PHILIP A. ROUSSEL? Tulane University, New Orleans, Louisiana
Tm
early history of organic compounds can often be traced to interest in their naturally occurring derivatives. I t is of no surprise, therefore, that indole has been extensively studied in world-wide laboratories for almost a century. Its wide occurrence in important biological and chemical systems has provided the stimulus which has resulted in many hundreds of puhlicat,ions devoted to a study of indole and its derivatives. The ancient dye, indigo, the essential amino acid, tryptophan, the plant hormone, heteroauxin, and the recently discovered powerful vasoconstrictor, serotonin, are prominent examples of naturally occurring substances which possess the indole nucleus as a parent. A number of important alkaloids have been shown to be derivatives of indole. Indole itself has been isolated from certain plant sources, notably the jasmines and certain citrus fruits, but by methods which suggest that the indole is actually the degradation product of some higher derivative. It should also be noted that Runge isolated indole from coal tar.
was successful in a complete reduction of oxindole to indole, which he accomplished by distilling a mixture of oxindole and zinc dust. This reaction was noteworthy in a second sense, herause it represented the first recorded application of zinc pyrolysis to the reduction of organic compounds. Intereshgly enough, this reductive technique was directly responsible for the subsequent confirmation of the structure of alizarin by Graebe and Liebermann,' "an achievement which was always a source of great satisfaction and delight to Bae~er."~ The structure of indole was finally confirmed by Baeyer and his student E~nmerling,~ who prepared the substance by the fusion of o-nitrorinnamic acid with iron filings and alkali; reduct,ion of the nitro group and ring closure to indole resulted. From this reaction, and by consideration of KekulB's new benzene structure theory, Baeyer assigned it the benzopyrrole structure which soon came into general acceptance.
DISCOVERY OF INDOLE
Indole \\.as discovered by Adolph Baeyer as an outgrowth of his famous studies on the constitution of indigo. During the course of his investigation of indigo, Baeyer had a t his disposal two indigo derivatives -isatin, its oxidation product, and indigo white, its redurtion product. His decision to concentrate his attention on the former is perhaps an example of "chemical intuition," for it led directly to the structure of indole and ultimately to that of indigo. Isatin had been known since 1841, when it was prepared by the oxidation of indigo independently by Erdmanna and by L a ~ r e n t ,hut ~ its chemical constitution was still unknown. Baeyer and his student, Knop, elected to reduce isatin, and under the conditions they employed obtained two reduction products, CsHiiY0andCsH,NO2, which they regarded as oxygen derivatives of a hypot,hetical parent, CsH7N.S The latter substance they named indole. The CsH7N0and CsH7N02compounds therefore became oxindole and dioxindole respectively. In a second publication later the same year,=Baeyer
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October 9, 1952, marked the centenary of the birth of (Hermann) Emil Fischer (1852-1919). This paper in a small way may serve as a trihute to the memory of this great organic c h e i -
.-+ ."".
Present address: Organic Chemicals Department, E. I. du Pont dc Ncmaurs & Co., Inc., P. 0. Box 525, Wilrningtan 99, 1)rlaware. ' ERDMANN .4., J. prakl. Chem., 24, 1 (1841). * LAURENT, A,, Ann. Chzm. P h p , 3, 371 (1841); J . prakl. Chem., 25, 430 (1842). BAEYER, A,, AND C. A. KNOP,Ann., 1 4 0 , l (1866). ' RAEYER,A,, Ann., 140,295 (1866)
LACK OF INTEREST
The decade following the discovery of indole saw only moderate interest evinced in its chemistry. At the close of this period Baeyer published two papers dealing with the properties of isatin and two new methods for the preparation of indole,'o but outside of Baeyer's laboratory the subject was for the most part neglected. Unt,il 1878 Baeyer purposely neglected any further pursuit of the problem out of a misplaced consideration for KekuM, who had announced his intention to begin an experimental study of i s a h . The lack of major interest outside of Baeyer's laboratories may probably he traced to two reasons. Indigo, the derivat,ive which had caused Baeyer to initiate his study, was still a chemiral mystery, although Baeyer had conceived, but not proved, its correct structure. After many centuries of speculation and study, holyever, its drama mas nearly ended, and it is not unexpected that indole would be t,emporarilyneglected in favor of the final solution of its more glamorous offspring. A second factor which may have contributed to the neglect of indole was the diffirulty faced by experimenters in preparing or obtaining
' GRAERE, C., AND C. LIEBERMANN, Ber., 2,
14, 332 (1869).
