K. Thomas Finley Rochester Institute of Technology Rochester, New York
The Synthesis of Carbocyclic Compounds A historical survey
J u s t 80 years ago, in the infaucy of cyclization studies, the eminent German chemist Adolf von Baeyer attempted to account for the difference in reactivity of cyclic compounds of different ring size ( I ) . This hypot,hesis, which was presented "in order that they could receive the widest possible evaluation,"' was unfortunately elevated by many into the status of a law and greatly retarded much productive work in the synthesis and study of rings larger than six carbon atoms. The success and limitation of the "Spannungs Theorie" are outlined in every textbook of elementary organic chemistry and will not be repeated here. Rather it is our purpose to review the fascinating course of the development of ring closure reactions-because of and in spite of the predict,ions of "Seiner Exzellenz Herr Geheimrat Professor Dr. Adolf Ritter von Baeyer."2 A Rash Young Man
I n the year 1880, a young Englishman studying orgauic chemistry iu Germany translated a paper by the great German chemist, Victor Meyer (2),for the purpose of improving his facility with the language. I n the course of this paper, Meyer presented his arguments against the existence of carbon rings of fewer than six atoms. It seemed to him that since they were not found in nature, and all reactions which might produce them gave only the isomeric unsaturated openchain compound, the likelihood of synthesizing them was very small. Soon after the English student had moved to Adolf von Baeyer's laboratory in Munich, Meyer paid a visit. Thus it was that William Henry Perkin had an opportunity to ask Meyer about his views on the construction of small carbon ring structures. The older chemist obviously had a very high regard for his friend's ambitious young student since he invited Perkin to supper and discussed at great length the problem of small ring preparation. The outcome of their discussion was very negative and to most men would have been sufficient to dissuade them from
Presented before the Division of History of Chemistry at the 149th Meeting of the American Chemical Society, Detroit, Michigan, April 7, 1965. The fact that the theory was intended largely as a prediction is made clear from Baever's rather definite statement taken from reference ( 1 ) . *The standard thesis acknowledgment of Baeyer's PhD students at Munich: ',His ~ ~ Mr. privy ~ ~ ~ ~ Professor Doctor Aldolf, Knight of the family Baeyer."
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attempting so bold (or foolish) an adventure. Meyer left no doubt in Perltin's mind that a t this early stage of his career he should work a t something more likely to give positive results (8). Fortunately Perkin was not most men, and in spite of the discouraging comments of Baeyer and Emil Fischer, as well as Meyer, he undertook the preparation of these exciting new molecules. He even felt later that there was some hope and encouragement in the fact that several times Baeyer asked him about the work. I n 1929, Perkin was asked to give the first Pedler Lecture, and he chose as his topic a personal account of these early years of development of small ring chemistry. One of his reasons for this selection is of historical interest: For many of us, most of all perhaps for the younger generalion of chemists, it must he very difficult to appreciate the fact that, not so many years ago-certainly not more than 50 years ago-it was thought to he so out of question that intermediate carbon rings containing 3, 4, or 5 atoms could be capable of existence that no one seems to have given them serious attention or to have attempted to construct them (3).
The 35 years since that lecture have greatly added to our difficulty. This generation has seen advances in cyclization technique which are the natural but still amazing result of Perltin's pioneering efforts. We think it perfectly normal to make use of the rigid geometry of ring systems to study the kinetics and stereochemistry of organic reactions. We are not surprised to read in journals of the preparation, p r o p erties, and reactions of highly strained bicyclic systems such as I (4) ; macrocyclic natural products, as I1 (5); or even the interlocking rings in the catenanes, 111 (6).
I11 The Earliest Recognized Preparation of Small Rings
One of the chief arguments against the small rings-
-
+,hefmt, t,ha,t no reaction resultine in them was known~ -. ~~~~~
~
was already untrue, but the products obtained had for several reasons recognized l ~ l ~ not~ been ~ ~i ~or l proved ~~ to con-~ tain such an arrangement of atoms ( 7 , 8 ) .
