Stereochemistry and the "Ether" in the Evolution of Molecular Structure Theory The Musings of a Chemist on Moller's Supplanted "Screw-Theory", Beginning with a View of the Obnoxious and Equally Outdated Cod-Liver Oil Arthur Greenberg Cook College, Rutgers University, New Brunswick, NJ 08903-0231 A Serendipitous and Historical Find I purchased an interesting old book with the unassuming title Cod-Lwr Oil and Chemistw ( 1 1 a t a used book st& in rural New Jersey one hot summer afternoon. My interests run to the history of chemical theory, not chemical technology, and since I do not fancy fish a s food, my interest in this book was marginal a t best. However, a qGck glance inside the book, which was published in 1895, indicated that its author F. Peckel Moller, PhD, had bigger fish to fry than cod. The book's 111-page preface and preliminary section, which quaintly ended with page c i , was titled "Cod-Liver Oil". The real book, comprising pages 1-508, the Chemistry section, started with its own separate title page: The Law ofAtomic Linking Diagrammatically Illustrated.
Processing of a Popular but Very Unpalatable Product
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F. P. Moller. a coauthor of the Norweeian Pharmacoooeia among other works, was apparently employed in the firm of Peter Moller. who himself devcloocd the "steam Drocess of preparing cod-liver oil" in 1853.'Prior to that development, the status of cod-liver oil could be summarized a s below (2). Cod-liver oil is undoubtedly one of the most valuable medicinal agents known to man. Its value has one remarkable proof in the fad that it was extensively used in the days when only the brown variety could be obtained. In those days cod-liver oil was not a desirable article of consumption; indeed, to put the matter plainly, it was an abomination, and no one could have taken it willingly, even once, not to speak of day aRer day and month after month. Nevertheless manv. .oeonle . did take it. and the only rearonabl~explanation is that the oil must hnvr gwrn strikingly favourable results; otherwxe, medical men would nut haw been jurtrfied in prerenbing i t , nor could their pntients have been induced to use it. The cod-liver oil section goes on to describe the old rewvery method. Fishermen would gut the cod and throw untrimmed livers, with the gall bladders still attached, into barrels that would then be covered. The mttinn contents could "age" for up to four months while liver czls decomposed and released their oil, which oozed out a s a yellow to light-brown substance. The oil, replete with putrescent decomoosition bv-~roducts.was skimmed off the to^ of the bagels' content; in ~a~ a n d sold. I n June, the "aging" accelerated, and the oil became brown to dark-brown. The Steam Process Peter Moller's steam process required fishermen to remove the gall bladder and trim the membranes and other extraneous matter from the livers. Then the fresh livers were heated over a steam bath. The oil collected by this "melting" process was clear to light yellow and essentially
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odorless, thus increasing the oil's palatability by a few orders of magnitude. Moller notes that the public was slow to accept the new product, fearing that it had lost its medicinal powers. He also describes the many pharmaceutical preparations then based on cod-liver oil. Descriptions of earlier research a s well a s state of the art knowledge are then provided by P. M. Heyerdahl, a major contributor to the technology The Problem with Hydmxyacids Heyerdahl discovered that cod liver oil had a dearth of saturated fatty acids and a high percentage of polyunsaturated fatty acids, including "therapic acid" (C1&&OOH) (31, the first reported tetra-unsaturated fatty acid. The reactivity of these fatty acids with oxygen was such that Heyerdahl carried out his chemistry under hydrogen. These fatty acids gave rise to hydroxyacids, which were the underlvine cause of the second oractical oroblem associated wit6 co&liver oil (4):
... the hydroxy acids were the cause of eructation, and ... this unpleasant symptom was more or less marked accordingto the quantity in which they were present. The steam process solved the problem with odor and appearance, but it did nothing to allay the hydroxyacid problem a s explained below (5). Of course. the taste of the oil when taken in no wav influrnrcs the taste of the eructations, and no matter how plemant the former may br madr, the latter will be quite dllfrrrnt.
We now know cod-liver oil a s a s o u m of vitamins A and D a s well a s the "trendy" 20:5 omega-3 pentaenoic acid (6). The Development of Stereochemishy and the Understanding of Molecular Structure This book was puhlished duringa very important time in the development of stereochemistry and the understandingof molecular structure in general. The Vortez Hypothesis These matters clearly wncerned Moiler. In a section titled "A Chat About Atoms" he reveals his belief in the socalled "vortex hypothesis", developed by Lord Kelvin (71, in which atoms are believed to be vortices in the universal ether (8). In and from this ether it is that the atoms have been formed by it having "once upon a time" been set in mtary motion; and once set rotatmg will always remain so, since rherr is no internal friction.The rotatingparta uftheether, or vortices, they are called, are, rfsmalv. the atnms, or, if linked. rhe molerules. A smoke ring, such& some tobacco smokers can produce to perfection, is an illustration of a gimple circular vortex atom.
