Textbook Errors, 113 R. 1. C. Pilgrim Department o f Zoology University of Canterbury Chrlstchurch, New Zeoland
I
The Number of Possible Isomers in the Porphyrins
I n discussing the structure of porphyrin compounds, it is common in textbooks of biochemistry and allied subjects to begin by considering substitution of the eight outer (&P' or 3,4) pyrrolic protons of the porphin ring by side groups of two different kinds. Various porphyrins are thereby obtained: 4 m and 4 e groups1 give the etioporphyrins; 4 m and 4 p groups the coproporphyrins; 4 a and 4 p groups the-uroporphyrins. It is further commonly stated that the numher of possihle isomers of each of these porphyrins is four. If, following Fischer (I), the positions of the suhstituent groups are numbered 1-8, the etioporphyrin isomers may he listed as in Tahle 1. There follow, mutatis mutandis, the corresponding isomers I-IV of coproporphyrin and of uroporphyrin. However, if eight side groups (four each of two kinds) are arranged around an ithenvise symmetrical molecule, the total number of isomers theoretically possible is, in fact. 13. the arraneements in the additional isomers being sh&n in Table 2. If now the eizht suhstituent floups are of three kinds, with 4 m, 2 p, a i d 2 e groups a G n the mesoporphyrini, or with 4 m, 2 p, and 2 v grnups as in the pnrtoporphyrins, it is torther rommonlv asserted that the number o i ~ossible -~ isomers is 15. ~ h e s eare conventionally related to t'he etioporphyrin series as shown in Tahle 3. But if 4 m, 2 e, and 2 p are arranged around the porphin ring, the number of isomers theoretically possible is 60, the extra configurations (Tahle 4) being derived from the additional etioporphyrins tabulated earlier. Blackman (2) attempted to correct the widely published h u t misleading accounts of the numbers of isomers possible in the porphyrin series. Unfortunately, his own account suffers from a number of omissions. In his Tahle 1, Blackman claims that there are eight possihle positional isomers for etio- and coproporphyrins; his arrangements, "
however, are hy no means exhaustive and even exclude Fischer's etioporphyrin isomers II, III, and IV, as well as two others. In his Tahle 2, Blackman claims that with three substituents there are 33 possihle isomers, rather than 15 as is usually stated. His lists are correct a s far as they go, but they include only I and I1 of Fischer's mesoand protoporphyrins I-XV, thus omitting the all-important protoporphyrin IX of heme, as well a s numerous other possihle configurations. In order to resolve the conflict between statements and facts, the precise wording was examined in more than 30 textbooks, advanced monographs, and review articles. Typical statements relating to the numbers of possible isomers are Porphyrins with two types of side chains (e.g., copra- or uroporphyrin) can form four isomerides . . . . Porphyrins with three types of side chains, such as protoporphyrin, can farm 15 isomers; . . . since the P positions of the pyrrole rings are substituted by three different side chains . . . the total number of possible isomers for protoporphyrin is 15. Fifteen isomers are possible by substituting four methyl, two propionic acid, and two vinyl groups an the basic porphyrinring.
~
Comments by the Editor
To our repet, Textbook Errors Xumher 111, "lsomers (>I' the Pornhvrins" -1. CHEM. KDIJC., 50, 258 (1973)l by avid lack man, is itself in error. This fact was ~ o i n t e dout to us by a numher of individuals. ~ a n i s c r i ~correcting ts the errors were suhmitted by David K. Lavallee of Colorado State University, S. Aronoff of Simon Fraser University, David Blackman of Federal City College, and R. L. C. Pilgrim; Professor Pilgrim's manuscript was submitted independently and prior to the actual puhlication of Textbook Error 111 in April, 1973. We have encouraged him to expand his original paper and to incorporate comments received from other individuals in so far as practicable in this paper. We trust it corrects our previous inaccuracies. We appreciate the interest and comments of the many individuals who have written us in connection with this problem and regret that space does not permit individual acknowledgments.
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1 Journal of Chemical Education
I
From his own statements, however, it is quite clear that Fischer (I) made his position absolutely unequivocal. When he developed the attack on the constitution of heme pigments, he t w k advantage of Kiister's observations that both oxidative and reductive degradation of haemin yielded pyrrole derivatives, all of which always bore two different side groups in the 3,4 positions. In Fischer and 01th (3) is a succinct, telling statement Die onalytische Forsehung hotte gelehrt, dass das ous Mesoporphyrin und den notiirliehen Porphyrinen erhaltliche Atioporphyrin o w uier firrolkemen aufgebaut ist, die jeweils eine Methyl- und eine Athylgruppe in @-Stellungtragen.
