 



aing one, two, or three meso-nitrogen bridging atoms have also been synthesized, using 

acetophenone derivatives and metal salts. [257–262] 

When phthalimidine derivatives, such as methylphthalimidine, 3-carboxymethylphthalimidine, 

or potassium phthalimide, are heated at 350–4008C in the presence of metals, 

such as iron, zinc, magnesium, cadmium, or metallic acetates, the corresponding 

metal tetrabenzoporphyrinates are obtained in yields of up to 26%. [261–271] The metal tetrabenzoporphyrinates 

isolated using this method are usually very impure and require extensive 

purification. A modification of this synthesis involves the use of acetophenone-2carboxylic 

acid and aqueous ammonia in the presence of iron or zinc acetate and molecular 

sieves, and heating at 4008C; this yields the zinc(II) complex of 361 in 17% yield. [272– 

274] The free-base tetrabenzoporphyrin 361 is then obtained in good yield after demetalation 

using acid. 

Scheme 81 Typical Phthalocyanine and Tetrabenzoporphyrin Structures 

NH 

N 

N 

360 

N 

N N 

N 

HN 

Isoindoles are fairly unstable intermediates for use in tetrabenzoporphyrin syntheses. 

Though the tetrabenzoporphyrin 361 is symmetrical, its synthesis by tetramerization of 

isoindoles is still low-yielding. Nevertheless, several metal complexes of octamethyltetrabenzoporphyrin 

361 have been prepared by pyrolysis (at 4008C) of 1,3,4,7-tetramethylisoindole 

in the presence of metals or metal salts, under an inert atmosphere, or by refluxing 

in a high boiling solvent (1,2,4-trichlorobenzene or 1-chloronaphthalene) in the 

presence of a metal salt. [275–277] A recently introduced improvement involves the 

cyclotetramerization of 1,3-dimethyl- and 1,3,4,7-tetramethylisoindoles in the presence 

of metals or their acetate salts; this leads to the metal complexes of 351 and 361 in yields 

as high as 81%. [278,279] As might be expected, use of unsymmetrically substituted isoindoles 

gives the four possible metal tetrabenzoporphyrinate isomers. 

The tetrabenzoporphyrin 351 has been prepared by a variation of the Rothemund 

methodology (see Section 17.8.1.2.1), using isoindole and formaldehyde in the presence 

of a metal or a metal salt. [280] High temperatures (3758C) are required for this reaction, 

but a 53% yield is reported for the preparation of the zinc(II) complex of 351. If the reaction 

is performed in the absence of a metal or a salt, very low yields of product are obtained, 

so compound 351 is generally obtained by demetalation of its zinc(II) complex. 

Condensation reactions between isoindole and benzaldehyde in the presence of a metal 

or metal salt, or of 3-benzylidenephthalimidine in the presence of zinc acetate, at high 

temperatures, afford a mixture of metal 5,10,15,20-substituted tetrabenzoporphyrinates; 

the major product is usually the metal complex of tetraphenyltetrabenzoporphyrin 

352. [281–286] Hexadecafluoro derivatives of tetrabenzoporphyrins 351 and 352 are also prepared 

using the same approach. [282,283] Pure 5,10,15,20-tetraphenyltetrabenzoporphyrins 

are prepared by tetramerization of 3-benzylidenephthalimidine, in the presence of zinc 

benzoate, [285] and also by condensation of potassium phthalimide with phenylacetic acid 

in the presence of zinc chloride. [270,287] The instability of isoindoles mentioned above can 

be circumvented by the use of a 4,7-dihydro-4,7-ethano-2H-isoindole ethyl ester (362; 

Scheme 82); reduction (lithium aluminum hydride) and tetramerization, followed by oxi- 


NH 

N 

361 

N 

HN


adation, affords the porphyrin 363 which, upon heating at 2008C (retro-Diels–Alder reaction), 

gives a quantitative yield of the tetrabenzoporphyrin 351. [288,289] 

Scheme 82 Preparation of a Tetrabenzoporphyrin [288,289] 

N 

H 

362 

CO 2Et 

1. LiAlH 4 

2. H + 


NH 

3. [O] 200 o C 

Butanoporphyrins, such as 364, can be transformed into the corresponding tetrabenzoporphyrins 

365 by metalation (e.g., with nickel, copper, or zinc) followed by treatment 

with 2,3-dichloro-5,6-dicyanobenzo-1,4-quinone (Scheme 83). [290] Tetrabenzoporphyrin 

351 has been prepared in good yield by cyclotetramerization of a phenylsulfonylcyclohexanepyrrole-2-carboxylate, 

followed by base-promoted elimination of the phenylsulfonyl 

groups and aromatization using 2,3-dichloro-5,6-dicyanobenzo-1,4-quinone. [291] 

N 

363 

N 

HN 

NH 

N 

351 

N 

HN 



aScheme 83 Preparation of a Tetrabenzoporphyrin from a Butanoporphyrin [290] 

MeO2C 

MeO 2C 

Ar 1 

NH 

N 

Ar 1 

364 

N 

HN 

CO 2Me 

Ar 1 

CO2Me 

Ar1 MeO2C 

CO2Me MeO2C CO2Me K. M. Smith and M. G. H. Vicente, Section 17.8, Science of Synthesis, 2003 Georg Thieme Verlag 

1. M 2+ 

MeO 2C 

2. DDQ, heat 

MeO 2C 

Ar 1 

NH 

N 

Ar 1 

365 

N 

HN 

CO 2Me 

Ar 1 

CO 2Me 

Ar1 MeO2C 

CO2Me MeO2C CO2Me 17.8.2.3.2 Method 2: 

Monobenzoporphyrins, Dibenzoporphyrins, and Benzoporphyrin 

Derivatives 

The main interest in these macrocycles with individual benzo-fused rings comes from 

their discovery in some petroleum and related deposits, although their origins in these 

deposits are still poorly understood. [292–297] In 1977, the first synthesis of a monobenzoporphyrin 

353 (Scheme 80) from a porphyrin precursor bearing a fused cyclohexanone ring 

was reported. [298] Sodium borohydride reduction of the ketone group and subsequent dehydration 

with benzoyl chloride/dimethylformamide gives the cyclohexene derivative, 

which is then oxidized with 2,3-dichloro-5,6-dicyanobenzo-1,4-quinone to give 353. Using 

similar methodology, the same group prepared a naturally occurring monobenzoporphyrin 

354 containing an isocyclic cyclopentane ring, which they obtained by acid-catalyzed 

cyclization of the corresponding b-vinylmonobenzoporphyrin. [299] 

The so-called adj- (adjacent) and opp- (opposite) dibenzoporphyrins 356 and 357 

(Scheme 80) are also prepared following the same methodology as above; [300] the fused cyclohexanone 

rings of the precursors are prepared by base-induced cyclization of acetic 

and propanoic acid side chains on adjacent b-pyrrolic positions, followed by hydrolysis 

of the resulting b-oxo esters with aqueous acid. 

Monobenzoporphyrins such as 353 can also be synthesized from the appropriate tetrahydrobenzoporphyrins 

by oxidation with 2,3-dichloro-5,6-dicyanobenzo-1,4-quinone. 

[301,302] opp-Dibenzoporphyrins, such as 357, can also be obtained from the corresponding 

saturated precursors by treatment with 2,3-dichloro-5,6-dicyanobenzo-1,4-quinone 

in refluxing toluene, [116] provided that the precursor porphyrin has been previously 

chelated with zinc(II). [303] 

Fischer-type self-condensation of benzopyrromethene hydrobromides (179, see Section 

17.8.1.2.2.1), prepared from haloformylisoindoles and 2-unsubstituted pyrroles,


agives good yields of opp-dibenzoporphyrins, such as 180 (Scheme 39). [123,304] The starting 

haloformylisoindoles are prepared from phthalimidine, by a double Vilsmeier reaction. 

Johnson and co-workers [305] were the first to show that the external vinyl groups and 

the neighboring peripheral b,b¢-double bonds of protoporphyrin IX dimethyl ester (366) 

(Scheme 84) react with activated dienophiles in Diels–Alder-type reactions, producing 

chlorins and isobacteriochlorins. This new approach to superstructured porphyrin systems 

was extended by others and has been applied to numerous b-vinyl-substituted porphyrins 

and chlorins to furnish chlorins, bacteriochlorins, isobacteriochlorins, and 

monobenzoporphyrins. [306–312] Monobenzoporphyrins, such as 355, can be obtained from 

Diels–Alder [4 +2]-cycloaddition reactions on the dimethyl ester 366 of protoporphyrin 

IX, followed by elimination of the angular methyl group in the presence of base, or simply 

by oxidation with benzo-1,4-quinone. [313] Catalytic hydrogenation of the Diels–Alder adduct 

obtained from the reaction with b-phenylsulfonylacrylonitrile, followed by base-promoted 

elimination of the phenylsulfonyl group, affords the corresponding cyclohexene 

derivative, which after aerobic oxidation and aromatization, produces the monobenzoporphyrin. 

[314] Monobenzoporphyrins are also obtained directly from Diels–Alder cycloaddition 

reactions of b-unsubstituted b¢-monovinylporphyrins in the presence of an excess 

of dienophile. [314] 

The so-called “benzoporphyrin derivatives” [e.g., benzoporphyrin derivative monocarboxylic 

acid, “BPD-MA”, Visudyne (359)] (Scheme 80) have been shown to be useful in 

the photodynamic therapy treatment of the wet form of age-related macular degeneration. 

They are obtained by rearrangement of the Diels–Alder adducts from protoporphyrin 

IX dimethyl ester (366) and dimethyl acetylenedicarboxylate, at room temperature, in 

the presence of triethylamine (to produce the trans-isomer) or 1,8-diazabicyclo[5.4.0]undec-7-ene 

(to produce the cis-isomer). [315–319] Benzobacteriopurins, for example 367, [320] 

and benzobacteriochlorins such as 368, [315,321,322] have also been synthesized using the 

above methodology (Scheme 84). 

Scheme 84 Benzoporphyrin Derivatives 

MeO2C 

EtO 2C 

Et 

NH 

N 

NH 

N 

366 

CO 2Et 

N 

HN 

EtO2C 

368 

N 

HN 

Et 

CO 2Me 

CO2Et 

MeO 2C 


Et 

NH 

N 

EtO2C 

367 

N 

HN 

O O O 

CO 2Et 



a17.8.3 Product Subclass 3: 

Isomeric, Contracted, and Expanded Porphyrin Systems 

This rapidly growing area has been extensively reviewed in the recent past. [323,324] 

Though the porphyrin ligand appears to be the one which dominates biology (being 

utilized in heme proteins and in chlorophyll systems), many scientific disciplines (e.g., 

chemistry, medicine, and materials science) have become interested in modification of 

the tetrapyrrole ligand system. Therefore, a large number of related macrocycles have 

been synthesized in the last few decades in order to study structure/function relationships, 

and possibly to improve upon some characteristics of the natural tetrapyrrole chromophore. 

Examples include porphyrin isomers; if the porphyrin macrocycle is regarded 

as the parent [18]porphyrin (1:1:1:1) system, where the numerals refer to the number of 

carbons between each pyrrole subunit, then isomers might have the (2,0,2,0) 369, 

(2,1,0,1) 370, (1,0,3,0) 371, etc., arrangement of meso-carbons (Scheme 85). The bestknown 

example of a contracted porphyrin system is found in corrole 372, and two commonly 

prepared expanded porphyrin systems (among many) are the sapphyrins 373 and 

pentaphyrins 374. The synthetic work, summarized below, has indeed been rewarded 

with new porphyrin analogues possessing novel and often unique chemical, physical, biological, 

and spectroscopic properties. 

Scheme 85 Isomeric, Contracted, and Expanded Porphyrin Types 

NH N 

N HN 

369 

NH N 

NH HN 

372 

N 

H 

NH N 


N 

N HN N HN 

N 

H 

370 371 

N 

H 

N N 

17.8.3.1 Syntheses of [18]Porphyrin (1,1,1,1) Isomers 

H 

N 

373 

17.8.3.1.1 Method 1: 

Porphycene {[18]Porphyrin (2,0,2,0)} 

NH N 

N HN 

Porphycene was the first porphyrin isomer to be synthesized, and has enjoyed a great 

deal of celebrity because of its novel properties and ingenious synthesis as part of Vogel s 

investigations of annulene systems. Exposure of 5,5¢-diformyl-2,2¢-bipyrrole (375) to the 

reductive McMurry conditions [titanium(IV) chloride/zinc–copper] followed by autoxidation 

of the presumed intermediate 376 gives porphycene 369 (Scheme 86). [325] Since this 

first synthesis, a large number of peripherally substituted porphycenes have been synthesized. 

[326–330] 

N 

374


aScheme 86 Synthesis of Porphycene [325] 

2 

OHC 

N 

H 

375 

N 

H 

CHO 

TiCl4 NH HN 

Zn/Cu [O] 

NH HN 

17.8.3.1.2 Method 2: 

Corrphycene (Porphycerin) {[18]Porphyrin (2,1,0,1)} 


376 

NH N 

N HN 

One other example of a porphyrin isomer synthesis will be discussed for completeness. 

This is the [2,1,0,1] isomer (named corrphycene [331] or porphycerin [332] ), and it has received 

attention from a number of groups. [331–333] The corrphycene 379 is obtained from the 1,18diformyltetrapyrrole 

377 using the low-valent titanium (McMurry) methodology to give 

378. [331] This is then oxidized with air or with iron(III) chloride to give 379 in low yield 

(Scheme 87). 

Scheme 87 Synthesis of Corrphycene (Porphycerin) [331] 

Et 

Et Et 

N 

H 

377 

N 

H 

NH HN 

CHO OHC 

Et 

TiCl 4 

Zn/Cu 

FeCl 3 

Et 

N 

H 

N 

H 

369 

Et NH HN Et 

Et 

378 

N 

H 

Et 

Et N HN Et 

379 

N 

Et 



a17.8.3.2 Contracted Porphyrins: 

Syntheses of Corroles 


Vol. E 9d, pp 665–672, 684 ff. 

Corroles 372 are analogues of porphyrins that are fully conjugated but lack one of 

the four meso-carbon atoms present in porphyrins. Because of this, metal-free corroles 

possess three NHs and, with their smaller-sized central core, can accommodate small 

metal ions or metal ions with high oxidation states. [334] The general and coordination 

chemistry of corroles, [175,176,323] and the various methods available for their synthesis, [335] 

have been reviewed recently. 