PERKIN, W. H., Adolph Bacyer Memorial Lecture, J. Chem. Sor., 1923, 1520. BAEYER, A., AND A. E Y ~ ~ E R L IBw., N G ,2, 679 (1869). lo BAEYER, A,, ASD H. CARO,Ber. 10, 1262 (1877): BAEYER, A.. ihid.. 12, 456 (1879).
MARCH, 1953
123
workable samples of the compound. Baeyer's route through indigo gave very unsatisfactory yields; his suhsequent syntheses through ring closure of o-nitrocinnamic acid or N-alkyl-o-toluidines mere of little more preparative value. Mohlau introduced a new synthesis of indole during this period,ll but the method as reported a t that time yielded only substituted indoles and was of limited practical value. It remained for Emil Fischer to provide a workable laboratory synthesis of indole and its derivatives, and thereby to open up the field of indole chemistry.
A
FISCHER'S WORK
After receiving his Ph. D. degree with Baeyer in 1874, Fischer remained with Baever in Strasshurn as an independent research studend. I n the fall 07 1874 the assistant in charge of the organic division left his post, and, at Baeyer's urging, Fischer accepted an appoine ment to that position. I n this capacity he was called upon to assist students who encountered difficulty in t,heir organic preparations. One student, who was assigned the preparation of diphenol by the diazotization of henzidine, regularly obtained muddy products. Not t.rusting the student's skill, Fischer undertook the preparation himself. Deciding that the disagreeable products were due to oxidation by the nitrous acid, Fischer added to the reaction sodium sulfite to prevent the presumable oxidation. Upon addition of the sodium sulfite he observed the formation of a yellow precipitate. Further experiments revealed the precipitate to be a salt of a phenylhydrazine and resulted in Fischer's discovery of phenylhydrazine itself, published in 1875.12J3 Fischer continued to investigate the preparation and propert,ies of various phenylhydrazines. Although he quirkly recognized the ability of aldehydes to combine with hydrazines, he does not appear to have appreciated the enormous value of the reaction as a route to the characterization of carbonyl compounds until 1883. In that year he prepared the phenylhydrazone and methylphenylhydrazone of pyruvic acid. These preparations proceeded mith ease and with the production of such heautiful crystalline products that Fischer was encouraged to examine them more closely. Working with his pupil, Jourdan, on the a-methyl-aphenylhydrazone of pyruvic acid, Fischer warmed the hydrazone with dilute aqueous hydrochloric acid. Upon examination of the product he noted that the original hydrazone had disappeared and there appearedasaproduct a new carboxylic arid of unknown constitution. With characteristic thoroughness he analyzed the suhstance and recognized that the following equation could account for its molecular f ~ r m u l a . ' ~
-
+
CloH12NzOa CloHuN02 NHI MOHLAU, G., Bw.,14,171 (1881). FISCHER, EMIL,Ber., 8,589 (1875). ' T h e account of the discovery of phenylhydrazine is taken from: FISCHER, EMIL,"AUS Meinem Leben," Springer-Verlag, Redin, 1922, p. 52. ' ' FISPHER, EMII.,A V D F.JOI;RUN,Ber., 16, 2241 (1883). l2
Fischer admitted that he could neither identify the product nor account for its formation, saying: "The foregoing (reaction) is so remarkable that lve meanwhile do not hazard to give an explanation for it. In any case, the new acid is representative of a remarkable class of substances, for which analogies until now are ahsent."" The publication of these results was succeeded by a paper the following year by Fischer and Hess, in which they identified the reaction as producing a derivative of indole according to t,he reaction below.'5
d. -
A
+ NHs
CH,,
COOll
&EL
..
u n'T-I 'C O O H
1
CHa
The yield of the I-methylindole-2-carboxylic acid prepared in this manner mas only about five per cent, a yield so low that a less capable experimenter might have missed it entirely.16 That Fischer recognized the potential value of the reaction, however, is clear from his statement that "For the synthesis of compounds of the indigo group a new and, as it appears, quite fertile territory is opened."l6 Fischer appreciated the reaction as a convenient route to indole derivatives of many types. Accordingly, he rontinued his investigations, publishing his results in the Berichte and the Annalen over the period of the next four years. His further researches led him to a number of refinements of the original procedure. He found, for example, that the original conversion of the methylphenylhydrazone of pyruvic acid into its corresponding indole derivative proceeded more smoothly and in better yield if anhydrous zinc chloride was substituted for hydrochloric acid as the catalyst." His modified procedure utilized a three to five molar excess of zinc chloride and heating in the neighborhood of 200°C. Using this technique, for example, Fischer was able to convert propionaldehyde phenylhydrazone t o skatole (3-methylindole) and acetone phenylhydrazone to 2methylindole mith respective yields of 60 and 35 per rent.l8 The announcement of these results undoubtedly served to stimulate interest in thechemistryof indole. A convenient route to indoles of widely different structures was made available, and one of the obstacles to the investigation of indole was largely eliminated. Conditions and catalysts have since been altered and improved, but the cyclization of a phenylhydrazone to an iudole is still correctly referred to as the Fischer indole synthesis. FlsceEn, EMIL,A N D V. F. HESS,Ber., 17, 559 (1884). ' I This reaction has been repeated by the author several times in tho Idmi-atories of Tulane University with yields of 71 to 78 per cent. R o u s s ~ P. ~ , A,, "The metalation of indole and pyrrole and some of their N-substituted homologs with n-butyllithium," dissertation, Howard-Tilton Memorial Library, Tulane University, New Orleans, La. " FISCHER,EMIL,Be?., 19, 1563 (1886). FISCHER, EMIL,Ann., 236, 116 (1886).