Figure 1. Projection structures for propionic acid (a) and the enantiomers of lactic acid (band c) (taken from ref 1 , p 462). Although the Michelson-Morley experiment, which was finally published in 1887, was inconsistent with the existence of the ether, scientific adherents remained until the ~ublicationof Einstein's S ~ e c i a Theory l of Relativity in i905. Thus, Mtiller was nodoutside mainstream scientific thought in 1895. Screw-Theory In a section titled "Position of Atoms In Space", the author introduces the concept he terms "Screw-Theory" (9). Moller's knowledge of st&eochemistry appears to be sophisticated and up to date. However, he explains the optical rotation of plane-polarized light by enantiomers in the following manner. First he notes that because the central atom in propionic acid is "balanced", it has the structure seen in Firmre l a and no torque. In contrast, he describes the behavior ot'the two enantiomers of lactic acid (Figs. Ib and lc) as follows. But, when a hydroxyl, instead of one of the hydrogen atoms, is planted upon this carbon atom, the balance is disturbed,and the carbon atom thrown over to one side by the centrifugal force of the asdllating movement. It can do this by a turn on one of the ares by which it is connected with the two other carbons; but in doing so it will have to carry with it the carbon atom to which it is bound by the other azis, transforming thereby the ring form into that of a smew, and the molecule, now rushing through the ether, must assume a rotatory motion. The form of the screw will depend upon the side to which the hydroxyl is attached;fig. 1B represents a right-hand screw, which, revolving many hundred thousand times per second, will throw the plane of the polarized light that enters one end of the s a w over to the lefl hand of the soectator at the other end. In the same manner the light will hc thmwn over to the right from the strucrurr (fig. IC,, which forms pan of a worm of a left-hand screw. Determining the Source of Optical Activiiy
The Group C 4 4 As shown. Mtiller wsits that the minimum number of connected Grbons necessary for optical activity is 3 because this is the minimum backbone for forming a carbon
helix. Moller therefore differs from J. H. van't Hoff, the first Nobel Laureate in Chemistry, in requiring a C-C-C unit in addition to an asymmetric carbon as a minimum condition for optical activity. In support of this view, Moiler noted that no two-carbon or one-carbon compounds had ever been resolved or found to be optically active. I n this particular fact, Moller was correct; van% Hoff himself provides a summary that lists the known compounds that had been obtained optically active, begining with three-carbon molecules, four-carbon molecules, etc. However, he does not comment on the absence of one- and two-carbon compounds in this series (10). Indeed, Arnold Eiloart, the translator of the second English edition of The Arrangement ofAtoms in Space, adds the following translator's note (11): The verdict of observation, then, up to the present time, is that an asymmetric carbon alone is not suff~eientto cause optical activity,but that the presence ofthe group C.C.Cis essential.
Eiloart's reference for support of this argument is Moller's C h ~ r n ~ s t and r y Cod-Ltuer Oil! One wonders what van? HofF's reactlon was to this bit of editorial license. The First Optically Active One-Carbon Molecule It was not until 1914 that a one-carbon compound was finally optically resolved by William Jackson Pope and John Read at Cambridge University (12). The compound, cNoroiodomethanesulfonic acid (11, was resolved readily with "hydroxyhydrindamine" (2-amino-1-indanol, 2) and, with greater difficulty and cleverness, with the alkaloid brucine. (The authors noted that a n earlier claim for isolation of an optically active two-carbon cornpound was not supported by adequate scientific evidence (12)). Other Asymetric Substances Pope was a seminal figure in early 20th century stereochemistry. He was interested in learning the aspects of molecular structure responsible for optical activity, and he successfully resolved compounds having asymmetric N, P, S, Se, Si, and Sn atoms (13).Furthermore, he pioneered the exploration of centro-asymmetric substances, including derivatives of spiro compounds such a s 3, and he resolved 5,5'-spirohydantoin (4) (13).a compound lacking a formal asymmetric center. Pope and Read synthesized optically active 2-amino-lindanol(2) for the following reason (14). We possess no very powerful and optically active base which is easily obtainable and the salts of which exhibit a tendency tawards crystallizing well and toward being sparingly soluble.