17.8.3.2.1 Method 1: 

From Monopyrroles 

17.8.3.2.1.1 Variation 1: 

Using 2-Substituted 1H-Pyrroles 

Treatment of the 5-[hydroxy(phenyl)methyl]-1H-pyrrole-2-carboxylic acid 380 with acidic 

ethanol, under conditions that would normally be expected to give the corresponding 

porphyrin (see Section 17.8.1.2.1), in the presence of cobalt(II) acetate and triphenylphosphine 

affords a 25% yield of the corresponding corrole cobalt complex 382, [336] possibly 

via the dipyrromethene 381 (Scheme 88). [337] If, for example, the copper(II) or nickel(II) 

salts are used, the corresponding metal octamethyltetraphenylporphyrinate is obtained. 

The cobalt pathway also yields corroles with a variety of substituents on the aryl rings if 

the appropriate pyrroles are used. Use of the 2-formyl-1H-pyrrole 27 under the same acidic 

conditions also results in the formation of corrole if cobalt(II) ions are used, but in this 

case a mixture of a porphyrin 383 and three corroles 384–386 are obtained (Scheme 

88); [338] it is again postulated that the corrole mixture is produced as a result of the intermediacy 

of dipyrromethenes. When other metals are used in the reaction, no corrole (and 

usually only porphyrin) is obtained. 

Scheme 88 Syntheses of Corroles from Monopyrroles [336–338] 

HO2C 

N 

H 

Ph 

OH 

H + , EtOH 

Co(OAc) 2, Ph3P Ph 

PPh3 N N 

N N 


NH 

+ 

380 381 

Ph 

N 

Ph 

Co 

Ph 

382 25% 

Ph

HO2C N 

CHO 

H 

a384 


Et 

Et 

27 

Et 

N N 

Co 

PPh 3 

N N 

Et 

H + , EtOH 

Co(OAc) 2, Ph3P 

Et 

N N 

N N 


Et 

Co 

385 

Et 

PPh3 

17.8.3.2.1.2 Variation 2: 

Using 2,5-Di-unsubstituted 1H-Pyrroles and Aldehydes 

Et 

+ 

Et 

Et 

N 

N 

383 

Et 

Co 

+ 

N 

N 

Et 

Et 

Et 

Et 

+ 

N N 

Co 

N N 

Two examples of serendipitous meso-substituted corrole formation during porphyrin syntheses 

using pyrrole and aldehydes have been reported. [339,340] It was subsequently shown, 

as part of a planned corrole synthesis, that reaction of pyrrole and benzaldehyde (4:3 

molar ratio) in refluxing acetic acid for four hours gives a 6% yield of 5,10,15-triphenylcorrole 

(387) (Scheme 89). [341] 5,10,15-Tris(pentafluorophenyl)corrole has also been shown to 

be produced from the analogous reaction using pentafluorobenzaldehyde. [342] 

Scheme 89 Syntheses of Corroles Using 2,5-Di-unsubstituted 1H-Pyrroles and 

Aldehydes [341] 

4 

N 

H 

17.8.3.2.2 Method 2: 

From Dipyrroles 

PhCHO (3 equiv) 

6% 

NH N 

NH HN 

Johnson and co-workers were the first to show that corroles can be synthesized by a Mac- 

Donald-type [2 +2] cyclization. [343] Thus, treatment of the 2,2¢-bipyrrole-5,5¢-dicarboxylic 

acid 388 with the 1,9-diformyldipyrromethane 283 in the presence of acid gives the corrole 

complex 389 after treatment with cobalt(II) acetate and triphenylphosphine; indeed, 

the reaction fails without the metal salt, and this has been shown to be due to the formation 

of a macrocyclic octapyrrole. [344] The reaction also works successfully if the bridging 

Ph 

Ph 

387 

Ph 

386 

PPh3 

Et 

Et 



aformyl carbons are switched to the other component in the [2 +2] reaction, i.e. using the 

5,5¢-diformyl-2,2¢-bipyrrole 390 and the dipyrromethane-1,9-dicarboxylic acid 391 

(Scheme 90). 

Scheme 90 Syntheses of Corroles from Bipyrroles and Dipyrromethanes [343,344] 

Et 

Et 

Et 

Et 

CO 2H 

NH 

NH 

CO2H 

CHO 

NH 

NH 

CHO 

+ 

388 283 

+ 

OHC 

OHC 

HO 2C 

HO2C 

HN 

HN 

HN 

HN 

390 391 

Et 

Et 

Et 

Et 

1. HBr, MeOH 

2. Co(OAc)2, MeOH 

Ph3P 

N N 

N N 

Et Et 

(2,8,12,18-Tetraethyl-3,7,13,17-tetramethylcorrolato)(triphenylphosphine)cobalt 

(389): [343] 

3,3¢-Diethyl-4,4¢-dimethyl-2,2¢-bipyrrole-5,5¢-dicarboxylic acid (388; 100 mg, 0.33 mmol) 

and 3,7-diethyl-1,9-diformyl-2,8-dimethyldipyrromethane (283; 100 mg, 0.35 mmol) were 

dissolved by warming to 608C in MeOH. The soln was cooled in ice and 49% aq HBr 

(0.5 mL) was added dropwise with stirring. A red precipitate formed and this was collected 

by filtration and washed with MeOH (5 mL) containing a few drops of HBr. The solid was 

dissolved in hot MeOH containing Co(OAc) 2 (200 mg) and Ph 3P (200 mg) and the soln was 

boiled on a steam bath for 10 min before being cooled at 08C overnight. The separated 

solid was collected by filtration, washed with MeOH, and then crystallized (CHCl 3/ 

MeOH) to give 389; yield: 54 mg (21%). 

17.8.3.2.3 Method 3: 

From a,c-Biladiene Salts 

As is true for the corresponding porphyrins, the a,c-biladiene route to corroles is the most 

general method, and the 1,19-di-unsubstituted a,c-biladiene hydrobromides are usually 

obtained by treatment of a dipyrromethane with 2 equivalents of a 2-formylpyrrole in 

the presence of hydrogen bromide. There exist numerous ways to achieve cyclization of 

the a,c-biladiene. In the earliest described syntheses this is accomplished photochemically 

in basic methanol. [345] When ammonia is used as the base, small amounts of monoazaporphyrins 

are also obtained, so the procedure is modified by addition of oxidizing agents 

(e.g., potassium ferricyanide). [174] meso-Substituted a,c-biladienes also give corroles. For example, 

the 5-phenyldipyrromethane-1,9-dicarboxylic acid 392 is treated with 2 equivalents 

of the 2-formyl-1H-pyrrole 393 in the presence of hydrogen bromide to give the crystalline 

a,c-biladiene dihydrobromide 394 (Scheme 91). This is then cyclized in basic methanol 

to give the 10-substituted corrole in good yield; [346–348] the cyclizations are, as usual, 


A 

B 

A: 21% 

Et 

Co 

389 

PPh 3 

Et


acarried out in the presence of cobalt(II) and triphenylphosphine, so the cobalt complexes 

395 are isolated. 

Scheme 91 Syntheses of Corroles from 1H-Pyrroles and Dipyrromethanes [346–348] 

HO2C 

HO2C 

HN 

HN 

392 

Ph 

(2 equiv) 

N 

CHO 

H 

393 

HBr, AcOH 

Co(OAc)2, NaOAc 

Ph3P, MeOH 


NH 

+ 

NH 

394 

HN 

+ 

HN 

Ph 

N N 

Co 

N N 

1,19-Dibromo-a,c-biladiene dihydrobromides can also be cyclized to afford corroles, the 

cyclization step usually involving thermolysis. [84,349,350] 1,19-Dibromo-a,c-biladienes (e.g., 

398) are typically prepared by condensation of two dipyrromethenes (396, 397) using 

the Friedel–Crafts alkylation developed by Johnson and co-workers for 1-bromo-19-methyl-a,c-biladiene 

and porphyrin syntheses (see Section 17.8.1.1.3.3.3). The metal-free corrole 

399 is obtained from 398 simply by refluxing in dimethylformamide followed by esterification 

with 5% methanol/sulfuric acid (Scheme 92). [84] Unsymmetrically substituted 

1,19-diiodo-a,c-biladienes have also been synthesized and similarly cyclized to give corroles. 

[351] 

Scheme 92 Syntheses of Corroles by Condensation of Two Dipyrromethenes [84] 

Et 

Br 

Br 

Br 

Et 

Et 

NH 

NH 

+ 

NH 

HN 

+ 

398 

HN 

+ 

HN 

Br − 

CO 2Me 

CO 2Me 

2Br − 

CO2H 

+ 

Br 

+ 

− 

NH HN 

396 397 

Et 

Br 

1. DMF, heat 

2. MeOH, H2SO4 26% 

Et 

Et 

Br 

CO 2H 

NH N 

NH HN 

399 

395 

PPh 3 

2Br − 

1. SnCl 4 

2. HBr 

72% 

Ph 

CO2Me 

CO2Me 



a3,18-Diethyl-8,12-bis[2-(methoxycarbonyl)ethyl]-2,7,13,17-tetramethylcorrole (399); Typical 


9-Bromo-1-(bromomethyl)-8-ethyl-2-(2-carboxyethyl)-3,7-dimethyldipyrromethene hydrobromide 

(397) and 1-bromo-3-ethyl-8-[2-(methoxycarbonyl)ethyl]-2,7-dimethyldipyrromethene 

hydrobromide (396) were condensed together (see Section 17.8.1.1.3.3.3) to 

give 1,19-dibromo-8-(2-carboxyethyl)-3,18-diethyl-12-[2-(methoxycarbonyl)ethyl]- 

2,7,13,17-tetramethyl-a,c-biladiene dihydrobromide (398); yield: 72%. This a,c-biladiene 

(188 mg, 0.225 mmol) in DMF (35 mL) was heated on a steam bath for 30 min. The solvent 

was removed under vacuum and the residue was esterified with 5% MeOH/H 2SO 4 before 

being worked up and chromatographed [alumina (Spence type H), CH 2Cl 2]. The corrole 

399 was isolated after crystallization (acetone/hexanes); yield: 33 mg (26%); mp 168– 

1708C. 

17.8.3.2.4 Method 4: 

By Porphyrin Ring Contraction 

Corroles have also been synthesized by way of sulfur extrusion, with concomitant ring 

contraction, from a thiaphlorin 401. The thiaphlorin is synthesized by the MacDonald 

[2+2] approach from a bis(5-formyl-1H-pyrrol-2-yl) sulfide 400 and the dipyrromethane- 

1,9-dicarboxylic acid 391. Ring contraction to give corrole 402 is then accomplished by 

heating in 1,2-dichlorobenzene; [352] using triphenylphosphine in the reaction affords 

higher yields of corrole (Scheme 93). 

Scheme 93 Synthesis of Corroles by Ring Contraction [352] 

EtO 2C 

S 

EtO2C 

NH 

NH 

CHO 

CHO 

+ 

HO 2C 

HO 2C 

17.8.3.3 Expanded Porphyrins 

HN 

HN 

EtO 2C 

EtO2C 

EtO2C 

NH N 

NH HN 

NH N 

NH HN 


Et 

Et 

HCl(g)/MeOH 

52% 

Ph 3P 

S 

EtO2C 

400 391 401 

Expanded porphyrins comprise a group of pyrrole-based macrocycles with an aromatic 

delocalized system larger than that found in the porphyrins. The most investigated examples 

are the sapphyrins 373 and pentaphyrins 374 (Scheme 85); the relationship between 

sapphyrin and pentaphyrin is similar to that between corrole and porphyrin. The expanded 

p-system facilitates the study of aromaticity in large “annulene” systems, and also ex- 

15% 

402 

Et 

Et 

Et 

Et


aamination of the characteristics of coordination of large metal ions because the core size 

is larger than that found in porphyrins. 

17.8.3.3.1 Method 1: 

Syntheses of Sapphyrins 

Sapphyrin 373 was the first example of an expanded porphyrin to be described, when it 

was accidentally obtained by Woodward and co-workers in the early stages of the Harvard 

synthesis of vitamin B 12. [353] The macrocycle possesses five pyrrole rings linked by only 

four methine bridges and therefore has one direct pyrrole–pyrrole bond. The beautiful 

green chromophore features an aromatic 22-electron p-system. 

17.8.3.3.1.1 Variation 1: 

The [3+2] Approach 

A rational [3+2] synthesis of sapphyrin 405 from 403 and 404 (Scheme 94) was eventually 

reported by the Harvard group, [64] and this was followed by a number of related [3+2] approaches. 

[354,355] With the new advances in tripyrrane synthesis, [65,66] a more efficient approach 

to sapphyrins was developed. [61,66] However, the synthetic pathway to sapphyrins 

was still based upon the original [3+2] approach pioneered by Woodward and co-workers, 

[64] and possessed some symmetry restrictions with regard to the peripheral substituent 

array. 

More recently, Sessler and co-workers have reported the preparation of symmetrical 

meso-diaryl substituted sapphyrins (e.g., 407) by way of a Lindsey-type reaction of arylaldehyde 

406, pyrrole, and a bipyrrole dialdehyde 390 under Lewis acid catalysis. [356] 

Though the reaction appears to be a [2+1+1+1] method, a tripyrrane is presumably 

formed in situ by reaction of two moles of the arylaldehyde and three of pyrrole, and 

this subsequently condenses with the bipyrrole unit, once again in a [3 +2] mode (Scheme 

94). 

Scheme 94 Syntheses of Sapphyrins by the [3 +2] Approach [64,356] 

OHC 

N N 

H H CHO 

403 

+ 

CO 2H CO 2H 

NH HN 


H 

N 

404 

TsOH, O2 

44% 

N 

H 

405 

N 

H 

N N 

H 

N 



OHC 

N 

H 

Et Et 

390 

N 

H 

CHO 

+ 2 

R1 R1 

a407 

17.8.3.3.1.2 Variation 2: 

The [3+(1) 2 ] Approach 

CHO 

R 1 

406 


+ 3 

N 

H 

1. BF3 MeOH 

2. DDQ 

N 

H 

Et Et 

N 

H 

+ 2Cl 

NH HN 

− 

+ 

Treatment of 1,14-diformyltripyrranes (e.g., 408) with 2 equivalents of a 2,5-di-unsubstituted 

3,4-diethyl-1H-pyrrole affords sapphyrins 409 in 28–34% yields (Scheme 95). [357] 

Scheme 95 Syntheses of Sapphyrins by the [3 +(1) 2 ] Approach [357] 

CHO OHC 

NH HN 

H 

N 

HO OH 

Et 

408 

Et 

1. 