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JOURNAL OF CHEMICAL EDUCATION
and the carbonyl compou~ld. Some reactions are remarkahly easy t,o bring about, uiz., the preparatiou of l-methylindole-2-carhoxylic acid from the methylphe~~ylhydrazone of pymvi(. acid merely by warming with dilute hydrorhloric arid. The extreme of diffirulty is represented hy the transformation of propionaldehyde phenylhydrazone into skatole (3-methylindole) which requires a temperature of about 200°C. As a general rule t,he ring closures to indoles are hrol~ght ahout by conditions within a smaller region lying hetween these two extremes, S,S- disuhstiluted phenylhydrazones usually reacting with greater ease than their unsubstituted homologues. The extensive application of his indole synthesis as a lahoratory route to substit,uted indoles has only corroh(rated Fischer's early prediction of the usefulness of t,he method. So few exceptions to t,he versat,ility of the reaction have appeared t,llat it hecomes possihle t o write for i t a general equation:
VERSATILITY OF SYNTHESIS
Although there are ohvious sterir requiremeiits,the R groups may in general he hydrogen. or any species of hvdrocarhon radical. The wide applicability of the Fischer indole synthesis to the preparation of indoles is illustrated in the examples following. Ketones ranging in complexity from acetone to surrinalclehydic acid form phenylhydrazones which readily give the corresponding indole derivatives. Phenvlhvdrazones derived from cvrlic . . ketones provide interesting evidence of the versatility of the Fischer synthesis. The phenylhydrazo~re of ryrlohexanone, for example, yields s partially reduced r"rhazole lyithgreat
of the Fischer illdole reactioll ~~d~~~ have resulted in a number of refinements and modifications. The use of large excesses of zinc chloride is now recognized as unnecessary, catalytic amounts being capable of causing reart,ion. A large number of nelr H 11 catalvsts harre heen introduced, their efficiencies de-pending on the sperific reaction they are called upon to The Fischer synthesis also permits wide variation in catalyze. Inclrded in the list of rerogl~izedratalysts are such diverse materiids as hydrorhloric, sulfwio, and the character of the phenylhyd~.azine. I t has already acetic acids, zinc chloride, ruprous chloride, robaltous heen noted that N,S-disuhstituted phenylhydrazones chloride, nirkelous i~hloridea r ~ dthe recently discovered are more readily transformed into indoles thau unsithcatalyst,^ st,annous chloride, horon trifluoride, and the stitut,ed phenylhydrazones. Similarly, the presence of suhstitutents in the phenyl nt~cleus of the phenylGrignnrd reagent . Other improvements in Fischer's early proress inchde hydrazone does not iu ge~~eralrerluceitsahilitytoundergo t,he substitution of inert solvents for the aqueous or ring closure. Bromo-, methyl-, and even such strongly fused media employed hy Fisrher. Met~hyhtapt~haletle deactirat,ing groups as nitro- do not preclude reaction. Indeed, even the presence of suhstituents in both of the has been observed to serve efficiently i n this respect. A survey of the literature regarding Fischer's indole positions ortho t,o the hydrazine group does not always reaction reveals that i t is indisputably the most versa- prevent ring closure. I t has rerently been demonstrated tile of all lahoratory indole preparat,ions. The synthe- that such a group may migrate to another position in sis permits a widelatitude of rhanges in both the phenyl- the moleoule io order to allow ryclization t,o occur in the hydrazine and t,he aldehyde or ket,one whose hydrazone ~ositionsortho t o the hvdrazi~ienitroeen.'* An exit forms. The ease with whirh the r e a h o n proceeds is R. n., J. G. \VA~.I,ACE, A N D E. E. FISHER, J. ilm. CARLIN, largely go~.enredhy the nature of the phenylhydrazine Chem. Soc., 74,000 (1052).
o\x.x90 - @,o ~
MARCH, 1953
125
ample of such a reaction is illustrated in the equation below.
in 1918.22 Although the Rohinsons' mechanism does not include electronic structures or interpretations, each postulated step is in accord with reactions which are known to occur in analogous cases. The cyclization of the phenylhydrazone of cyclohexanone provides an illustration of this mechanism.