Although Pasteur had resolved dl-tartaric acid by crystallizine salts of alkaloids (15). the aforementioned d~fficulty t k a t Pope and Read encountered with brucine illustrates their point. 2-Amino-1-indanol(2)was obtained through formation of the bromohydriu from indene, followed by reaction with ammonia (14). Interestingly, while the bromohydrin has trans stereochemistry (161, the nature of its conversion to the aminoalcohol is not obvious due to the possibility of neighboringVolume 70 Number 4 April 1993
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mvmN . H,
(+) - (1R.2S)
(-)-(I
2a
S.2R)
2b
group participation, particularly in the basic reaction medium. (See the following equation.) A published assign-
ment of cis and trans structures for 2 (17, 18) was subsequently corrected in 1970 (19). In 1971, all four stereoisomers of 2 were finally assigned absolute configurations (20). The specific rotations [ a ~ofl the hydrochlorides of dl-2 reported by Pope and Read (14) (f32.2 - 32.3') appear to best match the published values for the cis enantiomers 2a and 2b (f25') . . rather than the trans enantiomers (f13.4') (20). Pope and Read noted in their 1914 Daner that the o ~ t i cal~;~uresalts formed by combination if 1and 2 teni to mutarotate in alcohol or acetone solutions. Eleven years later, the problem was solved by Read, then Professor at the University of St. Andrews. who discovered that an epimerizationbf the methine hydrogen of 1occurred in the presence of either 2a or 2b to form a new eauilibrium mixture of diastereomeric salts (21, 22). A modem variant of this discovery has been used to convert a racemic substance with & epimerizahle proton into optically pure material through use of an optically active base. This technique is called d~racemization(23.24). Confessions of a Chemlcal Historian John Read continued his chemical studies at St. Andrew~,but he is probably best known today as a chemical historian. His two books, Prelude to Chemistry (25) and Humour and Humanism in Chemistry (26), are now classics.
quired the synthesis of methylethyl selenide, "a volatile and revolting liquid" (27). As a result, from the rooftop of the Universitv Chemical Laboratom ?. the demoralizingwhiffs afvapour swept down upon defenceless Cambridge ruifiine countless open-air tea parties celebrating - the Darwin~ktenary. Later Pope et al. brought their "thundering big stink" to the open country of the fens where they completed their work outdoors, disrupting nearby river traffic in the process. We also learn from Professor Read that the first public performance of any alchemical music (Count Michael Maier's alchemical "fugues")was accomplished on November 22,1935 by 'The Chymic Choir" of the University of St. Andrews (281, no doubt in harmony with the good professor. And what has become of "Screw-Theory"? Although interesting in 1895, it has since been consigned to the cod-liver barrel of chemical history. Literature Cited 1. MBler, F. P. CdLiuer Oil Md Chemistry;Peter MBUer, h d m , 1895 2. Ref I , p 1". 3. Apparently the same -pound was elsoealled "therapink stid" (see &me, P Or s a n k Chemistry, 4th English ed.; Elaevler: New Yark, 1950: p215.1 4. R e f l , ~ h . 5. Ref 1, p l e i . 6. Kindla, J. E. k f f d a and Fiah Oila in Human KooiNl ondDiaoia0; M m e l Dekker: New Yorh 1987. (We are msteful fa sn ananymove reviewer who w m sted . . noting these health aspeeta.1 7. I)lctionary of Scientifz Blapmphy, Vol. XIII, C. Selibnub Sons: New York. 1975; p
9. Ref I, pp 462412. 10, van% Hoff, J. H. T h e h n e m n J ofA&ms in S p e , 2nd ed., Eiloart, A. (banel.1; langmsnr, Green,and Company:landon, 1898. 11. Reflo, p 26. 12. Pap, W. J.; Read, J. J. Ckm. Soe 1814,105-I, 811. 13. Dictiomry ofSeiontifkBiagrqhy, Vol.XI; 0. Scribner's Som: New Yark, 1975; pp a"-0" UT"".
14. Pope, W J.; Read, J Chem Sm. 1812,101% 758. 15. Partington, J . R.AHi*ry ofChemisfry, Vol. 4; MacMiUan:l o d o n , 1964: p 754. 16. Suter, C. M.: MBne, H. B. J. Am. Chem. Sm. 1840,62,3473. 17. Rose". W. E.; Green, M. J. J. OF@C h . lW,28,2197. 18. Rose".~.W. E.: Dorfman. L.: Linfield. M. P. J Om. Chem. 1964.29, . . 1723. 19. Hueher, C. F.; Dmoghue, E. M.; NO"&, C. J.; D o h , L;Wenhert, E. J O g Chem 1910,36,1149. 20. Domhege. E. JustuaLiebig'allnn. Chem. 1911. 743,42. 21. Read, J.; MeMsth,A M.J. Chem. Soc 1926, 1572. 22. Eliel. E. L. S t e m h i s f r y of Carbon Compounds: MeCrsw-HilL New Ywk, 1962; pp 4243. 29. Duhame1,L. C.R. Amd. Sci. F'aris 1918,28X, 126. 24. Duhamel, L.;Duhamel.P:Launay. J. C.;Plaguevent.J.C.Buli. Sac. Chim. fi l W ,
..
t,d?l
More Unpalatable Contributions Read informs us that Pope's "replacement" of asymmetric sulfur by asymmetric selenium in a chiral molecule re-
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25. Read, J. PmIu& to Chemistry;MaeMillan:NewYork, 1937. 26. Read, J.Humour ondHumanism in Ckmisfry; O. Bell and S m Landm, 1947. 27. Ref26 pp 284-296. 28. Ref25, p iodii.