Et 

N 

H 

Et 

TFA, CH2Cl2 2. DDQ, Et3N 

34% 

(2 equiv) 

HO 

Et 

N 

H 

H 

N 

409 

N 

H 

N N 

Et 

Et Et 

H 

N 

Et 

Et 

OH


a2,3,12,13,22,23-Hexaethyl-8,17-bis(2-hydroxyethyl)-7,18-dimethyl-1,24-sapphyrin (409); 


5% TFA in CH 2Cl 2 (200 mL) was added to 1,14-diformyl-7,8-diethyl-3,12-bis(2-hydroxyethyl)-2,13-dimethyltripyrrane 

(408; 96 mg, 0.2 mmol) and 3,4-diethyl-1H-pyrrole (49 mg, 

0.4 mmol). The mixture was stirred at rt overnight before being neutralized with Et 3N, 

and then DDQ (45 mg, 0.2 mmol) was added. The mixture was concentrated to a volume 

of 100 mL on a rotary evaporator and then washed with aq NaHCO 3 (2 ” 100 mL) and H 2O 

(2 ” 100 mL). The organic phase was dried (MgSO 4), filtered, and concentrated, and the residue 

was chromatographed (silica gel, CH 2Cl 2/MeOH 96:4) to afford the sapphyrin 409; 

yield: 47 mg (34%); mp > 3008C. 

17.8.3.3.1.3 Variation 3: 

The [4+1] Approach 

Corroles are readily obtained by cyclization of 1,19-di-unsubstituted a,c-biladienes (Section 

17.8.3.2.3), a reaction in which the direct pyrrole–pyrrole link is formed as the last 

stage in the cyclization process; attempts have, therefore, been made to apply this approach 

to sapphyrin syntheses. Since 1,19-di-unsubstituted a,c-biladiene salts have been 

shown to react with aldehydes in acidic ethanol to afford the corresponding porphyrins 

in good yields, a new route involving condensation of an a,c-biladiene 410 with a 2-formyl-1H-pyrrole 

411 was investigated; this was based on the hypothesis that a transient 

pentapyrrolic intermediate 412 might subsequently cyclize to produce sapphyrin 413 

rather than a meso-pyrrolylporphyrin. In this way, the sapphyrin 413 was successfully obtained 

in good yield (presumably via the intermediate 412), along with small amounts of 

2,3,7,8,12,13,17,18-octaethylporphyrin (414, R 1 = Et), another porphyrin 414 (R 1 =Me), 

and corrole 415 (Scheme 96). [358] 




aScheme 96 Syntheses of Sapphyrins by the [4+1] Approach [358] 

Et 

NH HN 

+ 

+ 

NH HN 

410 

Et 

2Br − 

Et Et 

N 

CHO 

H 

411 

A: TsOH, abs EtOH 

B: AcOH, reflux, 1 h 

Et 

+ 

Et 

Et 

N 

H 

+ N 

H 

+ 

NH HN 


N 

H 

N 

H 

N N 

Et 

H 

N 

Et 

413 A: 20% 

B: 18% 

Et 

Et 

Et Et 

NH N 

N HN 

Et 

+ 

+ 

R 1 

R 1 

Et 

H 

N+ 

412 

R 1 

R 1 

Et 

NH N 

N HN 

414 R 1 = Me, Et 

NH N 

NH HN 

415 

3OTs − 

2,3,13,17-Tetraethyl-7,8,12,18,22,23-hexamethylsapphyrin (413); Typical Procedure: [358] 

Method A: 2-Formyl-3,4-diethyl-1H-pyrrole (411; 0.5 g, 3.31 mmol), 8,12-diethyl- 

2,3,7,13,17,18-hexamethyl-a,c-biladiene dihydrobromide (410; 0.5 g, 0.83 mmol), and 

TsOH (0.25 g) were dissolved in abs EtOH (100 mL) and the mixture was refluxed in the 

dark (aluminum foil). Progress of the reaction was monitored spectrophotometrically; 

when absorbances attributable to 410 disappeared the solvent was removed under vacuum, 

the resulting solid was redissolved in CH 2Cl 2, then washed with H 2O (” 3) and dried 

(Na 2SO 4). The solvent was removed and the crude mixture was chromatographed (silica 

gel, CH 2Cl 2) to yield two bands. The first (red-brown) fraction to be eluted contained 

2,3,7,8,12,13,17,18-octaethylporphyrin (21); yield: 65 mg, together with traces of 8,12-diethyl-2,3,7,13,17,18-hexamethylporphyrin 

414 (R 1 = Me), while the second (red-violet) 

fraction contained 8,12-diethyl-2,3,7,13,17,18-hexamethylcorrole (415); yield: 48 mg. 

The column was then eluted with CH 2Cl 2 containing increasing amounts of methanol 

(2–10%). A green fraction was collected, the solvent was removed under vacuum, and the 

residue was crystallized (CH 2Cl 2/hexanes) to give 413 as its 4-toluenesulfonate salt; yield: 

158 mg (20%); mp > 3008C. The dihydrochloride derivative was obtained by washing a 

Et 

21 

Et 

Et 

Et 

R 1 

R 1 

Et 

Et 

Et 

Et


aCH 2Cl 2 soln of [2H•413] 2+ (OTs) 2 with sat. aq Na 2CO 3 until spectrophotometry showed the 

formation of the corresponding free base; subsequent treatment with dil HCl quantitatively 

afforded [2H•413] 2+ Cl 2; mp > 300 8C. 

Method B: Formylpyrrole 411 (0.5 g, 3.31 mmol) and a,c-biladiene 410 (0.5 g, 

0.83 mmol) were dissolved in AcOH (100 mL) and refluxed in the dark for 1 h. The solvent 

was removed under vacuum, the resulting solid was redissolved in CH 2Cl 2, washed with 

sat. Na 2CO 3, and with dil HCl, and dried (Na 2SO 4). The solvent was removed under vacuum 

and the crude mixture was chromatographed (silica gel, as outlined in Method A). The appropriate 

green fraction was collected, and the solvent was removed in vacuo to give 

[2H•413] 2+ Cl 2; yield: 98 mg (18%). 

17.8.3.3.1.4 Variation 4: 

The [1] 5 Approach 

5,10,15,20-Tetraphenylsapphyrin (416) has been shown to be formed in low yield during 

the Rothemund synthesis of meso-tetraphenylporphyrin (Section 17.8.1.2.1) (Scheme 

97). [359] 

Scheme 97 5,10,15,20-Tetraphenylsapphyrin [359] 

Ph N N Ph 

H H 

N N 

H 

N 

Ph Ph 

416 

17.8.3.3.2 Method 2: 

Syntheses of Pentaphyrins 


Vol. E 9d, pp 700–708. 

Pentaphyrins 374 are fully conjugated macrocycles with five pyrrole subunits linked 

by methine (sp 2 carbons); they differ from the more highly investigated sapphyrins in that 

pentaphyrins do not possess a direct pyrrole–pyrrole bond. The first pentaphyrin synthesis 

was reported by Rexhausen and Gossauer, [360] and employed a [3+2] MacDonald-type 

approach. [361–363] Thus, the 1,14-diformyltripyrrane 418 reacts under acid catalysis with 

the 1,9-di-unsubstituted dipyrromethane 417, presumably to give the macrocycle 419, 

which is subsequently oxidized with chloranil to give the pentaphyrin 420 in good yield 

(Scheme 98); several other versions of this same approach have subsequently been reported, 

along with the revelation that pentaphyrins cannot be obtained if the new mesobridge 

carbons (i.e., the 1- and 14-formyl groups in 418) are situated on the dipyrromethane. 

[364–367] Presumably, the unprotected tripyrrane is subject to acid-catalyzed ring 

redistribution reactions and, therefore, the more favorable porphyrin products are produced. 




aScheme 98 Syntheses of Pentaphyrins by the [3+2] Approach [360] 

NH HN 

417 

H + 

+ 

N 

H 

+ N 

H 

+ 

NH HN 


H 

N 

419 

CHO OHC 

NH HN 

H 

N 

MeO 2C CO 2Me 

418 

2X − 

MeO2C CO 2Me 

17.8.4 Reactions around the Porphyrin Periphery 

N 

H 

N 

N HN 

N 

MeO2C CO2Me Very thorough reviews of reactivity in both the 2,3,7,8,12,13,17,18-octaalkyl- [368] and 

5,10,15,20-tetraalkyl/aryl- [369] porphyrin series are now available. Since porphyrins are aromatic 

molecules, this dominates their overall reactivity patterns and profiles. 

17.8.4.1 Method 1: 

Electrophilic Substitution Reactions 

Substitution and addition reactions can take place at the b—b¢ peripheral double bonds, 

with retention of the 18p-aromatic delocalization pathway, leading to functionalized porphyrins, 

chlorins, bacteriochlorins, or isobacteriochlorins. Substitutions at the meso positions 

can also occur, with formation of meso-substituted porphyrins, phlorins, porphodimethenes, 

or nonaromatic expanded “homo-type” macrocycles. The basic inner nitrogen 

atoms of porphyrins react with electrophilic reagents and are easily protonated (thereby 

deactivating the porphyrin nucleus toward electrophilic attack), unless previously protected 

by metalation; zinc(II) is often the ion of choice for metalation because it is moderately 

robust and does not draw electron density away from the porphyrin p-system. However, 

the zinc(II) ion can be removed under acidic conditions, [370] so nickel(II) or copper(II) 

420 

[O]

aare sometimes used instead; these metals are more electronegative within the porphyrin 

core, but at the same time they are also more resistant to demetalation by mild acids. Copper(II) 

and nickel(II) porphyrinates are usually demetalated using trifluoroacetic acid in 

sulfuric acid. 

17.8.4.1.1 Variation 1: 

Halogenation 


Porphyrins undergo halogenation at the peripheral unsubstituted b- and meso positions. 

Fluorination and chlorination usually take place at the more-reactive meso positions, 

whereas bromination and iodination occur mainly at the less sterically congested b-positions. 

N-Fluoropyridinium triflates [371] or cesium fluoroxysulfate [372] have been used for 

meso-polyfluorination of porphyrins, such as 2,3,7,8,12,13,17,18-octaethylporphyrin 

(21), which gives the mono-, di- (two isomers), tri-, and tetrafluoro-2,3,7,8,12,13,17,18-octaethylporphyrins 

421–425 shown in Scheme 99. b-Fluorination of zinc(II) 5,10,15,20-tetraphenylporphyrinate 

has been accomplished with cobalt(II) fluoride or silver(II) fluoride 

in dichloromethane. [373] 

Scheme 99 Fluorinated Porphyrin Isomers 

Et 

Et 

Et 

Et 

Et 

Et 

Et 

Et 

F 

NH N 

N HN 

421 

F 

NH N 

N HN 

F 

424 

Et 

Et 

Et 

Et 

Et 

Et 

Et 

Et 

Et 

Et 

Et 

Et 

NH N 

N HN 


F 

422 

Et 

Et 

NH N 

F F 

F 

Et 

Et 

N HN 

Et 

F 

Et 

Et 

Et 

Et 

Et 

F 

NH N 

N HN 

Chlorination of porphyrins is achieved using N-chlorosuccinimide, [374–379] chlorine/iron(- 

III) chloride, [380] hydrogen chloride/hydrogen peroxide, [377,380] and phenylselenium trichloride. 

[381] Mono- and dichloro-2,3,7,8,12,13,17,18-octaethylporphyrin are usually obtained 

with N-chlorosuccinimide or with hydrogen chloride/hydrogen peroxide in aqueous 

tetrahydrofuran, but meso-tetrachlorination occurs with hydrogen chloride/hydrogen 

peroxide or chlorine in acetic acid. 

Porphyrins are brominated with N-bromosuccinimide, [375,376,379,382–387] hydrogen bromide/hydrogen 

peroxide, [380,385] bromine in various solvents, [376,385–389] or phenylselenium 

tribromide. [381] Electrophilic bromination of 5,15-diphenylporphyrin (426) with 2 equivalents 

of N-bromosuccinimide occurs selectively at the unsubstituted meso positions with 

formation of dibromide 427 (Scheme 100). [384] Regioselective tetrabromination of metalfree 

meso-tetraarylporphyrins, such as 5,10,15,20-tetraphenylporphyrin (22), is accomplished 

using an excess of N-bromosuccinimide, and regioselectively affords 2,3,12,13-tet- 

Et 

Et 

F 

F 

425 

Et 

Et 

Et 

Et 

F 

423 

Et 

Et 

Et 

Et 



arabromoporphyrins, such as 428 (Scheme 100); [390] the initial b-bromo substituent perturbs 

the position of the tautomeric equilibrium, favoring the tautomer with the substituent 

on an isolated double bond and thereby causing bromination on the opposite pyrrolic 

unit. [390,391] 2-Nitro-5,10,15,20-tetraphenylporphyrin also undergoes vicinal dibromination 

with N-bromosuccinimide at the pyrrole subunit opposite the nitro group to give 

12,13-dibromo-2-nitro-5,10,15,20-tetraphenylporphyrin (429) (Scheme 100). The nitro 

group can be removed using sodium borohydride to give the dibromonitrochlorin 430 

which eliminates nitrous acid to afford 2,3-dibromo-5,10,15,20-tetraphenylporphyrin 

(431). The nitrochlorin 430, also reacts with copper(I) cyanide to give the copper(II) 2,3dicyano-5,10,15,20-tetraphenylporphyrinate 

(432) by nucleophilic displacement of the 

two bromines and metalation (Scheme 100). [390] 

Scheme 100 Bromination of Porphyrins [384,390] 

Ph 

NH N 

N HN 

Ph 

426 

Ph 

NH N 

Ph Ph 

N HN 

Ph 

22 

NBS (2 equiv) 

CHCl3 NBS (excess) 

CHCl3 NH N 

N HN 


Ph 

Br Br 

Ph 

Br 

Ph 

427 

Br 

Ph 

NH N 

N HN 

Ph 

428 

Br 

Br 

Ph


Ph 

NH N 

Ph Ph 

N HN 

Ph 

a429 

NO 2 

Ph 

NH N 

82% 

Ph Ph 

Br 

Br 

N HN 

Ph 

430 

NO2 

NBS 

CHCl3 

NH N 

N HN 


Ph 

Ph Ph 

Br 

Br 

silica gel 

CHCl3, reflux 

− HNO 2 

98% 

CuCN 

quinoline, heat 

− HNO 2 

75% 

Ph 

NO 2 

Ph 

N N 

Ph Cu 

Ph 

NC 

NC 

Ph 

NH N 

Ph Ph 

Br 

Br 

N HN 

Ph 

431 

N N 

Although less favored, iodination of porphyrins has been accomplished using bis(trifluoroacetoxy)iodobenzene–iodine 

[392] and with iodine in 1,2-dichlorobenzene. [385] b-Iodination 

is favored for deuteroporphyrin IX dimethyl ester (433), which produces 434 by reaction 

with iodine at high temperature (Scheme 101). 