~
This was quickly followed by the application of the reaction to the preparation of a cyclopropyl system (W.
These experiments were repeated much later and the accuracy of the original work verified (9, 10). I n 1929, Perkin expressed his amazement, ". . . that these observations should have called forth so little comment" (3). Perkin's first experimental results were misinterpreted and this represents one of those examples where a correct understanding might have discouraged the young chemist, strengthened the stand of those who predicted failure, and thus cut short what was to be most frnitful work. This was indeed to be a most productive error. The plan was to react trimethylene bromide with the sodium salt of acetoacetic ester. From this reaction was isolated a small quantity of an ester which analyzed correctly for the expected cyclobutane derivative.
Hydrolysis of this 8-ketoester gave a compound which seemed to be the corresponding 8-ketoacid.
The fact that this compound did not lose carbon dioxide surprised Perkin, but in view of the evidence, Baeyer decided to communicate the results at oncedistaste of being "scooped" is as old as science (11). Later experiments showed that instead of a cyclobutane derivative, the isomeric dihydro-1,Cpyran had been obtained.
The effect of this error was never felt and the work which followed presents a truly brilliant chapter in the history of organic chemistry. Later, in July of 1883, the first true and recognized synthesis of a fourmembered ring was reported (If?).
The Ubiquitous Normal Rings
That natural products abound with six-membered carbon rings was well known to the nineteenth century organic chemist. Today, we know that there are also a large number and variety of five-membered rings and even a few cases of seven-carbon alicyclic molecules. Thus, the "normal" rings seem to have the great stability predicted by the calculation of strains from consideration of the geometric requirements of planar systems. I n 1885, with the new knowledge of three- and fourmembered rings, it was very important to prepare an authentic example of a five-membered carbocycle. Perkin's great success indicated the logical next step.
As is frequently the case in scientific work, the obvious reaction was not the possible one a t that particular time. It was to be another 10 years before Perkin was able to prepare the required 1,4dibromobutane (tetramethylene bromide) (14). The importance of finding a method for the preparation of five-carbon systems led Perkin to begin a t once to investigate a method which did not require the missing bromide. His agile mind and great laboratory skill quickly found such a route and just four months after the strain theory, the first recognized synthesis of a cyclopentane derivative was published (15).
At this point the synthesis of a five-membered ring was important principally for theoretical reasons; but because of the great interest in preparing natural products, numerous methods for both five- and sixcarbon rings were rapidly developed. Of all these synthetic procedures, there are two that even the briefest review must a t least mention. Using dicarboxylic acid esters and basic conditions, excellent yields of five- and six-carbon cyclic ketones can be obtained via decarboxylation of the intermediate 8-ketoester (16).
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This reaction, usually identified as the Dieckmann reaction, is clearly an intramolecular Claisen condensation. Recent work has shown that it is also applicable to the formation of large ring cyclic ketones when carried out under high dilution conditions (17, 18). The reaction which won the 1950 Nobel Prize for Otto Diels and I h - t Alder, and is known either by their names or as the diene synthesis, is almost certainly the most used, investigated, and debated reaction of the first half of the twentieth century (19, 20). While it is exclusively useful in the preparation of cyclohexane derivatives, the great need to construct such rings, the very wide range of starting materials employed, and finally the interesting and controversial mechanism of the reaction have brought about its great contribution to the organic chemical literature.
R
=
electron-withdrawing group,
The derivatives of cycloheptane occupy a very interesting place in the alicyclic series. For a long time they were considered to be members of the very difficult to synthesize medium ring class. Today, the evidence indicates that they more nearly resemble the normal rings (21). This is in spite of the fact that they are much less common in nature and are frequently difficult to prepare. The final word on this problem awaits the synthetic and theoretical efforts of future chemists. Perhaps the most remarhble thing about sevenmembered carbocycles is the fact that one was prepared in fair yield long before any of the work thus far described took place. I n fact, it appears that the preparation of cycloheptanone (suberone) is one of the earliest recorded cyclization reactions, albeit an unrecognized one (22).