As a general rule in substituted phenylhydrazones, ring closure is directed to the carbon atom ortho or para to the substituent, regardless of its nature. An interesting extension of the Fischer indole synthesis which further testifies to its utility is found in the reactions of phenylhydrazones derived from ketones which possess no alpha methylene Eroup. Such a case is fourid in the phenylhydrazone if methyl isopropyl ketone, which reacts within the framework of the Fischer synthesis to yield a substituted indolenine, indolenine being a tautomer of indole. One such reaction, discovered by Plancher in 1898,20is illustrated below.
~h~ initial step involves the shift of a in the hydrazone to form a substituted hydrazine, which is tautomeric with the hydrazone. The second step involves an o-benddine follolved in the third step by the elimination of a molecule of ammonia as a salt of the catalyst. Strong experimental support CHs ran be cited for each of these ~ostulatedstem. The last decade has seen the appearance of a number of refinements of the Robinsons' mechanism, interpreting it in terms of modern electronic theory. These publications, notably those of C a r l i ~ considerably ~,~~ Despite this summary of reactions which illustrates strengthen the mechanism of the Robinsons, though by the wide scope of the reaction, certain exceptions to the no means do they exclude further argument. Although the Robinson and Robinson mechanism generality of the Fischer indole synthesis are recognized. Perhaps the most significant of these is the failure of seems to provide an adequate explanation for the acetaldehyde phenylhydrazone to yield indole itself. Fischer indole synthesis, certain other mechanisms have The other important exception is noted in the phenyl- appeared which should not be excluded from con~,~~ and an English hydrazones of 8-keto esters, which usually yield sub- sideration. R e d d e l i e ~Bamberger,zs school led by PausackerZ6have advanced mechanisms stituted pyrazolones rather than indoles. which have certain strong points in their favor. MECHANISM Modern organic chemistry is indeed indebted to A ereat deal of s~eculationhas a ~ ~ e a r in e dthe litera, Emil Fischer for the indole svnthesis that has come to ture regarding the mechanism of the Fischer indole r e bear his name. What began as a study of the reactions action. Fischer wrote the equation for the reaction as of phenylhydrazine led a remarkable chemist to a reproceeding through the elimination of a molecule of markable reaction, a discovery that has contributed ammonia from the phenylhydrazone. In his reactions immeasurably to the development of the chemistry of involving the ring closure of N,N- disubstituted hydra, indole and of its natural products. zones both of the groups atttached to the hydrazine ACKNOWLEDGMENT nitrogen remained in the indole which was ultimately The anthor is indebted to Dr. Clara deMilt for her formed, and Fischer considered this evidence that it was the other nitrogen atom which was lost as ammonia invaluable assistance in the preparation and correction (ref. 15). Recent advances in the use of isoto~eshave of this manuscript. enabled modern chemists to examine this proposal. LITERATURE Allen and Wilson investigated the Fischer indole synFor general reviews of the chemistry of indole the thesis using phenylhydrazones bearing N15in the hydrareader is directed to: zone group and as a result of their studies offered conclusive evidence that it is the nitrogen more distant VANORDER,R. B., AND H. G. LINDWALL, Chem. Reas., 1942. R. C., Editor, "Heterooyelic Compounds," John from the phenyl group which is lost as a m m ~ n i a . ~ 'EI~ERFIELD, Wilev & Sons. Inc.. Ncw York. 1952. Xrol. 111. DD. 1-275. Fischer's postulation was therefore confirmed. Perhaps the most tenable mechanism which has been 2 ' R o ~ 1 ~ s G. o ~M., , AND R. ROBINSON, J . Chem. Soc., 113, advanced to explain the Fischer indole synthesis hasbeen 639 11918): ibid.. 125.827 11924). CARL&, R. B., J . ' A ~ hem: . Soe., 74, 1077 (1952). that of Robinson and Robinson, which first appeared ~
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..
2'
PI,ANCHER, G., BET.,31, 1496 (1898). ALLEN,C. F. H., AND C. Y. WILSON, J. Am. Chem. Soc., 6 5 ,
611 (1943).
REDDELIEN, G., Ann., 388, 179 (1912). BAMBERGER, E., AND A. LANDAU, Ber., 52,1097 (1919). 2 6 1 3 ~C.~S.,~ K.H. ~ ~ PAUSACKER, , AND C. I. SCHUBERT, J. Chem. Sac., 1949, 1381 26