F i c h e r then went on to show that, with this restriction, only four etio- or coproporphyrins, and thence only 15 meso- or protoporphyrins, were theoretically possible. It is Suggestions of material suitable for this column and columns suitable for publication directly should be sent with as many details as possible, and particularly with reference to modern terthooks, to W. H. Eherhardt, School of Chemistry, Georgia Institute of Technology, Atlanta, Georgia 30332. Since the purpose of this column is to prevent the spread and continuation of errors and not the evaluation of individual texts, the sources of errors discussed will not be cited. In order to be presented, an error must occur in at least two independent recent standard hooks. lAhhreviations used throughout this paper: rn = methyl, e = ethyl, a = acetic acid, p = propionic acid, v = vinyl. ZThroughout this discussion, Roman numerals are used for Fischer's isomers I-IV in the etioparphyrin series, and for his I-XV in the mesoparphyrin series. The other theoretical isomers of etioparphyrin tabulated in this paper are referred to by Arabic numerals 5-13. and those of meso~orohvrin . . . bv. 16-60. 3 Fiseher's positions 1-8 on the parphin ring correspond to positions 2,3,7,8,12,13,11,18inIUPAC nomenclature.
Table 1. Isomers of Etioporphyrin
Fischer's etioporphyrin2
1
2
3
I I1 111 IV
m m m m
e e e e
m e e m m e e m
Table 4. Additional 'Theoretical' lsomers of Mesoporphyrin
Ring position' 4
5
6
7
8
m e m e m e e m
m e e m
e m m e
Table 2. Additional "Theoretical" Isomers of Etio~orphyrin
Ring position
"Theoretical" etioporphyrin 5 6
7 8 9 10 11 12 13
1
2
3
m e m e m m m m m
m m m m m m m m m m m e m e m e m e
4
5
6
7
8
m m e m e m e m m
e m m e e m m e e
e e e e e e m e m e e e m e m e e m
e e e e e e e e e
Table 3. Isomers of Mesoporphyrin
Fischer's parent etioporphyrin I I1 111
IV
Fischer's mesoporphyrin I I1 I11 IV V VI VII VIII IX
X XI XI1 XI11 XIV XV
Ring position 1
2
3
m m m m m m m m m m m m m m m
p p e p p p p e e e p e p p p
m m e e e m m m m m m e p e e
4
5
p m e m m m m m m m p m e m p m e m p m e m m p m e m e m p
7
8
e m p m p p e p p e e e p e p e p p e p e p m m m m m m m m
e e m m m m m m m m m p e p e
6
the too-frequent omission of clear reference to this restriction which has led many.writers to make patently ambiguous or frankly erroneous statements. Fortunately there are some texts in which Fischer's restrictions are clearly stated. Thus. Kine 14). in one of the first full reuorts in the English language bf Fischer's achievements, faithfully re~roducedKiister's results and included. for the ~ o r o h v r i k , the condition that each pyrrole nudeus m i s t bear one methyl group together with one of another species. Equally clear adherence to Fischer's stand is evident in Granick (5), Karlson (6), McGilvery (7), Reindel (8),and Stevens (9). ~noth'e;statement which sometimes appears is a gross misre~resentationof Fischer's deductive analvsis: "Making the tacit assumption that like groups do n i t substitute in the same pyrrole nucleus, Fischer pointed out that a porphyrin with two different substituent groups could have four position-isomers; . . . ." As shown above, Fischer did not need to make anv tacit assum~tions-he alreadv had evidence that the 314 positions oi each constituen"t uvrrole were occu~iedbv different e r o u ~ s From . his work. &"was quite clear'that there was imposed, on the theoreti: cal arrangements of substituent groups around the porphin ring, the restriction that no pyrrole ring may have two like groups. This restriction eliminates all the additional "theoretical etioporphyrins" 5-13 (Table 21, and the derived mesoporphyrins and like compounds 16-60 (Table 4) in this paper.
