UREA IN THE HISTORY OF ORGANIC CHEMISTRY Isolation from Natural Sources FREDERICK KURZER and PHYLLIS M. SANDERSON Royal Free Hospital School of Medicine, London, England
INTRODUCTION
There can be but few textbooks of organic chemistry, however elementary, which fail to stress the significance and importance of Wohler's synthesis of urea. This great discovery is fittingly regarded to mark the beginning of organic chemistry as we know it today. Although Wohler's achievement naturally overshadows other aspects of the story of urea, an examination of the history of this simple substance is most rewarding in many other connections, for few other organic compounds, if indeed any, reflect more closely the development of organic chemistry from its earliest beginnings than does urea. Tracing its record, we are guided past some of the highlights of scientific endeavor, from the age of iatrochemistry to present-day organic technology. Moreover, a study of the early literature, published in more leisurely days, affords us the pleasure of glimpsing something of the personality of the authors whose excitement, hopes, and disappointments enlivened their writings to a degree unknown and impossible today. Although the significance of Wohler's synthesis of urea has been the subject of numerous studies and appreciations (see, for example, (I-6)),a more detailed consideration of the history of urea has received comparatively little attention. The only comprehensive account available appears to be the excellent though brief history written by Chattaway (6) nearly 50 years ago. Since then, much further material concerning the earlier literature has come to light. The present study, compiled from the primary sources, is intended to review concisely the role of urea in the history of organic chemistry. THE IATROCHEMICAL PERIOD
discovery of the process of isolating phosphorus from urine about the year 1670 bears witness of the extensive work that must have been carried out on urine in the age of alchemy and iatrochemistry. But for its solubility, urea might well have been discovered in those very early days (compare Chattaway (6)). As it is, the beginnings of the story of urea, though not its isolation, are to be found in the iatrochemical age, more than three centuries ago. This eporh, founded by the teachings of Paracelsus (1493-1541), marked the fusion of the entire contemporary chemical and medical art. Chemistry, having proved itself a valuable helpmate to the physician by providing many useful remedies, came to be regarded as the very basis of medicine. Van Helmont (1577-1644), one of the first exponents of this doctrine, realized (7) the importance of a knowledge of the composition of the hody fluids for prescribing remedies. Being still imbued xrith religious, supernatural, and alchemistic ideas, Van Helmont a t times wrote rather obscurely, but, upon examination of urine he undoubtedly recognized the presence of a "salt of urine, that never occurs outside man's body and which is bred in the course of digestion from a substance not a salt. . . . It differs from seasalt [i. e., sodium chloride], also present in urine, by remaining unchanged in its course through the hody and on putrefaction of urine." Besides the difference in taste, Van Helmont observed a difference in crystalline form: "The sea-salt in its cooling, adheres to a wooden vessel even while it is separated from saltpeter, hut the salt, of urine grows together in the bottom of the liquor." Lastly the salt of urine, unlike sea salt, is volatile and may, therefore, he separated from it "by fire and flight." Thus early in the seventeenth century the uresence in urine of an unnsnal animal substance, salt-like (presumably because crystalline) and yet differentfrom sea salt, was at least sensed. ~
The curiosity and interest aroused by the functions and constituents of the living body is as universal as it is timeless. I t is reflected i n the alchemists' search for the elixir of life and the scope of their armory, which ineluded all manner of materials of animal origin, such as dried blood, bones, and urine. Their experiments dealing with these and other substances, however misdirected and unorganized, were hound to accumulate a useful store of empirical chemical experience. The
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EARLIEST WORK
The first isolation of urea from urine in 1773, if only in a very impure state, has persistently been attributed to Rouelle le cadet (8). As pointed out by Backer (9) in 1943, however, credit for this discovery is unquestionably due t,o Herman Boerhaave (1668-1738) who
VOLUME 33, NO. 9, SEPTEMBER, 1956
some time before 1727 prepared urea (or its addition compound with sodium chloride) from urine. There is every indication that Boerhaave's specimen was in fact. purer than the one described by Rouelle more that 50 years later, or th?t obtained by Fourcroy and Vauquelin during their first researches in 1799 (10) (see below). A description of this discovery is to be found in Boerhaave's (11) celebrated "Elementa Chemiae" published in 1732. This book is based on the course of lectures delivered by Boerhaave while professor of chemistry and botany a t Leyden between 1704 and 1729 and was written, much against his will after his retirement from this post, in order t,o disclaim any knowledge of a spurious mork "full of false notions, absurdities, and barbarisms" published by his st,udents and appearing under his name in 1727. I t is pertinent to our story that this "pirated" edition of 1727, however unsatisfactory