Scheme 101 Iodination of Porphyrins [385] 

MeO2C 

NH N 

N HN 

433 

CO2Me 

I2, 1,2-Cl2C6H4 

180 o C 

MeO2C 

I 

Ph 

NaBH4 

THF 

432 

NH N 

N HN 

434 

84% 

I 

CO2Me 

Iodine, bromine, and N-bromosuccinimide can produce the p-cation radicals of porphyrins, 

which are known to react with a variety of nucleophiles, or to participate in dimerization 

reactions (vide infra). The reaction of 2,3,7,8,12,13,17,18-octaethylporphyrin (21) 

with N-bromosuccinimide in the presence of 2,2¢-azobisisobutyronitrile produces (E)-(2- 



abromovinyl)porphyrin 436 by way of a 2-(1-bromoethyl)porphyrin intermediate 435, 

which can be trapped as an ether derivative if alcohols are present (Scheme 102). [378,393] 

Scheme 102 Bromovinylporphyrin Synthesis [378,393] 

Et 

Et 

Et 

Et 

NH N 

N HN 

21 

Et 

Et 

Et 

Et 

NBS, AIBN 

1,2-dichloroethane 

NH N 

N HN 


Et 

Et 

Et 

Et 

435 

Et 

Et 

Br 

Et 

Et 

Et 

Et 

Et 

NH N 

N HN 

436 92% 

Bromoporphyrins are important starting materials in various metal-catalyzed reactions. 

[394,395] Nucleophilic substitutions of bromo substituents by cyanide (e.g., 

430fi432), [241,384,396] nitrite, [397] or by thiolates [398] are also known. 

Fluorination of 2,3,7,8,12,13,17,18-Octaethylporphyrin (OEP, 21); Typical Procedure: [372] 

2,3,7,8,12,13,17,18-Octaethylporphyrin (21; 100 mg, 0.187 mmol) was dissolved in dioxane 

(350 mL) with heating (908C, 2 h) and then treated at rt with an excess of freshly prepared 

aq cesium fluoroxysulfate (500 mg in 3 mL) with vigorous stirring. After 10 min the 

soln was poured into H 2O (800 mL) and extracted with CHCl 3 (2 ” 100 mL). The combined 

organic extracts were washed with H 2O (3 ” 200 mL), dried (Na 2SO 4), concentrated, and 

subjected to preparative TLC (silica gel, CHCl 3/petroleum ether 1:2) to give six bands: (1) 

recovered 2,3,7,8,12,13,17,18-octaethylporphyrin (21); 19.8 mg. (2) 2,3,7,8,12,13,17,18-octaethyl-5-fluoroporphyrin 

(421); yield: 29 mg (29%); mp 235–2378C. (3) 

2,3,7,8,12,13,17,18-octaethyl-5,10-difluoroporphyrin (422); yield: 12 mg (11%); mp 280– 

2828C. (4) 2,3,7,8,12,13,17,18-octaethyl-5,15-difluoroporphyrin (423); yield: 10 mg (9.5%); 

mp 290–2928C. (5) 2,3,7,8,12,13,17,18-octaethyl-5,10,15-trifluoroporphyrin (424); yield: 

5 mg (4%); mp 232–2348C. (6) 2,3,7,8,12,13,17,18-octaethyl-5,10,15,20-tetrafluoroporphyrin 

(425); yield: 3 mg (2%); mp 208–2098C. 

12,13-Dibromo-2-nitro-5,10,15,20-tetraphenylporphyrin (429); Typical Procedure: [390] 

A mixture of 2-nitro-5,10,15,20-tetraphenylporphyrin (1.0 g, 1.52 mmol) and NBS (0.68 g, 

2.42 equiv) in dry CHCl 3 (EtOH-free; 150 mL) was refluxed overnight. After cooling to rt, 

the mixture was filtered through a neutral alumina plug (Brockmann Grade III) eluting 

with CH 2Cl 2. The filtrate was concentrated to dryness and the resulting residue was crystallized 

(CH 2Cl 2/MeOH) to give 429; yield: 1.01 g (82%); mp > 3008C. 

Et 

Br 

Et 

Et

a12,13-Dibromo-2,3-dihydro-2-nitro-5,10,15,20-tetraphenylporphyrin (430); Typical Procedure: 

[390] 

To a cold soln (ice/NaCl) of dry THF (30 mL) under argon was added a mixture of 12,13-dibromo-2-nitro-5,10,15,20-tetraphenylporphyrin 

(429; 500 mg, 0.61 mmol) and NaBH 4 

(40 mg, 1.11 mmol). The resulting mixture was stirred for 2 h, the ice bath being removed 

after 1 h. The progress of the reaction was monitored by spectrophotometry; after 2 h the 

Soret band had shifted from 436 to 424 nm. CH 2Cl 2 (100 mL) was then added and the mixture 

was poured into H 2O. The organic phase was washed with H 2O (2 ”) and concentrated 

to dryness. The residue was redissolved in CH 2Cl 2 and filtered through a short neutral alumina 

plug (Brockmann Grade V, eluting with CH 2Cl 2). The filtrate was concentrated to 

dryness, and the residue was crystallized (CH 2Cl 2/MeOH) to yield 430; yield: 420 mg 

(84%); mp > 3008C (dec with elimination of HNO 2 >808C). 

2,3-Dibromo-5,10,15,20-tetraphenylporphyrin (431); Typical Procedure: [390] 

A mixture of nitrochlorin 430 (200 mg, 0.24 mmol), silica gel (20 g), and CHCl 3 (100 mL) 

was refluxed for 1 d under argon. The mixture was cooled to rt and the silica gel was removed 

by filtration and washed thoroughly with CH 2Cl 2. After concentration of the solvents 

from the combined filtrate and washings, the residue was crystallized (CH 2Cl 2/ 

MeOH) to yield 431; yield: 185 mg (98%); mp > 300 8C. 

(2,3-Dicyano-5,10,15,20-tetraphenylporphyrinato)copper(II) (432); Typical Procedure: [390] 

A mixture of nitrochlorin 430 (500 mg, 0.61 mmol), CuCN (1.1 g, 12 mmol), and quinoline 

(15 mL) was heated at 2008C under argon for 2 h. The mixture was allowed to cool and 

CH 2Cl 2 (100 mL) was added. The excess of CuCN was removed by filtration and the organic 

phase was washed with 10% HCl (3 ” 100 mL), H 2O (” 2), dried (Na 2SO 4), and then concentrated 

to dryness. The residue was crystallized (CH 2Cl 2/cyclohexane) to give 432; yield: 

330 mg (75%); mp > 3008C. 

2-[(E)-2-Bromovinyl]-3,7,8,12,13,17,18-heptaethylporphyrin (436); Typical Procedure: [378] 

NBS (39.5 mg, 0.22 mmol) in 1,2-dichloroethane (3 mL) was added to a soln of 

2,3,7,8,12,13,17,18-octaethylporphyrin (21; 61.4 mg, 0.12 mmol) in 1,2-dichloroethane 

(40 mL). AIBN (2.7 mg, 0.02 mmol) in 1,2-dichloroethane (0.5 mL) was added with continuous 

stirring. The mixture was then refluxed for 5 h, concentrated under vacuum, and then 

chromatographed on preparative TLC plates (silica gel, 30% petroleum ether/CH 2Cl 2). The 

front-running band was collected and crystallized (CH 2Cl 2/MeOH) to give porphyrin 436; 

yield: 57.9 mg (83%); mp >350 8C. Recovery of 2,3,7,8,12,13,17,18-octaethylporphyrin (21) 

from a minor TLC band raised the yield to 92%, based on consumed starting material. 

17.8.4.1.2 Variation 2: 

Nitration 


Nitration of porphyrins is accomplished by aromatic electrophilic substitution or via pcation 

radical intermediates, and takes place preferentially at the meso positions, though 

b-nitrations occur when these positions are sterically accessible. [399] Electrophilic nitration 

is achieved with fuming nitric acid, [400,401] nitric acid in acetic or sulfuric acid, [402–405] 

copper(II) or zinc(II) nitrate in acetic anhydride, [406] or with nitronium tetrafluoroborate. 

[402,407] Reaction of nitrogen dioxide [408–411] or nitrite ion [397,412–414] with the p-cation radicals 

of porphyrins accomplishes efficient nitration of the porphyrin ring, even on a large 

scale (e.g., preparation of 438 from 437, Scheme 103). The electron-withdrawing effect of 

the nitro groups deactivates the macrocycle toward further electrophilic substitutions, 

therefore the mono-nitro derivatives can be obtained in good yields. This fact notwithstanding, 

heptanitration of 439 to produce 440 has been accomplished using fuming ni- 




atric acid in nitromethane in the presence of acetic anhydride and montmorillonite K-10 

clay (Scheme 103). [415] 

Scheme 103 Nitration of 5,10,15,20-Tetraarylporphyrins [408–411,415] 

N 

N 

Ph 

437 

N 

Ph Cu Ph 

N 

Ph 

Ar Zn 

1 Ar1 N 

Ar 1 = 2,6-Cl 2C 6H 3 

Ar 1 

Ar 1 

439 

N 

N 

N 

N2O4, CH2Cl2 

88% 

1. HNO3, Ac2O, K-10 clay 

2. TfOH 


N 

N 

Ph 

438 

N 

Ph Cu Ph 

Ph 

O 2N 

N 

NO2 

Ar1 O2N NO2 NH 

N 

Ar 

440 

1 

N 

Ar 1 Ar 1 

Reduction of peripheral nitro groups to amino groups can be achieved with tin(II) chloride/hydrogen 

chloride, [416] or with sodium borohydride and 10% palladium on carbon in 

methanol. [412,417] b-Aminoporphyrins undergo a variety of reactions, such as acylation, [404] 

diazotization, [418,419] and reactions with aldehydes and ketones. [242,420,421] 5,10,15,20-Tetraaryl-2-nitroporphyrins 

and their metal derivatives can undergo ipso-substitution of the 

nitro group [243,412,422–424] and nucleophilic Michael additions [242,243,411,425–429] with several nucleophiles. 

b-Fused pyrroloporphyrins 442 are synthesized from metal 2-nitro-5,10,15,20tetraphenylporphyrinates 

(e.g., 441) by reaction with -isocyanoacetic esters in the presence 

of a base (Scheme 104); a transesterification of the ester takes place during the reaction 

unless tert-butyl alcohol is used as the solvent. [430,431] 

O2N 

Scheme 104 Reaction of 5,10,15,20-Tetraaryl-2-nitroporphyrins [430,431] 

Ph 

N 

N 

Ph 

Ni 

Ph 

441 

N 

N 

NO2 

Ph 

CNCH2CO2Me 

DBU, BnOH 

Ph 

N 

N 

Ph 

Ni 

N 

N 

Ph 

442 

HN 

NH 

Ph 

NO2 

CO 2Bn 

(2-Nitro-5,10,15,20-tetraphenylporphyrinato)copper(II) (438); Typical Procedure: [411] 

A suspension of (5,10,15,20-tetraphenylporphyrinato)copper(II) (437; 25.0 g, 37.0 mmol) 

in CH 2Cl 2 (2.0 L) was stirred vigorously. N 2O 4/petroleum ether soln (preparation given be- 

NO 2 

NO 2


alow) was added dropwise over 2–3 h. The addition was performed rapidly at the beginning, 

but was slowed down near completion of the reaction to avoid over-nitration. Close 

reaction monitoring by TLC (alumina, CHCl 3/cyclohexane 1:2) was essential. In this way, 

all of the (5,10,15,20-tetraphenylporphyrinato)copper(II) was converted into the mononitro 

product with minimal dinitro product formation. The mixture was filtered to remove 

any unreacted (5,10,15,20-tetraphenylporphyrinato)copper(II) and then concentrated to a 

volume of about 100 mL. The product 438 was precipitated by addition of MeOH; yield: 

22.0 g (88%). 

N 2O 4/Petroleum Ether Solution: N 2O 4 gas was prepared by the dropwise addition of 

concd HNO 3 (150 mL) from a dropping funnel into a 500-mL three-necked flask (with an 

argon inlet) containing Zn metal (50 g). The gas was carried by a slow stream of argon toward 

a trap containing P 2O 5 to remove any H 2O or HNO 3. The P 2O 5 trap was connected to a 

hose leading to a container of petroleum ether (ca. 150 mL) cooled with liq N 2 and the 

N 2O 4 was bubbled through the cold petroleum ether. The petroleum ether quickly dissolved 

the N 2O 4, producing a soln that was blue at low temperatures and dark orange at rt. 