Parent etioporphyrin
Derived mesoporphyrin 16 17 18 19 20
Ring position 3
m m m m m m m m m m m m m m m m m m m m m m m m m m p p p e e e p p p p p p e e e p p p
4
5
6
m r n p r n p m e m m m m m m m m p m p m p m e m e m e m m p m p m p m e m e m e p p p e p e e p e p e e m m m m m m m m m m m m p m e m e m m p m e m e m p m p m e m p m e m e
~
p
e e
p p p p e p e e p p e m m m m m m m m m m m m p e e p p e m m m m m m m m m e p e
em^^
A further curious confusion is introduced to compound the error in some recent advanced treatises which describe the arrangement of side chains in relation to the four pyrrole rings A, B, C, and D: "In the case of porphins containing two substitutents A and B in rings A and B and two substituents A and C in rings C and D, 15 isomers are possible." This inadvertently limits the number of isomers to a ereater deeree than is the case; from this statement it is not possible-to obtain ~ischer'smeso-or protoporphyrins 11, V, VII, X, or XV, all of which have similar substitutions on alternate pyrroles, i.e., on rings A and C, or B and D. It is obvious that only a minority of texts in the English language give credit to Fischer and his school and rigorouslv outline the conditions under which his several series of iorphyrins were established. Of the remainder, a few are e~uivocalin their presentation, but most describe the situation in an erroneous or inadequate fashion, suggesting a slavish adherence to an earlier text, or a failure to test properly the statements made. It cannot he argued, in defense, that only unlike groups can substitute on any one pynole ring and that it is unnecessary to spell out the conditions as fully as are here claimed desirable. Already in 1937, Fischer and Orth (3) had reported the laboratory Volume 51, Number 5, May 1974 / 317
Fischer's school, but is liable to be misleading to those not synthesis of numerous compounds with like groups on the same pyrrole, e.g., 1,3,5,6,7,8-hexamethyl-porphin; intimately acquainted with the subject. The writer wishes to thank Drs. J. A. Coxon, B. G. 1,2,3,4,5,6,7,8-octamethyl-porphin; 1,2.3,4,5,6,7,8-octapropyl-porphin; 1,3,4,5,8-pentamethyl-2-ethyl-porphin-6,l- Odell, and D. R. Robinson, for their encouragement as dipropionic acid-dimethyl ester. Admittedly, no comwell as for their independent checks on the theoretical arrangements within the isomer series. pounds of these types have been shown to occur naturally; their laboratory synthesis was performed using intermediLiterature Cited ates other than the porphobilinogen involved in natural 111 Fiseher. H.. "Nobel Leefuro~.Chemistry. 1922-41." Nobel Foundation. Elsevier, systems. Summary
The literature contains numerous invalid or incomplete accounts of the basis for stating that there are only four possible isomers of etio-, copro-, and uroporphyrins, and only 15 possible isomers of meso- and protoporphyrins. Unless Fischer's restriction is included-that no pyrrole ring may have two like groups-the number of isomers is not limited to these figures. A plea is made here for greater precision in giving accounts of porphyrin isomerism in texts, especially those which are directed to student consumption. Careless and inadequate handling of the problems not only fails to do justice to the brilliant work of
318
/
Journal of Chemical Education
Amsterdam. 1966.p. 165. 121 Biaekman,D..i.CHEM. EDUC..50,25811973). (31 Fincher. H.. and Orth. H.. "Dk Chemip dps mrrols." Akademiseha Veriagagesdl=chaff M.B.H.. Leipzig. 1937.11111, p . 161. 191 Kine. H.. Ann. Reg(. Pmer Cham. for 1932, (Chrm. S o c London), XXIX. 211 li9331. (5) Granick. S.. "Chemical Pathways of Metabolism." Editor: Greenberg, D. M.I. AcademicPresr. Inc.. NeuYork. 1954.11, p. 298. (61 Karlron, P.. "lntmduefion to Modern Biochemiary." (nmslafor: Onring. C. H.1. 3rdEd..AcademicPren. Inc.. UewYork, l968,p. 185. (7) McCiiuery. R. W.. "Biochemistry; a Functional Approach." W. B. Saundem Co.. Phiiadelphia, 1970. p. 495. (81 Reindol. F., "The Heternyelie Compounds,'~( T m ~ l o l o r :Darken, M. F.1, in "0" Richter. V.. "The Chemistry of the Carbon Compounds," (Editor: Ansehutr. R.I. IXhGermanEd.,ElsevierPubllshingCompsny,Inc. NeuYork. 1931.IV.p. 42. Rodd, E. H. (Editor). "Chemistry oftha (91 Stevens.T. S.. "The pynoie Pigments." Csrbon Compounds." Elsevier Publishing Company, Amsterdam. 1959. IV B, p. 1125.1128.