in the true author's eyes, contains practically the same account on the isolation and properties of urea as the genuine textbook of 1732, thus clearly dating the discovery sometime before 1727. Although the exact date cannot now be determined with certainty, the researches on urea may well have been completed a good many years earlier, for Boerhaave states in his preface that "those (experiments) which are now contained in this work are what I made in public many years ago,and this I think proper to mention lest anybody should suspect I borrowed them elsewhere without making mention of the author's name." I n view of the very limited knowledge and simple practical techniques a t his disposal, Boerhaave's experimental skill, acute observations, and deductions therefrom are truly remarkable. His procedure for isolating urea, which he called "the native salt of urine" (sal nativus urinae), is rlearly detailed in his mork (12) and can be follo~r-edwit,hont difficultyby the modern reader (cf. Figure 2). I n another section of his book (18) dealing with animal fluids Boerhaave discusses some properties of his "native salt of urine." He stressed its difference from the mineral salts ingested by animals, which pass unchanged through their system. Unlike "fixed salts," it volatilized, though only above the temperature of boiling water; it proved neither acidic nor alkaline, but was converted to an alka.li on putrefaction. In Boerhaave's experience, it seemed to resemble sal amm o n i a ~most closely, but was clearly distinct t,herefrom (18). In short, after a great many experiments made on purpose to determine the true nature of this animal salt, ar it really exists in sound bodies and acts there by its own peculiar virtue, it appears to be of a.mild disposition; possessing a.sapponacious quality from an oil that is united with it; heing a kind of middle salt, hetween a fixt and volatile one; having not the least mark either of an alkali or an acid; heing easilg, however, resolvable into a volatile foetid oil and a volatile alkaline salt and hence very much disposed to putrefaction. Nor let anyone be here led into a mistake by the 6x1 aalt, whioh is produced from the %shesof the urine when hurnt in the b e ; for this is nothing else hut the sea-sdt, that was first taken into the body, which is able to beer dl the
actions and powers of the animal machine, without suffering any alteration in its nature.
The fact that half a century or more elapsed before Boerhasve's findings were independently rediscovered speaks eloquently for his outstanding genius as a chemical experimenter. Yet the modesty of this great man is evident from his clear and plaiu style, uot often cultivated by his lesser contemporaries, while his humility shines through almost every line of the preface to his "Elementa," of which the following are typical passages: "Nothing was formerly further from my thoughts than that I should trouble the world with anything in chemistry. There are so many hooks already upon this subject and many of them wrote so well, that it is hardly possible for me, either to represent things in a better light, or to offer anything that has not been said before"; and again, "But to detain my Reader no longer, please to accept this performance, such as it is, in a favourable manner, excuse the trouble I by this means give you, and impute the liberty I take of appearing in print upon this subject, to the very good reception the spurious copy, which mas vorse, met with from the Public." In establishing Boerhaave's prior claim to the discovery of urea, Backer and De Jonge (9) went so far as to confirm experimentally that his technique is in fact, capable of yielding urea from urine. They n.ere able to show that, after treatment with charcoal (a refinement which had admittedly not. been a t Boerhaave's disposal), urine afforded appreciable quantities of pure urea or its addition compound with sodium chloride, depending on the mode of evaporation. I t is remark-
Figure 1.
A Lecture by Herman Baerhnoue
JOURNAL OF CHEMICAL EDUCATION
P R 0 C E S S XCVIIL Tk Native Salt of Urinr. APPARATUS.
T A K , E fome very f i c b wcll-concoficd Urine o f perlanr in pcrfrLt H n l r h , put apnfcnrly inroa w r y clcan VcKcl, and wirh an equable Hc~ro f za, dc. grm, cvaporaic ir till you hrvc rcduc'd ir ro the conliffcnee of frtlh Cram, m d whilfl i t conriwcr rhur hot flrrin ir through a Bag, that rhc tcnariaurOil may in lome mrrfuic be rcrain'd rhcrc, and leprrared from it ; and rhc m o w rccvrarrly this ir donc, the bcrrer. Pur r lnrgc quantity o f rhis r h t k infpir. ;ind Liquor inio e wll cylindrical glals Vcrcl, wirh a papcr tied over ir, and lrr ir ltind quirt in a cool placc for the fpsre of a Yew. .By this means, t k n , yo* will hrvc a tolid. Ihrrlf, Ilb-pellucid, brown, faline MAIS, fir'd all r b o a riie borrom of rhe Venil; and over rllir r thick, black, pinguious L i quid, f c p ~ n r c d m d iiirfied n; ir ncr; fiom rlie concrircd Salr. Dccm rhia Liquor, r r l : ~aor i1.e Inlinc hlrfs, pur i t ihio rnorhcr Vcfil, pour Iome "cry cold W m r upon ir, md h k e ir about to free it from irroily Impuririrr, whicb may be donc pmry ~ % B l y , n i t will not readily dillblvs in cold WAW. Keep chin lrline M m r r under irr proprr tide. lfrhir is dillblvcd in hot Wlrcr, 2nd Rrnind rill rhe Lixivirm becomes exceeding limpid, and wrporarcd co a Pcllicle in a "cry clcrn glrls Vcfil, then, if you rtr ir by in n cold place, ic will lhnor into l r l w Glrbcr of r pmiculrr kiod, rtiar are perf&ly diRinfi from wcry oihir Salr In