17.8.4.1.3 Variation 3: 

Formylation and Acylation 

The Vilsmeier formylation of porphyrins has long been one of the most effective and popular 

methods for introducing carbon substituents onto the porphyrin periphery. Because 

zinc(II) porphyrinates are usually demetalated by the acidic Vilsmeier reagent (POCl 3/ 

DMF), the nickel(II) or copper(II) complexes are normally used; the initial product obtained 

from the Vilsmeier reaction is an imine, and this is subsequently hydrolyzed by 

treatment with base. Thus, metal b-octaalkylporphyrinates (e.g., 443) are converted into 

the corresponding meso-formyl derivatives 444 in high yields, [432,433] whereas metal mesotetraarylporphyrinates 

undergo b-formylation, giving, for example, 446 from 445 

(Scheme 105). [434–436] Under the Vilsmeier conditions, copper(II) deuteroporphyrin IX dimethyl 

ester (447) gives a complex mixture of b- and meso-formylated products. [437] As 

would be expected, sterically hindered Vilsmeier reagents (e.g., diisobutylformamide/ 

POCl 3) favor b-substitution. [438] Alternatively, trimethyl orthoformate in trifluoroacetic 

acid selectively mono-b-formylates metallodeuteroporphyrin IX dimethyl esters (e.g., 

447) to give the two regioisomeric b-monoformyl products 448 and 449 after demetalation 

(Scheme 105). [221,439] 

Scheme 105 Syntheses of Formylporphyrins [221,432–436,439] 

Et 

Et 

Et Et 

Et 

N 

N 

Ni 

443 

N 

N 

Et 

Et 

Et 

1. POCl3, DMF 

2. H2O 92% 


Et 

Et 

Et 

N 

N 

444 

N 

Ni CHO 

N 

Et 

Et Et 

Et 

Et 



a445 

N 

N 

Ph 

N 

Ph Cu Ph 

Ph 

N 

N 

N 

Cu 

MeO 2C CO 2Me 

447 

N 

N 

1. POCl3, DMF 

2. H2O 1. HC(OMe) 3, TFA 

2. H2SO4 3. CH2N2 K. M. Smith and M. G. H. Vicente, Section 17.8, Science of Synthesis, 2003 Georg Thieme Verlag 

N 

N 

Ph 

Ph 

446 

N 

Ph Cu Ph 

+ 

OHC 

N 

NH 

N 

CHO 

MeO2C CO2Me 448 39% 

NH 

N 

N 

HN 

N 

HN 

MeO2C CO 2Me 

449 50% 

Vinylporphyrins such as 450 react faster with Vilsmeier reagents to give (E)-(2-formylvinyl)porphyrins 

451 after hydrolysis of the intermediate imine (Scheme 106). [440] 2-Formylvinyl 

groups can be directly introduced at the meso positions by treatment of copper(II) or 

nickel(II) 2,3,7,8,12,13,17,18-octaethylporphyrinates 452 with a vinylogous Vilsmeier reagent 

prepared from 3-(dimethylamino)acrolein and phosphoryl chloride, followed by basic 

hydrolysis to afford 453 (Scheme 106). [441,442] 

Scheme 106 Syntheses of Formylvinylporphyrins [440–442] 

N 

N 

Ni 

MeO 2C CO2Me 

450 

N 

N 

1. POCl3, DMF 

2. H2O OHC 

N 

N 

Ni 

CHO 

MeO2C CO2Me 

451 

N 

N 

CHO

a452 


Et 

Et 

Et 

Et 

M = Cu, Ni 

N 

N 

M 

N 

N 

Et 

Et 

Et 

Et 

1. POCl3, CH2Cl2 CHO 

Me2N 

2. H 2O 

M = Cu 57% 

The formyl group has a very rich organic chemistry, which makes formylporphyrins very 

versatile as synthetic intermediates. For example, meso- and b-formyl groups are transformed 

by standard chemical routes into oximes, which can be dehydrated to produce 

the corresponding cyanoporphyrins. [435,443–445] Reactions of formylporphyrins with Wittig-type 

reagents (Ph 3P=CHR 1 ,R 1 = H, Me, Ph, Br, Cl, CO 2Me, CO 2t-Bu) [434,446–453] yield a 

wide variety of E- and Z-(2-substituted vinyl)porphyrins. Reduction of acrylates to propanoates 

is achieved with Raney nickel or by catalytic hydrogenation in formic acid. [447,453] 

Metalloalkynylporphyrins are obtained by dehydrobromination of metal (2-bromovinyl)porphyrinates 

[454] and participate in palladium-catalyzed cross-coupling reactions with 

aryl iodides and with b-bromovinylporphyrins. [394,455] Metalloethynylporphyrins undergo 

oxidative couplings using tetra(triphenylphosphine)palladium, copper(I) iodide, and triethylamine, 

or copper(I) chloride–N,N,N¢,N¢-tetramethylethylenediamine complex in the 

presence of air, to give butadiyne-linked bisporphyrins. [456] Reactions of metal formylporphyrinates 

with Grignard and aryllithium reagents usually produce the corresponding alcohols. 

[457,458] Allylboronic acid reacts with 3- and 8-formyldeuteroporphyrin IX dimethyl 

ester to afford (1-hydroxybutenyl)porphyrins. [459] Borohydride reduction of the meso-formyl 

group of 444 gives the corresponding meso-hydroxymethylporphyrin 454, but use of 

sodium borohydride/acetic acid results in complete reduction to the methyl group, with 

formation of 455 (Scheme 107). [460,461] 

Scheme 107 Reductions of 5-Formylporphyrins [460,461] 

Et 

Et 

Et 

Et 

N 

N 

Ni 

444 

N 

N 

Et 

Et 

Et 

CHO 

Et 

NaBH 4, EtOH 

NaBH 4, AcOH 


Et 

Et 

Et 

Et 

Et 

Et 

Et 

Et 

N 

N 

Et 

Et 

Et 

Et 

M 

453 

N 

N 

N 

N 

N 

N 

Ni 

454 

Ni 

455 

Et 

Et 

N 

N 

N 

N 

Et 

Et 

Et 

Et 

Et 

Et 

Et 

Et 

Et 

Et 

CHO 

OH 



aIt was discovered during attempts to demetalate the nickel(II) meso-hydroxymethylporphyrinate 

454 that these compounds undergo a self-condensation reaction under acidic 

conditions to give bisporphyrins 456 linked by ethane bridges (Scheme 108); [462] these 

can be transformed into trans-ethene bisporphyrins 457 by a strange dehydrogenation 

in acetic acid. [463–466] 1,2-Ethene–bisporphyrins (cis- and trans-isomers), such as 457, are accessible 

directly by reductive coupling of metal formylporphyrinates, such as 444, using 

low-valent titanium reagents. [394,441,442,467–469] Similar dimerization of metal (2-formylvinyl)porphyrinates 

458 yields hexatriene-bridged bisporphyrins 459 (Scheme 108). 

Et 

Et 

Et 

Et 

Et 

Et 

Et 

Et 

N 

N 

N 

N 

Ni 

454 

Ni 

444 

N 

N 

Scheme 108 Self-Condensation Reactions of Formylporphyrins [394,441,442,462–469] 

N 

N 

Et 

Et 

Et 

Et 

Et 

Et 

Et 

CHO 

Et 

OH 

H2SO4 

Et 

Et 

Et 

Et 

Et 

Et 

Et 

TiCl3(DME) 1.5 

N N Et 

Zn/Cu, DME 

Ni 

N N 

N N 

Ni 

Et 

Et 

Et 

N N 

Et 

Et 

457 

Et 


Et 

Et 

N 

N 

Ni 

N 

N 

Et 

Et 

Et 

Et 

Et 

Et 

456 

Et 

Et 

AcOH 

N 

N 

Ni 

N 

N 

Et 

Et 

Et 

Et 

Et 

Et 

Et 

Et

Et 

a458 


Et 

Et 

Et 

N 

N 

Ni 

N 

N 

Et 

Et 

Et 

Et 

Et 

Et 

CHO 

Et 

Et 

N 

N 

TiCl 3(DME) 1.5 

Zn/Cu, DME 

Hydroxymethylporphyrins (e.g., 461, obtained by borohydride reduction of 460) are converted 

into the “benzylic” acetoxymethyl derivatives with acetic anhydride/pyridine, and 

these react with a range of nucleophiles to give a variety of functionalized porphyrins. [469– 

472] Reaction of hydroxymethylporphyrins 461 with thionyl chloride gives chloromethylporphyrins 

462 that can be converted into phosphonium salts, such as 463, by treatment 

with triphenylphosphine (Scheme 109); [473] compound 463 subsequently undergoes Wittig-type 

reactions to yield a variety of functionalized compounds, as well as porphyrin 

oligomers linked by, e.g., butadiene and styryl moieties. [454] 

Scheme 109 Reactions of Formylporphyrins [470–473] 

Ph 

N 

N 

Ph 

Ph 

Ni 

Ph 

460 

N 

N 

CHO 

N 

N 

Ph 

Ph 

462 

N 

NaBH 4 

Ni Ph 

Ph 

N 

Cl 


Ni 

N 

N 

Ph 

Et 

Et 

Ph 3P 

Et 

Et 

N 

N 

459 

Ph 

461 

N 

N 

Et 

Et 

Et 

Et 

Ni Ph 

Ph 

Ph 

OH 

N 

N 

Ph 

N 

N 

463 

N 

N 

Ni 

N 

N 

SOCl2 

Et 

Et 

Ni Ph 

Ph 

Et 

Et 

PPh 3 + Cl − 



aElectrophilic acetylation of metal porphyrinates can be achieved with acetic anhydride in 

the presence of Lewis acid catalysts, and occurs preferentially at the more accessible b-positions. 

[474] Diacetylation (at positions 3- and 8-) of iron(III) deuteroporphyrin IX was a key 

step in Fischer s synthesis of hemin. [124] Acetylation of copper(II) deuteroporphyrin IX dimethyl 

ester (447) is accomplished using acetic anhydride and tin(IV) chloride to give 3,8diacetyldeuteroporphyrin 

IX dimethyl ester (464) after demetalation; the reaction conditions 

can be controlled so that the individual 3- and 8-monoacetyl derivatives 465 and 

466, respectively, can be isolated in high yield (Scheme 110). [437,475] 

Both b- and meso-acetylation are accomplished on nickel(II) heptaalkylporphyrinate 

467, using a large excess of acetic anhydride and tin(IV) chloride, to afford 468 and 469 

(Scheme 110); b-acetylation occurs preferentially with the vanadium(IV) and palladium(II) 

heptaalkylporphyrinate complexes. [476] 

Scheme 110 Friedel–Crafts Acetylations of Metal Porphyrinates [437,475,476] 

N 

N 

Cu 


Ac 

NH 

N 


N 

N 

N 

HN 

1. Ac2O, SnCl4, CH2Cl2 

2. TFA, H2SO4 

3. CH2N2 



NH 

N 

Ac 

NH 

N 

N 

HN 


N 

HN 

Ac 

Ac

a467 


Et 

Et 

N 

N 

Ni 

N 

N 

Et 

Ac2O, SnCl4, CH2Cl2 

468 82% 


Et 

Et 

N 

N 

Ni 

N 

N 

Et 

Et 

Ac 

N 

N 

Et 

Ni 

N 

N 

469 43% 

Acetylporphyrins can be converted into vinylporphyrins by reduction with sodium borohydride 

followed by dehydration using 4-toluenesulfonic acid in hot 1,2-dichlorobenzene, 

or using benzoyl chloride/dimethylformamide. [477] The enantioselective reduction 

of a monoacetyl- and of diacetyldeuteroporphyrin IX dimethyl ester 464 to the corresponding 

(R)-(1-hydroxyethyl) (i.e., hematoporphyrin) derivatives is accomplished with 

borane dimethyl sulfide in the presence of methyloxazaborolidine as catalyst. [478–480] Acetylporphyrins 

464 react with the Vilsmeier reagent producing novel (1-chloro-2-formyl)vinyl 

derivatives 470, which can be converted into ethynylporphyrins 471 upon treatment 

with base (Scheme 111). [481,482] 

+ 

Ac 

Ac 

Et 



aScheme 111 Synthesis of 3,8-Ethynyldeuteroporphyrin [481,482] 

MeO2C 

Ac 

NH 

N 

464 

N 

HN 

Ac 

CO 2Me 

POCl 3, DMF 


base 

OHC 

MeO2C 

MeO 2C 

Cl 

NH 

N 

470 

N 

HN 

NH 

N 

471 

N 

HN 

Cl 

CO 2Me 

CHO 

CO2Me 

(2,3,7,8,12,13,17,18-Octaethyl-5-formylporphyrinato)nickel(II) (444); Typical Procedure: 

[433] 

POCl 3 (1.20 mL, 12.0 mmol) was added dropwise to DMF (2.0 mL, 25.8 mmol) and the mixture 

was stirred under N 2 at 08C for 30 min. It was then added to a soln of 

(2,3,7,8,12,13,17,18-octaethylporphyrinato)nickel(II) (443; 196 mg, 0.33 mmol) in CH 2Cl 2 

(100 mL) at rt and stirred at 388C for 7 h. Sat. aq Na 2CO 3 (100 mL) was added and the soln 

was stirred overnight at rt. The mixture was extracted with CH 2Cl 2, the combined organic 

layers were washed with H 2O (3 ” 200 mL), dried (Na 2SO 4), and the solvent was removed 

under vacuum. The resulting residue was chromatographed (silica gel, petroleum ether/ 

CH 2Cl 2 2:5). The product was collected and crystallized (CH 2Cl 2/MeOH) to give 444; yield: 

190 mg (92%); mp 277–278 8C. 

3-Formyl-13,17-bis[2-(methoxycarbonyl)ethyl]-2,7,12,18-tetramethylporphyrin (3-Formyldeuteroporphyrin 

IX Dimethyl Ester, 448) and 8-Formyl-13,17-bis[2-(methoxycarbonyl)ethyl]-2,7,12,18-tetramethylporphyrin 

(8-Formyldeuteroporphyrin IX Dimethyl Ester, 

449); Typical Procedure: [439] 

TFA (3.0 mL) was added slowly to a suspension of copper(II) deuteroporphyrin IX dimethyl 

ester (447; 860 mg, 1.43 mmol) in HC(OMe) 3 (3.0 mL) at rt. During the addition, the mixture 

became homogeneous and its color changed from red to green. After further stirring 

at rt for 1 h, H 2O (100 mL) was added and the product was extracted with CH 2Cl 2. The organic 

layer was washed with aq NaHCO 3, and brine, and then dried by filtration through 

cotton wool. After removal of the solvent, the product was chromatographed on a short 

column (silica gel, CH 2Cl 2/EtOAc 10:1); concentration of the appropriate eluates yielded 

recovered starting material (447; 267 mg) and a mixture of Cu•448 and Cu•449; yield: 

601 mg (97% based on recovered starting material). The mixture of Cu•448 and Cu•449 

was separated by preparative MPLC. For demetalation of the separate isomers, each was


atreated with concd H 2SO 4 (5 mL) for 1 h. Subsequent addition of H 2O, extraction with 

CH 2Cl 2, re-esterification with CH 2N 2, and crystallization afforded 448; yield: 218 mg (39% 

based on consumed 447); mp 231 8C; and 449; yield: 278 mg (50% based on consumed 

447); mp 2668C. 