Eight years after the publication of the ring strain theory the true structure of suberone was determined, and the slow but irresistible assault on rings larger than six carbon atoms was launched (25). This was made an even more serious threat the following year when Perkin again applied his method which had shown such great success with smaller rings ( 2 ) .
The Theoretical Importance of the Macrocyclic Musks
The story of the development of ring closure reactions shifts now from the small carbocycles, which 538
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Journal of Chemical Education
beautifully support the ring strain theory, to the large rings which demolish it. Very early in this century it was shown that the compounds responsible for the fragrance of extracts from the Asiatic musk deer and the African civet cat were high molecular weight ketones (25, 26). It was a quarter of a century later when Leopold Ruzicka showed that muskone and civetone were 15 and 17 carbon cyclic ketones (27, 28). At just this time a young Swiss chemist, Max Stoll, began his doctoral work a t the Federal Polytechnical School in Ziirich. Stoll later recalled that when Ruzicka reached the conclusion that civetone contained a single ring with 17 carbon atoms (work which brought him the 1939 Nobel Prize), he appeared very sad (29). He was, of course, dismayed by the twin problems of preparing such a large ring in the face of Baeyer's theory and (even if it could be made) of making the yield high enough to be of any value to the perfume company for which he worked (Firmenich et Cie, Geneva). Fortunately, his sadness did not lead to inaction. If the rings were found in nature, it must be possible to prepare them synthetically, and he set Stoll to the task of pyrolyzing the divalent metal salts of thapsic acid. ,COT ~ a + +or ~ h + + (CH*)*& \ COT
Ad
n
(CH2)u C=O
w
CaCO3 or Thco,
+
Stoll's great patience and laboratory skill brought success in time, but the results were still of little practical use. For although he made the important contribution of demonstrating the possibility of the existence and preparation of large rings, the 5% yields found in the most favorable cases were something short of sensational (SO, 51). Industrial work was started anyway, and continued efforts were made to improve the yield. One of these efforts, although unsuccessful, deserves special mention. Using the high dilution principle (SZ), an attempt was made to form the intramolecular salt in preference to the intermolecular salt. It was reasoned that such a salt, which would have a greater tendency to form in very dilute solution, would also have a much better chance of reacting to form the intramolecular or monocyclic product. The yields failed to improve by this or any other method. I n this case, it was presumed that the pyrolysis caused a rearrangement of the ionic bonds before the cyclization reaction. The lack of success clearly points out the basic difficulty with the Ruzicka method of cyclization-the very nature of the reaction prohibits high dilution in the cyclization step and promotes intermolecular polymer formation. This was a ready-made opportunity for Karl Ziegler to employ his condensing agents which were soluble in solvents of low polarity. Such a system, being homogeneous, would permit taking full advantage of the high dilution cycle. The system which appears to be most useful employs the a,w-dinitriles as substrates and
the lithium salt of N-ethylaniline as the condensing agent ($3).
With this method, the yield of the large rings showed very great improvement as did the reaction leading to seven- and eight- membered cycloalkanones. For example, those homologs of 14 and more carbons were produced in 80y0 yield as opposed to the 5% cited for salt pyrolysis. Only the medium rings of 9-11 atoms refused to be formed in more than trace amounts, if a t all. Much the same story is true of several later attempts to apply this concept of a,wdifunctional molecules under conditions of high dilution (17, 18, 34,35). There is, however, one very bright exception; its full potential has not yet beer! explored. The Value of Competition
The vastly improved yields of macrocyclic ketones possible by the Ziegler method put great economic pressure on the perfume firm for which Stoll had now succeeded Ruzicka as Director of Research. As he put it, "Now, the ball had been taken from our hands and we had to get it back" (927). The approach was to make a systematic study of all condensation methods which might be applied to long chain a,w-systems. One of those investigated was Bouveault's acyloin condensation of esters using sodiumin ether (56). When this method was applied to -
CIH,~CO~CH,
ether
Na
---
c,alhll&-c,HIS (isolated as the glycol)
a dicarboxylic acid ester in order to form the cyclic acyloin, the results were very discouraging and nothing tried seemed to produce the desired product. Then an American patent described the use of finely dispersed molten sodium in refluxing xylene (37). The original intent of the work was to prepare polymers, but by a systematic investigation Stoll and Vladimir Prelog independently and simultaneously developed a cyclization reaction of the very first order (58, 39).