[2,3,7,8,12,13,17,18-Octaethyl-5-(2-formylvinyl)porphyrinato]copper(II) (453, M = Cu): [442] 

POCl 3 (0.40 mL, 4.0 mmol) was added dropwise to a soln of 3-(dimethylamino)acrolein 

(0.40 mL, 4.0 mmol) in dry CH 2Cl 2 (4.0 mL) and the mixture was kept at 08C for 15 min. 

This mixture was then added to a soln of (2,3,7,8,12,13,17,18-octaethylporphyrinato)copper(II) 

(452, M = Cu; 80.7 mg, 0.135 mmol) in dry CH 2Cl 2 (20.0 mL) with continuous stirring 

at 08C. The mixture was then allowed to warm to rt and stirred for 18 h. Sat. aq Na 2CO 3 

(100 mL) was then added and the soln was stirred overnight. The mixture was extracted 

with CH 2Cl 2, the combined organic layers were washed with H 2O (3 ” 200 mL), dried 

(Na 2SO 4), and the solvent was removed under vacuum. The residue was chromatographed 

(silica gel, 30% petroleum ether in CH 2Cl 2) and the product was collected and crystallized 

(CH 2Cl 2/MeOH) to give 453 (M = Cu); yield: 50.2 mg (57%); mp 230–2318C. 

3,8-Diacetyl-13,17-bis[2-(methoxycarbonyl)ethyl]-2,7,12,18-tetramethylporphyrin (464); 


Copper(II) deuteroporphyrin IX dimethyl ester (447; 200 mg, 0.33 mmol) in ice-cold 

CH 2Cl 2 (100 mL) was treated with Ac 2O (20 mL) and then with SnCl 4 (1.5 mL). After stirring 

for 15 min at 20 8C, the mixture was diluted with ice water and extracted with CH 2Cl 2. The 

organic phase was concentrated and the residue was dissolved in concd H 2SO 4 (25 mL) and 

left to stand for 1 h at 20 8C. The mixture was worked up once more with CH 2Cl 2 and ice 

water and the residue from the organic phase was treated with an excess of ethereal 

CH 2N 2, then chromatographed (alumina, CHCl 3/EtOAc 9:1). The red eluates were collected, 

concentrated to dryness, and the residue was crystallized (CHCl 3/MeOH) to give 464; 

yield: 120 mg (58%); mp 2448C. 

3- and 8-Acetyl-13,17-bis[2-(methoxycarbonyl)ethyl]-2,7,12,18-tetramethylporphyrin (465 

and 466); Typical Procedure: [475] 

Acetylation: Copper(II) deuteroporphyrin IX dimethyl ester (447; 1.92 g, 3.2 mmol) in 

CH 2Cl 2 (150 mL) was treated with Ac 2O (40 mL). The mixture was cooled to 0 8C (which 

caused the porphyrin to precipitate) before SnCl 4 (4 mL) was added. The resulting homogeneous 

green soln was stirred for 20 s before being poured onto ice (200 g). The mixture 

was diluted with CH 2Cl 2 (200 mL) and the organic phase was collected and then concentrated 

to dryness to give a residue. This was chromatographed [neutral alumina (Brockmann 

Grade III), CH 2Cl 2 then 0.5% MeOH in CH 2Cl 2] to recover diacetylated material. The 

separated fractions were concentrated to dryness and the residues were crystallized 

(CH 2Cl 2/heptane) to give a mixture of Cu•465 and Cu•466; yield: 804 mg (60%). Copper(II) 

3,8-diacetyldeuteroporphyrin IX dimethyl ester (Cu•464) was also obtained; yield: 364 mg 

(27%). 

Separation of isomers: Small quantities of the copper(II) monoacetyl isomers (ca. 30– 

50 mg per plate) could be separated on thick LC plates (20 ” 40 cm ” 1 mm, silica gel, 2% 

THF in CH 2Cl 2). More convenient large-scale separation (1–2 g) was achieved by means of 

MPLC (6.8–10.2 atm). With the aid of an infusion pump, the monoacetyl mixture (ca. 1.5 g) 

in CH 2Cl 2 (30 mL) was transferred from a 35-mL plastic syringe at a rate of 2.5 mL•min –1 

onto a column of silica gel (2.5 ” 100 cm) which had previously been equilibrated with 

25% THF in CH 2Cl 2. Once all the soln had been applied to the column the compounds 

were eluted with 2% THF in CH 2Cl 2, a process usually requiring 6–10 h before the first fraction 

began to exit the system. An additional 3–6 h was required for the compounds to 

completely pass through the column. The effluent was collected in 15-mL aliquots using 




aa Gilson microfractionator, and each aliquot was assayed by means of analytical HPLC 

(microporasil column, 25 ” 0.4 cm, 1% THF in CH 2Cl 2). 

Demetalation: To the concentrated fractions containing each isomer was added TFA 

(30 mL) and concd H 2SO 4 (3.0 mL). The mixtures were allowed to stand for 1 h at rt before 

each was diluted with CH 2Cl 2 (100 mL) and washed with H 2O. The organic phases were 

treated briefly with an excess of ethereal CH 2N 2, and concentrated to dryness. After this, 

the residues were taken up in CH 2Cl 2 and individually passed through a plug of neutral 

alumina (Brockmann Grade III) eluting with CH 2Cl 2. Evaporation of the solvent and crystallization 

gave separated 465 and 466. In a typical separation, copper(II) complex mixture 

(1.538 g) gave 465 (the more mobile fraction); yield: 658 mg (48%); mp 238–2398C, 

and 466 (the less mobile fraction); yield: 608 mg (44%); mp 214–2168C. Total recovery 91%. 

(3,5-Diacetyl-7,13,18-triethyl-2,8,12,17-tetramethylporphyrinato)nickel(II) (469); Typical 


(7,13,18-Triethyl-2,8,12,17-tetramethylporphyrinato)nickel(II) (467; 20 mg, 0.04 mmol) in 

CH 2Cl 2 (20 mL) and Ac 2O (4.5 mL) was cooled to 0 8C and treated with SnCl 4 (1.2 mL) (molar 

ratio of 467/Ac 2O/SnCl 4 1:1200:260). After 15 min, the green soln was diluted with CH 2Cl 2 

(15 mL), hydrolyzed with ice for 1.5 h, and washed with H 2O. The organic phase was dried 

(Na 2SO 4) and concentrated to dryness. Chromatography (silica gel, CH 2Cl 2/hexanes 2:1) 

gave the nickel(II) diacetylporphyrinate 469, which was crystallized (CH 2Cl 2/MeOH); yield: 

10 mg (43%). 

(3-Acetyl-7,13,18-triethyl-2,8,12,17-tetramethylporphyrinato)nickel(II) (468); Typical Procedure: 

[476] 

(7,13,18-Triethyl-2,8,12,17-tetramethylporphyrinato)nickel(II) (467; 18 mg, 0.035 mmol) 

in CH 2Cl 2 (20 mL) and Ac 2O (0.3 mL) was cooled to 0 8C and treated with SnCl 4 (0.08 mL) 

(molar ratio of 467/Ac 2O/SnCl 4 1:80:17). After 2.25 min the green soln was hydrolyzed 

with ice for 1.5 h, and washed with H 2O. The organic phase was dried (Na 2SO 4) and concentrated 

to dryness. Chromatography (silica gel, CH 2Cl 2) gave the nickel(II) acetylporphyrinate 

468, which was crystallized (CH 2Cl 2/MeOH); yield: 16 mg (82%). 

17.8.4.1.4 Variation 4: 

Peripheral Metalation 

Mercuration [e.g., of zinc(II) deuteroporphyrin IX dimethyl ester (472)] occurs preferentially 

at the least sterically hindered b-positions to produce metalated derivatives (e.g., 

473), which undergo transmetalation in the presence of lithium trichloropalladate and 

alkenes (such as methyl acrylate, acrolein, styrene, vinylnaphthalene and vinylferrocene) 

to provide a variety of interesting substituted porphyrins, such as 474, after demetalation 

(Scheme 112). [483–486] Mercurated porphyrins also react with bromine/trichloromethane 

and iodine/sodium iodide, producing the corresponding halogenated derivatives in good 

yields. [485] In a similar way, vinylporphyrins react with arylmercurials in the presence of 

lithium trichloropalladate to produce the corresponding styrene derivatives. [487,488] 



aScheme 112 Synthesis of Porphyrin Acrylates via Mercuration [483–486] 

N 

N 

Zn 


N 

N 

1. 

1. Hg(OAc) 2, MeOH, THF 

2. NaCl 

CO2Me 

LiPdCl 3, MeCN 

Et3N, DMSO, THF 

2. TFA 

37% 


MeO2C 



ClHg 

NH 

N 

N 

N 

N 

HN 

Zn 

N 

N 

HgCl 

CO2Me 

{3,8-Bis(chloromercurio)-13,17-bis[2-(methoxycarbonyl)ethyl]-2,7,12,18-tetramethylporphyrinato}zinc(II) 


Under a dry N 2 atmosphere, Hg(OAc) 2 (1.8 g) in MeOH (25 mL) was added rapidly but dropwise 

to zinc(II) deuteroporphyrin IX dimethyl ester (472; 860 mg, 1.43 mmol) in dry THF 

(100 mL) with stirring at 60 8C. After 5 h, sat. aq NaCl (100 mL) was added and the biphasic 

mixture was vigorously stirred for 10 min while the soln cooled. The mixture was diluted 

with CH 2Cl 2 (100 mL) and the organic phase containing a large amount of precipitated 

porphyrin was collected and washed with H 2O (4 ” 125 mL). The organic layer was separated 

and concentrated to give a residue, which was triturated with EtOH (95%, 50 mL) and 

brought to a gentle boil. The dark metal porphyrinate was scraped from the side of the 

flask and collected by filtration. The product was dried at rt under high vacuum to give 

473; yield: 1.543 g (contaminated with some trimercurated material) which did not melt. 

3,8-Bis[2-(methoxycarbonyl)vinyl]-13,17-bis[2-(methoxycarbonyl)ethyl]-2,7,12,18-tetramethylporphyrin 


3,8-Bis(chloromercurio)-13,17-bis[2-(methoxycarbonyl)ethyl]-2,7,12,18-tetramethylporphyrin 

473 (609 mg, 0.70 mmol) in dry DMSO (25 mL) was treated with dry THF (25 mL) 

and freshly distilled methyl acrylate (10 mL). The mixture was stirred under N 2 at 508C. 

Following addition of Et 3N (0.5 mL), a soln of LiPdCl 3 in MeCN (15 mL) [prepared by refluxing 

for 30 min PdCl 2 (250 mg) in MeCN (15 mL) containing LiCl (20 mg)] was added dropwise 

but rapidly to the porphyrin soln. As the reaction proceeded the mixture became 

dark and reduced Pd metal was observed. After 40 min the mixture was removed from 

the heat, allowed to cool for 15 min, and then filtered through a 4-cm thick pad of Celite. 

The pad was then rinsed with THF/CH 2Cl 2 and the combined filtrates were washed with 

H 2O (3 ” 100 mL), dried (Na 2SO 4), concentrated to dryness, and then placed under high vacuum 

to remove a small amount of residual oil. The residue was dissolved in TFA (30 mL), 

and this soln was stirred for 5 min and then diluted with CH 2Cl 2 (100 mL) before being 



awashed with H 2O (3 ” 100 mL). Concentration of the organic fraction gave a residue, 

which was chromatographed on thick-layer plates (silica gel, 3.5% MeOH in CH 2Cl 2). Three 

major bands were eluted. The least mobile fraction was crystallized (CH 2Cl 2/heptane) to 

give the bisacrylate 474; 146 mg (37%); mp 259–2618C. 

17.8.4.1.5 Variation 5: 

Reactions with Carbenes and Nitrenes 

Electrophilic additions of carbenes and nitrenes to porphyrins [e.g., (2,3,7,8,12,13,17,18octaethylporphyrinato)zinc(II) 

(475)] tend to occur at the inner nitrogen atoms with formation 

of N-substituted porphyrin derivatives 476. Metal chelation at the central nitrogens 

induces intramolecular migration of the N-substituent to the macrocyclic periphery, 

affording chlorins and meso-substituted porphyrins (e.g., 477, Scheme 113). Ring expanded 

meso-homoporphyrins are believed to be intermediates in the formation of the mesosubstituted 

porphyrins. [489–495] Treatment of 2,3,7,8,12,13,17,18-octaethylporphyrin (21) 

with O-mesitylsulfonylhydroxylamine (OMSH) affords the stable N-aminoporphyrin 478 

(Scheme 113). [496] Examples of the formation of cyclopropanechlorins by additions of carbenes 

to a porphyrin peripheral b—b¢ double bond are also known. [306,497] 

Scheme 113 Carbene/Nitrene Reactions with Porphyrins [489–496] 

Et 

Et 

Et 

Et 

Et 

N 

N 

Zn 

475 

N 

N 

Et 

Et Et 

Et 

NH 

N 

21 

N 

HN 

Et 

Et Et 

Et 

Et 

Et 

Et 

1. N2CH2CO2Et 2. HCl 


45% 

OMSH, CHCl3 

41% 

Et 

Et 

Ni(acac)2, benzene 

39% 

Et 

Et 

Et 

Et 

N 

N 

476 

N 

CO 2Et 

HN 

Et 

Et Et 

Et 

Et 

N N 

NH2 N 

478 

HN 

Et 

N 

N 

Et 

Et 

Ni 

CO2Et Et 

N 

N 

Et Et 

477 

Et 

Et Et 

Et 

Et 

Et 

Et


aN-Ethoxycarbonylmethyl-2,3,7,8,12,13,17,18-octaethylporphyrin (476); Typical Procedure: 

[492] 

A refluxing soln of (2,3,7,8,12,13,17,18-octaethylporphyrinato)zinc(II) (475; 340 mg, 

0.57 mmol) in bromobenzene (10 mL) was treated dropwise with ethyl diazoacetate 

(0.7 mL, 6.1 mmol) over 12 min and then refluxed for a further 30 min. The solvent was 

removed under vacuum and the residue was dissolved in CH 2Cl 2 (40 mL) and treated 

with concd aq HCl (4 mL). The soln was neutralized with aq (NH 4) 2CO 3, washed with H 2O 

(” 2), and concentrated to dryness. Chromatography [alumina (200 g), toluene/cyclohexane 

1:1] gave some 2,3,7,8,12,13,17,18-octaethylporphyrin (21), followed by 476, which 

was crystallized (CHCl 3/MeOH); yield: 160 mg (45%). 

(5-Ethoxycarbonylmethyl-2,3,7,8,12,13,17,18-octaethylporphyrinato)nickel(II) (477); 


N-Ethoxycarbonylmethyl-2,3,7,8,12,13,17,18-octaethylporphyrin (476; 40mg, 

0.064 mmol) in benzene (12 mL) (CAUTION: carcinogen) was treated with nickel(II) acetylacetonate 

(120 mg) and refluxed for 12 h. The solvent was removed under vacuum and the 

residue was chromatographed (alumina or silica gel, benzene), to give 

(2,3,7,8,12,13,17,18-octaethylporphyrinato)nickel(II) (443); yield: 6 mg, followed by the 

5-substituted porphyrin. Crystallization (CH 2Cl 2/MeOH) gave 477; yield: 17 mg (39%); mp 

207–2088C. 

N-Amino-2,3,7,8,12,13,17,18-octaethylporphyrin (478); Typical Procedure: [496] 

An excess of O-mesitylsulfonylhydroxylamine (OMSH; 500 mg) and 2,3,7,8,12,13,17,18-octaethylporphyrin 

(21; 500 mg, 0.93 mmol) were stirred for 16 h at 208C in CHCl 3. Concentration 

and chromatography of the residue [alumina (100 g), CH 2Cl 2] gave recovered 

2,3,7,8,12,13,17,18-octaethylporphyrin (21); yield: 216 mg, and a green fraction. Crystallization 

of the green fraction (MeOH) gave 478; yield: 120 mg (41% based on recovered 21). 

17.8.4.2 Method 2: 

Reactions with Nucleophiles 

The porphyrin macrocycle also undergoes reactions with nucleophiles. As would be expected, 

electron-withdrawing peripheral substituents and electronegative chelated metal 

ions facilitate nucleophilic attack on the porphyrin ring. For example, 2-nitro-5,10,15,20tetraarylporphyrins 

and their metal complexes display useful chemical reactivity at the 2and 

3-positions, undergoing ipso-substitution of the nitro group [243,412,422,424] and nucleophilic 

Michael-type additions [242,243,411,425–429] with a variety of nucleophiles, as previously 

mentioned. Several functionalized macrocycles, such as chlorins, 2-substituted porphyrins 

and 3-substituted 2-nitroporphyrins and chlorins have been obtained by using this 

methodology. [498] 

The most studied nucleophilic addition reactions occur on the p-cation radicals of 

metal porphyrinates, which can be obtained by mild chemical or electrochemical oxidation 

(Scheme 114). The magnesium(II) and zinc(II) complexes of porphyrins are usually 

employed since these display the lowest oxidation potentials, and iodine (usually in the 

presence of silver perchlorate or silver hexafluorophosphate), tris(4-bromophenyl)ammoniumyl 

hexachloroantimonate, or N-chlorobenzotriazole are the oxidants of choice. Although 

relatively stable in methanol, the p-cation radicals of metal porphyrinates react 

with a variety of soft nucleophiles to produce the corresponding meso- and b-substituted 

metal porphyrinates. For example, meso-nitroporphyrins (e.g., 480) are obtained by treatment 

of metal porphyrinates [e.g., dipyridine magnesium(II) etioporphyrin I (479)] with 

nitrogen dioxide, [408–411] iodine/silver nitrite, [397,412–414] or with thallium(III) nitrate or cerium(IV) 

ammonium nitrate. [499] Pyridinium porphyrin salts (e.g., 481) are obtained by reaction 

of p-cation radicals from, for example, (2,3,7,8,12,13,17,18-octaethylporphyrinato)- 




azinc(II) (475), with various pyridines. [500–504] Other nucleophiles (cyanide, thiocyanate, 

chloride, acetate, imidazole, triphenylphosphine) also react with the p-cation radicals of 

porphyrins to give, for example, 5-chloro-2,3,7,8,12,13,17,18-octaethylporphyrin 

(482); [505] dimeric and higher oligomeric porphyrin systems have been obtained by the 

use of bidentate nucleophiles, such as bipyridine. [506–508] 

Scheme 114 Reactions of Porphyrin p-Cation Radicals with Nucleophiles [397,412–414,500–505] 

Et 

Et 

Et 

Et 

Et 

N 

N 

N 

N 

py 

Mg 

py 

479 

Zn 

475 

N 

N 

N 

N 

Et 

Et 

Et Et 

Et 

Et 

Et 

1. I2, MeCN, CH 2Cl 2 

2. NaNO 2, MeCN 


98% 

1. Tl(NO3) 3, THF, MeOH 

2. py, SO2 (g) 

60% 

1. ammoniumyl salt 

THF, CH2Cl2 2. Et4NCl, CH2Cl2 31% 

Et 

Et 

Et 

Et 

Et 

Et 

NH 

N 

NO 2 

480 

Et 

N 

HN 

NH 

N 

Et 

N + 

481 

N 

HN 

Et 

Cl − 

Et 

Et Et 

Et 

NH 

N 

Cl 

482 

N 

HN 

Et 

Et Et 

Chemical and electrochemical oxidative couplings of zinc(II) 5,15-diarylporphyrinates 

lead to the formation of meso–meso and meso–b linked porphyrin arrays, through nucleophilic 

attack of the p-cation radicals by neutral porphyrins; [414,509] (5,10,15-triphenylporphyrinato)zinc(II) 

(483) produces dimer 484 in the presence of silver hexafluorophosphate 

(Scheme 115). [510] Treatment of zinc(II) 5,15-diarylporphyrinates with silver hexafluorophosphate 

and iodine in the presence of pyridine leads to regioselective meso-iodination. 

[511] 

Et 

Et 

Et 

Et


aScheme 115 Radical Dimerization of Porphyrins [510] 

Ph 

N 

N 

Ph 

Zn 

Ph 

483 

N 

N 

AgPF6 


Ph 

N 

N 

Ph 

Zn 

Ph 

N 

N 

484 

Ph 

N N 

Zn 

N N 

The more electrophilic p-dications of porphyrins are formed under stronger oxidation 

conditions and react with, for example, methanol, preferentially at the meso positions, 

leading to isoporphyrin derivatives, such as 486 from (5,10,15,20-tetraphenylporphyrinato)zinc(II) 

(485) (Scheme 116). [512,513] 

Scheme 116 Reaction of p-Dications of Porphyrins with Methanol [512,513] 

Ph 

N 

N 

Ph 

Zn 

Ph 

485 

N 

N 

Ph 

2e − oxidation 

MeOH 

Ph 

Ph OMe 

Reactions of organometallic reagents with iron(III) and cobalt(III) porphyrins occur at the 

metal center with formation of s-bonded species; [514,515] migration of the s-bonded groups 

(alkyl, vinyl, aryl) from the metal ion to the nitrogen atom is induced by oxidation or by 

acid treatment. [516–522] Nucleophilic attack upon unsubstituted meso positions gives phlorins 

[523] and porphodimethenes, [524] which can be oxidized to the corresponding meso-substituted 

porphyrins; for example, (2,3,7,8,12,13,17,18-octaethylporphyrinato)nickel(II) 

(443) is mono- (487), di- (488, 489), tri- (490), and tetra-meso-alkylated (491) by successive 

additions of alkyllithium at low temperature, followed by hydrolysis and oxidation with 

2,3-dichloro-5,6-dicyanobenzo-1,4-quinone (Scheme 117). 5,5¢-Linked bisporphyrins are 

isolated when the hydrolysis step is omitted. [525] 

N 

N 

+ 

Zn 

Ph 

486 

N 

N 

Ph 

Ph 

Ph 



aScheme 117 Addition of Butyllithium to (2,3,7,8,12,13,17,18- 

Octaethylporphyrinato)nickel(II) [525] 

Et 

Et 

Et Et 

Et 

BuLi 

N 

N 

Ni 

443 

N 

N 

Et 

Et 

Et 

Bu 

Et 

Et 

Et 

Et Bu Et 

Et 

N 

N 

Ni 

488 

N 

N 

490 

100% 

Et 

Et Bu Et 

Et 

Et 

N 

N 

Ni 

Bu 

1. BuLi, THF 

2. DDQ 

N 

N 

Et 

Et Bu Et 


Et 

Bu 

Et 

Et 

Et 

Et 

Et 

Et 

Et 

N 

N 

N 

N 

Ni 

487 

Ni 

489 

N 

N 

N 

N 

Et 

Et Bu Et 

Et 

Bu 

Et Et 

Et 

N N 

BuLi 

Bu 

Ni 

Bu 

Et 

Et 

Et 

Et 

Et 

Et 

Et Bu Et 

meso-Tetrasubstituted porphyrins react with alkyllithiums to produce porphodimethenes, 

[524] phlorins, [526] and chlorins. [526] Nucleophilic addition of hydroxide ion to 

gold(III) 5,10,15,20-tetraphenylporphyrinate (492) occurs at a meso position with formation 

of hydroxyphlorin 493 (Scheme 118), but the copper(II), palladium(II), cadmium(II), 

and manganese(III) complexes of 5,10,15,20-tetraphenylporphyrin (22) are unreactive under 

the same conditions. [527] A regioselective 15-meso-alkylation of (5-formyl- 

2,3,7,8,12,13,17,18-octaethylporphyrinato)zinc(II) (494) to produce 495 via a readily oxidizable 

phlorin intermediate is accomplished by addition of methyl (or ethyl) magnesium 

bromide (Scheme 118). [528] Under similar conditions the metal-free and nickel(II) derivatives 

react preferentially at the meso-formyl group, as might be expected, to yield the corresponding 

1-hydroxyalkyl derivatives. 

+ 

Et 

N 

Bu 

491 

N 

BuLi 

Et 

Et


aScheme 118 Reactions of Metal Porphyrinates with Nucleophiles [528] 

N Cl N 

Ph Au Ph 

Et 

Et 

N 

Ph 

Ph 

492 

N 

Et CHO Et 

N 

N 

Zn 

494 

N 

N 

Et Et 

Et 

Et 

1. NaBH4, MeOH 

2. NaOH 

MeMgBr 


Et 

Ph 

N 

N 

Ph 

493 

OH 

N 

Ph Au Ph 

Et CHO Et 

5-Nitro-2,7,12,17-tetraethyl-3,8,13,18-tetramethylporphyrin (480); Typical Procedure: [505] 

Dipyridine (2,7,12,17-tetraethyl-3,8,13,18-tetramethylporphyrinato)magnesium(II) (479; 

50 mg, 0.076 mmol) in CH 2Cl 2 (50 mL) was treated with a soln of I 2 (21 mg, 0.08 mmol) in 

MeCN (10 mL) and CH 2Cl 2 (40 mL). The mixture was then treated with NaNO 2 (100 mg, 

0.65 mmol) in MeCN (10 mL), and the resulting red porphyrin soln was washed immediately 

with H 2O. The organic phase was dried (Na 2SO 4) and concentrated to dryness before 

addition of TFA (1 mL) and neutralization by washing several times with H 2O. The product 

was chromatographed [short neutral alumina column (Brockmann Grade III), CH 2Cl 2]. The 

red-brown eluates were collected and concentrated, and the residue was crystallized 

(CH 2Cl 2/MeOH) to give 5-nitroetioporphyrin I (480); yield: 39 mg (98%); mp >3008C. 

5-N-Pyridinium-2,3,7,8,12,13,17,18-octaethylporphyrin Chloride (481); Typical Procedure: 

[505] 

A soln of (2,3,7,8,12,13,17,18-octaethylporphyrinato) zinc(II) (475; 300 mg, 0.50 mmol) in 

THF (30 mL) was flushed with N 2 for 10 min prior to addition of Tl(NO 3) 3 (234 mg, 

0.60 mmol) in MeOH (25 mL). After stirring for 30 s, an excess of pyridine (10 mL) was added. 

The mixture was stirred for 30 min and then SO 2(g) was bubbled into the soln. HCl 

(20 mL) was added to the residue obtained by evaporation of the solvents, and after stirring 

for 5 min, the mixture was poured into CH 2Cl 2 (300 mL), washed with brine 

(300 mL), dried (CaCl 2), and concentrated. The residue was chromatographed [alumina 

(Brockmann Grade V), CHCl 3]. A red forerun contained 2,3,7,8,12,13,17,18-octaethylporphyrin 

(21; 17 mg). Further elution (CHCl 3/MeOH 20:1) gave red eluates which were washed 

with brine, dried (CaCl 2), and concentrated. Crystallization (CH 2Cl 2/hexanes) gave 481; 

yield: 157 mg (60% based on consumed 2,3,7,8,12,13,17,18-octaethylporphyrin); mp 

>300 8C. 

5-Chloro-2,3,7,8,12,13,17,18-octaethylporphyrin (482); Typical Procedure: [505] 

A soln of (2,3,7,8,12,13,17,18-octaethylporphyrinato)zinc(II) (475; 300 mg, 0.50 mmol) in 

CH 2Cl 2 (100 mL) and THF (30 mL) was treated with tris(4-bromophenyl)ammoniumyl hexachloroantimonate 

(902 mg, 1.10 mmol) in THF (30 mL) and CH 2Cl 2 (100 mL). This soln 

was treated slowly with Et 4NCl (375 mg, 2.26 mmol) in CH 2Cl 2 (50 mL) and the mixture 

Et 

Et 

N 

N 

Zn 

495 

N 

N 

Et 

N 

Et 

Et 



awas stirred for 2 h. A soln of HCl (5 mL) in THF (10 mL) was added and, after stirring for 

5 min, the mixture was poured into H 2O. The organic phase was washed with H 2O 

(300 mL), dried (Na 2SO 4), and concentrated to dryness. Chromatography of the residue 

on TLC plates (silica gel, petroleum ether/toluene 3:2) gave three bands. The middle 

band contained 482; yield: 99 mg (31%); mp 270–2728C. 