The ball had certainly been recovered. Not only were the yields higher than in any other method, but there was no need to resort to high dilution in the case of the large rings. The yields of the rings of interest (greater than 14 carbons) were nearly quantitative and soon a good reductive reaction for removing the hydroxyl group was developed to complete the preferred industrial route to the important carbonyl compounds. Perhaps of even greater consequence than the
synthesis of perfumes was the effect the acyloin condensation was to have on the new branch of physicalorganic chemistry. As the exciting work of investigating reaction mechanisms developed, it became increasingly clear that the predictable geometry of alicyclic molecules offered interesting new reactions to be studied. Further, a consideration of their geometry and stereochemistry provided a new method of approach to the rather subtle problems frequently encountered. The reason for the importance of the acyloin condensation in this development was that this reaction at last provided a method of preparation of the illusive medium rings (C9-Cn) in very respectable yields of 50y0 and great,er. Eighty Years Later
There are numerous examples of the industry and ingenuity of the organic chemist during the past century. However, the history of the development of cyclization reactions is one of particular interest and significance. Few specific types of reactions have been so important to so many different subdivisions of our branch of science. Few synthetic processes have contributed so heavily to our theoretical understanding. Few areas of organic chemistry have excited and absorbed the work of so many truly first rank men over so long a period.
It might well be said that the history of cyclization reactions, which certainly spans the time of greatest development of organic chemistry, also provided the incentive and means for an astonishing share of that development. Even a casual reading of the current chemical literature indicates that the preparation of cyclic systems is likely to continue undiminished and to produce exciting developments. The importance of Baeyer's theory in stimulating much of this work should not be lost in our haste to point out its shortcomings (40).
Literature Cited (1) VON BAEYER, A., Bw., 18,2269,2277 (1885). ~., (2) M E Y E R , V . , A ~180,192(1876). (3) P E R K I NW. , H., J . Ckem. Sac., 131,1347 (1929). Volume 42, Number 10, Odober 1965
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(4) WIBERG,K. B., AND CIULA,R.. P., J . Am. Chem. Soe., 81, 5261 (1959). F.,ET AL., Collection. Czech. Chem. Cwnmun., 19, 570 (5) SORM, (1964) - - - ,. (6) WASSERMAN, E., J . A m . Chem.Soc., 82,4433(1960). W., AND KRESTOVNIKOV, A,, Ann., 208, (7) MARKOVNIKOV, 333 (1881). O., Monatsh., 3, 626 (1882). (8) FREUND, E., h N D PERKIN,W. H., J . Chem. Soc., 73, 330 (9) HAWORTH, (IRQR). ~-...,. (10) SHORTRIDGE, R. W., ET AL., J . Am. Chem. Soc., 70, 946 (1449) , --,. (11) PERKIN,W. H., Ber., 16,208 (1883). (12) PERKIN,W.H., Ber., 16, 1793 (1883). (13) PERKIN,W.H., Ber., 17, 54 (1884). E., AND PERKIN,W. H., J . Chem. Soe., 65, 96 (14) HAWORTH, (1894). Re%., -1% (15) PE'RKIN.'W. H.. - , 224R - - - - (lRII5I * - --- ,. (16j DIEC&ANN,~W., Ann., 317, 51 (1901). (17) L E O N A ~N. D , J., A N D OWENS,F . H., J . Am. Chem. Soe., 80, fin74 (law -"-" ,-""-,. (18) LEONARD, N. J., A N D SCHIMELPFENIC-, C. W. JR., J . @g. C h a . . 23. 1708 (1958). (19) l)l~!.b,O.,.ASDALI)FI