(5-Butyl-2,3,7,8,12,13,17,18-octaethylporphyrinato)nickel(II) (487); Typical Procedure: [524] 

(2,3,7,8,12,13,17,18-Octaethylporphyrinato)nickel(II) (443; 100 mg, 0.17 mmol) in THF 

(60 mL) at –70 8C was treated, immediately after cooling, dropwise with 2 M BuLi in cyclohexane 

(0.6 mmol). The cooling bath was removed and H 2O (1 mL) in THF (5 mL) was added 

dropwise. The mixture was stirred for 10 min, 0.06 M DDQ in CH 2Cl 2 (10 mL) was added, 

and the mixture was stirred for another 20 min. The mixture was filtered [neutral alumina 

(Brockmann Grade I), CH 2Cl 2] and then chromatographed [neutral alumina (Brockmann 

Grade III), hexanes/CH 2Cl 2 4:1] to give a quantitative yield of 487. Preparation of 

higher alkylated porphyrins (e.g., 488–491) required lower temperatures (–80 to –1008C) 

and less solvent. 

17.8.4.3 Method 3: 

Oxidation Reactions 

Oxidations of porphyrins and metal porphyrinates using osmium tetroxide to give vicinal 

diols 340 and 2-oxochlorins 341 have been mentioned previously (Section 17.8.2.1.3). 

Porphyrins can also be oxidized at the meso positions to afford, for example, oxophlorins 

(e.g., 497) and oxochlorins (e.g., 498). 5-Oxophlorins (such as 497) are produced 

from hydrolysis of metal meso-trifluoroacetoxyporphyrinates 496, obtained from zinc(II) 

and magnesium(II) b-substituted porphyrinates (e.g., 475) by reaction with thallium(III) 

trifluoroacetate. [529,530] Benzoyl peroxide also accomplishes meso-oxidation, although less 

selectively. [531,532] More extensive meso-oxidation leads to the formation of di-, tri-, and tetraoxoporphyrins 

(the so-called xanthoporphyrinogens, 499) (Scheme 119). 

Scheme 119 Syntheses of meso-Oxoporphyrin Systems [529,530] 

Et 

Et 

Et Et 

N 

N 

Zn 

N 

N 

Et Et 

475 

Et 

Et 

Tl(OCOCF 3) 3 

THF, CH2Cl2 


Et 

Et 

SO2, H3O + 

Et Et 

Et 

N 

N 

Zn 

496 

Et 

Et 

N 

N 

Et 

Et 

O 

Et O 

NH 

N 

HN 

HN 

497 79% 

CF 3 

Et Et 

Et 

Et 

Et 

Et 

O


Et 

O 

Et 

Et Et 

Et 

NH 

N 

HN 

HN 

a499 

498 

Et 

Et 

Et 


Et 

O 

Et 

Et O Et 

2,3,7,8,12,13,17,18-Octaethyl-5-oxophlorin (497); Typical Procedure: [530] 

(2,3,7,8,12,13,17,18-Octaethylporphyrinato)zinc(II) (475; 415 mg, 0.69 mmol) in THF 

(30 mL) and CH 2Cl 2 (100 mL) was treated with a dry soln of thallium(III) trifluoroacetate 

(480 mg, 0.88 mmol) in THF (20 mL) and then stirred for 1 min to give 496. H 2O (0.25 mL) 

in THF (10 mL) was added and, after stirring for 10 min, the soln was treated briefly with 

SO 2(g). Concd HCl (2 mL) was added and the soln was stirred for 5 min before being poured 

into H 2O (250 mL) and extracted with CH 2Cl 2 (250 mL). The organic phase was washed 

with H 2O (2 ” 500 mL), dried (Na 2SO 4), and concentrated to dryness. The residue was chromatographed 

[neutral alumina (200 g), CH 2Cl 2]. A small forerun containing pink material 

was discarded and the blue eluates were collected and concentrated to dryness. Crystallization 

[CH 2Cl 2/MeOH] gave 497; yield: 302 mg (79%); mp 254–2568C. 

17.8.4.4 Method 4: 

Cycloaddition Reactions 

17.8.4.4.1 Variation 1: 

Intermolecular Reactions 

Numerous cycloaddition reactions of porphyrins are described in Section 17.8.2.3.2. Pyrroloporphyrin 

500, obtained from cleavage and decarboxylation of the benzyl ester 442 

(Scheme 104), reacts with dimethyl acetylenedicarboxylate in refluxing 1,2,4-trichlorobenzene 

to produce benzoporphyrin 501 as the main product (Scheme 120), along with 

a bis-adduct. [533] A N-tert-butoxycarbonyl-protected derivative of 500 also undergoes cycloaddition 

reactions with dimethyl acetylenedicarboxylate. [534] 

Porphyrins (e.g., 22) react with pyrrolo-fused 3-sulfolene 502 [291] and related systems, 

[535] to afford pyrrolochlorins 503, pyrroloporphyrins 504, isoindoloporphyrins 

505, and dipyrrolobacteriochlorins (Scheme 120). [536] A porphyrin bearing a b-fused 3-sulfolene 

has also been reported; this reacts with dienophiles to give the corresponding 

Diels–Alder adducts. [537] 

Scheme 120 Intermolecular Cycloadditions [533,536] 

Ph 

N 

N 

Ph 

Ni 

Ph 

500 

N 

N 

NH 

Ph 

MeO2C 

heat 

Et 

CO2Me 

NH 

NH 

O 

HN 

HN 

Ph 

Et 

Et 

Et 

O 

N 

N 

Ph 

Ni 

Ph 

N 

N 

501 

CO2Me 

Ph 

CO2Me 



Ph 

NH 

N 

a503 

22 

Ph 

Ph 

Ph 

N 

HN 

NH 

N 

Ph 

Ph 

Ph 

N 

HN 

504 

17.8.4.4.2 Variation 2: 

Intramolecular Reactions 

+ 

O O 

S 

N 

H 

502 

Ph 


CO 2R 1 

NH 

, heat 

CO 2R 1 

+ 

Ph 

Ph 

NH 

N 

NH 

N 

Ph 

Ph 

Ph 

Ph 

N 

HN 

N 

HN 

505 

Ph 

Ph 

NH 

NH 

CO 2R 1 

CO 2R 1 

Acid-catalyzed intramolecular cyclizations of 5-[2-(ethoxycarbonyl)vinyl]porphyrins 506 

lead to purpurins (e.g., 507) in the absence of a chelated metal ion (Scheme 121). When 

nickel(II) or copper(II) 5-(2-formylvinyl)porphyrinates (e.g., 453) are used, benzochlorins 

such as 508 result. [212,441,442] The metal-free benzochlorins 509 are obtained either by demetalation 

or by acid-catalyzed cyclization of meso-(2-hydroxymethyl)vinylporphyrins 

(Scheme 121). [538] meso-Substituted benzochlorins, [539–541] benzoisobacteriochlorins, [442] 

and benzobacteriochlorins [442] are similarly produced. Hydroxybenzochlorins and oxobenzochlorins 

(e.g. 511, obtained from 510 by reaction with borontrifluoride–diethyl 

ether complex) [542] are produced when the electrophilic cyclization is directed toward an 

unsubstituted b-position. [441,442] Methods for the synthesis of meso-(2-formylvinyl)porphyrins 

were mentioned earlier; the 5-[2-(ethoxycarbonyl)vinyl]porphyrins (e.g., 506) are usually 

prepared by treatment of nickel(II) 5-formyloctaethylporphyrinate 444 (Scheme 105) 

with (carbethoxymethylene)triphenylphosphorane, followed by demetalation. [213] The 

thermodynamically favored trans-purpurins are obtained from regioselective cyclizations, 

in refluxing acetic acid, of 5-(2-formylvinyl) or meso-acrylic ester porphyrins. [212– 

214,218] Cyclizations, using triethylamine or potassium hydroxide/methanol, have been 

used for the preparation of 5,15-disubstituted purpurins. [216,217] Macrocycles containing 

both purpurin and benzochlorin species have also been obtained from porphyrin precursors 

bearing both meso-(2-formylvinyl) and meso-acrylic ester substituents; [543] meso-[3-(dimethylamino)prop-1-enyl]porphyrin 

512 undergoes thermal intramolecular cyclization 

to give the ethylenechlorin 513 as a Z/E mixture (Scheme 121). [544] Porphyrin 512 is obtained 

by electrophilic substitution of nickel(II) octaethylporphyrinate 443 with 3dimethylacetamide/phosphoryl 

chloride followed by reduction of the resulting iminium 

salt with sodium borohydride and final quaternization with iodomethane. 

b-Vinylporphyrins undergo acid-catalyzed cyclization onto either a vicinal meso position 

[545] (514fi515) or to an adjacent 2-phenyl position (516fi517) (Scheme 121). [546] 

Naphthochlorin 519, can be obtained [547] from 518 by reduction with lithium aluminum


ahydride/aluminum trichloride followed by treatment with base. Porphyrin 518 is in turn 

obtained by acid-catalyzed cyclization of the 2-formyl group of 446 onto one of the ortho 

positions of the adjacent phenyl group. [434–436,548,549] A related cyclization of a b-methoxycarbonyl 

group in the presence of acetic acid, copper(II) acetate and sodium acetate has 

also been described. [550] A naphthochlorin 520 is produced from condensation of tert-butyl 

isocyanoacetate with (2-nitro-5,10,15,20-tetraphenylporphyrinato)nickel(II) 441; it 

subsequently undergoes radical dimerization in the presence of air, or with benzoyl peroxide 

to afford 521 (Scheme 121). [394,551] 

Scheme 121 Intramolecular Cyclizations 

Et 

Et 

Et 

Et 

M = Cu, Ni 

Et Et 

NH 

N 

N 

HN 

Et Et 

N 

N 

506 

Et Et 

Et Et 

453 

Ar 1 

Cu 

Ar 2 

510 

N 

N 

N 

N 

M 

N 

N 

Et 

Et 

Et 

Et 

CHO 

CO 2Et 

CHO 

BF3 OEt2 

AcOH, heat 


68% 

18% H2SO4/TFA 

H + 

Et 

Et 

N 

N 

Ar 1 

Cu 

Ar 2 

511 

Et Et 

NH 

N 

N 

HN 

Et Et 

Et 

Et 

N 

N 

Et 

Et 

Et 

507 

N 

N 

Et 

Et 

M 

NH 

N 

Et 

N 

N 

Et 

Et 

Et Et 

508 

O 

Et 

N 

HN 

509 70% 

CO2Et 

Et 

Et 

Et 

Et 

Et 



a512 

Et 

Et 

Ph 

Ph 

Et 

N 

N 

Ni 

N 

N 

Et 

Et Et 

NH 

N 

N 

N 

514 

N 

N 

N 

HN 

Ph 

Ni 

Ph 

516 

Ph 

Cu 

Ph 

446 

N 

N 

N 

N 

Et 

Et 

Ph 

CHO 

Ph 

I 

NMe3 − 

+ 


heat 

TsOH, benzene-1,2-dicarbonitrile 

160 oC 1% H2SO4, TFA 

TsOH, p-chloroaniline 

1. LiAlH4, AlCl3 

2. base 

Et 

Et 

Ph 

Ph 

Et 

N 

N 

Ni 

N 

N 

Et Et 

513 

Ph 

N 

N 

Ph 

Ni 

Ph 

N 

N 

N 

N 

517 

Ph 

Cu 

Ph 

518 

N 

N 

NH 

N 

N 

N 

Ph 

Cu 

Ph 

519 

515 

N 

N 

Et 

N 

HN 

Et 

O

a441 


Ph 

N 

N 

Ph 

Ni 

Ph 

N 

N 

NO 2 

Ph 

CNCH 2CO 2t-Bu 

CH 2Cl 2, O 2 


Ph 

Ph 

N 

N 

Bu 

Ph 

tO2C N 

N 

Ni 

Ph 

Ph 

Ni 

Ph 

N 

N 

N 

N 

520 

521 

Ph 

N N 

CO 2Bu t 

N N 

Ni Ph 

CO2But Ph 

5-[2-(Ethoxycarbonyl)vinyl]-2,3,7,8,12,13,17,18-octaethylporphyrin (506); Typical Procedure: 

[213] 

A soln of (5-formyl-2,3,7,8,12,13,17,18-octaethylporphyrinato)nickel(II) (444; 506 mg, 

0.82 mmol) and an excess of (carbethoxymethylene)triphenylphosphorane (1.024 g) in xylene 

(50 mL) was refluxed for 18 h. The soln was cooled, the solvent removed in vacuo, and 

the residue was chromatographed (silica gel, CH 2Cl 2). A minor fraction of 

(2,3,7,8,12,13,17,18-octaethylporphyrinato)nickel(II) was collected first, followed by a 

major red band. Collection, removal of the solvent, and crystallization (CH 2Cl 2/MeOH) 

gave Cu•506; yield: 455 mg (81%). Compound Cu•506 (621 mg) was then dissolved in 

concd H 2SO 4 (10 mL) and kept at rt for 2 h. CH 2Cl 2 (100 mL) was added, followed by sat. 

aq NaHCO 3. After neutralization the organic phase was collected, washed with H 2O, dried 

(Na 2SO 4), and concentrated to dryness. The residue was crystallized (CH 2Cl 2/MeOH) to give 

506; yield: 552 mg (100%). 

2,3,7,8,12,13,17,18-Octaethylpurpurin 3¢-Ethyl Ester (507); Typical Procedure: [213] 

5-[2-(Ethoxycarbonyl)vinyl]-2,3,7,8,12,13,17,18-octaethylporphyrin (506; 100 mg, 

0.158 mmol) in AcOH (20 mL) was refluxed in a N 2 atmosphere for 24 h. After cooling the 

solvent was removed under reduced pressure and replaced with a little CH 2Cl 2. Chromatography 

(silica gel, CH 2Cl 2) gave a major green band which was concentrated to dryness. 

The product was crystallized (CH 2Cl 2/MeOH) to give 507; yield: 68 mg (68%); mp 135– 

1388C. 



a2,2,3,4,5,6,7,8-Octaethylbenzochlorin (509); Typical Procedure: [442] 

[5-(2-Formylvinyl)-2,3,7,8,12,13,17,18-octaethylporphyrinato]copper(II) (453, M = Cu; 

50 mg, 0.077 mmol) was stirred in 18% H 2SO 4/TFA (10 mL) for 15 min. The mixture was 

then neutralized with 20% aq NaHCO 3 (100 mL), extracted with CH 2Cl 2 and the combined 

organic layers were washed with H 2O (3 ” 200 mL). The soln was dried (Na 2SO 4), the solvent 

was removed and the resulting residue was chromatographed (silica gel, petroleum 

ether/CH 2Cl 2 7:3). The product was collected and crystallized (CH 2Cl 2/MeOH) to give 509; 

yield: 32 mg (70%); mp 241–2438C. 


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