UREA IN THE HISTORY OF ORGANIC
CHEMISTRY
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 begin-
ning of organic chemistry as we know it today. Al-
though 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 com-
pounds, if indeed any, reflect more closely the develop-
ment 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 tech-
nology. Moreover, a study of the early literature,
published in more leisurely days, affords us the pleas-
ure of glimpsing something of the personality of the
authors whose excitement, hopes, and disappointments
enlivened their writings to a degree unknown and im-
possible today.
Although the significance of Wohler's synthesis of
urea has been the subject of numerous studies and ap-
preciations (see, for example, (I-6)),a more detailed
consideration of the history of urea has received com-
paratively 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
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 in-
eluded all manner of materials of animal origin, such as
dried blood, bones, and urine. Their experiments deal-
ing with these and other substances, however mis-
directed and unorganized, were hound to accumulate a
useful store of empirical chemical experience. The
Isolation from Natural Sources
FREDERICK KURZER and
PHYLLIS M. SANDERSON
Royal Free Hospital School of Medicine,
London, England
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 solu-
bility, 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 re-
ligious, supernatural, and alchemistic ideas, Van Hel-
mont a t times wrote rather obscurely, but, upon ex-
amination of urine he undoubtedly recognized the pres-
ence 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 sea-
salt [i. e., sodium chloride], also present in urine, by re-
maining 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 cen-
tury the uresence in urine of an unnsnal animal sub-
~ ~~~ ~ ~~ ~ ~ ~~ ~
stance, salt-like (presumably because crystalline) and
yet differentfrom sea salt, was at least sensed.
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 unques-
tionably due t,o Herman Boerhaave (1668-1738) who
VOLUME 33, NO. 9, SEPTEMBER, 1956

some time before 1727 prepared urea (or its addition actions and powers of the animal machine, without suffering any
compound with sodium chloride) from urine. There is alteration in its nature.
every indication that Boerhaave's specimen was in fact. The fact that half a century or more elapsed before
purer than the one described by Rouelle more that 50 Boerhasve's findings were independently rediscovered
years later, or th?t obtained by Fourcroy and Vauque- speaks eloquently for his outstanding genius as a
lin during their first researches in 1799 (10) (see be- chemical experimenter. Yet the modesty of this great
low). man is evident from his clear and plaiu style, uot often
A description of this discovery is to be found in cultivated by his lesser contemporaries, while his
Boerhaave's (11) celebrated "Elementa Chemiae" humility shines through almost every line of the preface
published in 1732. This book is based on the course of to his "Elementa," of which the following are typical
lectures delivered by Boerhaave while professor of passages: "Nothing was formerly further from my
chemistry and botany a t Leyden between 1704 and thoughts than that I should trouble the world with any-
1729 and was written, much against his will after his thing in chemistry. There are so many hooks already
retirement from this post, in order t,o disclaim any upon this subject and many of them wrote so well, that
knowledge of a spurious mork "full of false notions, it is hardly possible for me, either to represent things in
absurdities, and barbarisms" published by his st,udents a better light, or to offer anything that has not been
and appearing under his name in 1727. I t is pertinent said before"; and again, "But to detain my Reader no
to our story that this "pirated" edition of 1727, how- longer, please to accept this performance, such as it is,
ever unsatisfactory in the true author's eyes, contains in a favourable manner, excuse the trouble I by this
practically the same account on the isolation and prop- means give you, and impute the liberty I take of ap-
erties of urea as the genuine textbook of 1732, thus pearing in print upon this subject, to the very good
clearly dating the discovery sometime before 1727. reception the spurious copy, which mas vorse, met with
Although the exact date cannot now be determined from the Public."
with certainty, the researches on urea may well have In establishing Boerhaave's prior claim to the dis-
been completed a good many years earlier, for Boer- covery of urea, Backer and De Jonge (9) went so far as
haave states in his preface that "those (experiments) to confirm experimentally that his technique is in fact,
which are now contained in this work are what I made in capable of yielding urea from urine. They n.ere able
public many years ago,and this I think proper to men- to show that, after treatment with charcoal (a refine-
tion lest anybody should suspect I borrowed them else- ment which had admittedly not. been a t Boerhaave's
where without making mention of the author's name." disposal), urine afforded appreciable quantities of pure
I n view of the very limited knowledge and simple urea or its addition compound with sodium chloride,
practical techniques a t his disposal, Boerhaave's ex- depending on the mode of evaporation. I t is remark-
perimental 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 ani-
mal fluids Boerhaave discusses some properties of his
"native salt of urine." He stressed its difference from
the mineral salts ingested by animals, which pass un-
changed 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 am-
m o n i a ~most closely, but was clearly distinct t,here-
from (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 dis-
posed 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 Figure 1. A Lecture by Herman Baerhnoue

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 <heir figure, and ididiry, howrvcr, rhcy come prerry nor
ro lhc Cryfldr of Sugar. There arc no1 feud, nor alcalinc, bur very volarilc.
This is the nsrivc Salr of Urinr.
able that onz century after Boerhaave's discovery,
Berzelius ( 1 4 had considered it impossible to obtain
crystalline urea from urine by evaporation because of
its alleged association xith lactic acid in this fluid.
The loss t o chemical literature for over 200 years of
Boerhaave's discovery may be due partly to the claim of
Fourcroy and Vauquelin, made many years later in
their famous monographs on urea (10,15) (see below), to
have vainly searched the old records for previous con-
tributions to this subject. Although they refer with
admiration to the "illustre professeur de Leyde," they
obviously overlooked the appropriate sections of his
writings.
Researches concerning urine appeared from time to
time throughout the early eighteenth century. Borel-
li (16), Lemery (l?'), Geoffroy (IS), Hellot (19), and,
above all, Margraff (20) and Scheele (21) published
papers on this subject, but their interest was mainly
focused on the mineral salts present, particularly the
phosphates from which phosphorus had originally been
obtained, and on uric acid (Scheele's "lithic acid") in
view of its connection with the formation of stones in
the urinary organs. It mas, however, not until the end
of the century that the time was ripe for the redis-
covery of urea. An examination of the contemporary
"abstract literature," comprising such periodicals as
Nicholson's (later Thomson's) Annals of Philosophy
(22), issued in London; Scherer's (later Gehlen's)
Journal (25), published on the Continent; and, above
all, Berzelius' celebrated Annual Reports (241, clearly
shows the trend of chemical researches of this time.
In addition to the steady progress in mineral chemistry
and much careful work of a quantitative nature, which
mas beginning to place chemical theory on a firm foot-
ing, an increasing volume of research concerned itself
with vegetable and animal chemistry. Improved tech-
nique, sounder ideas, and better facilities enabled
chemists, many of whom incidentally, had entered
chemistry after obtaining pharmaceutical or medical
degrees, to turn their attention t o those fascinating
JOURNAL OF CHEMICAL EDUCATION
substances contained in living matter that mere be-
lieved to owe their existence to the agency of an indis-
pensable though mysterious "vital force." Although
no one dared hope to imitate Nature's ways by pro-
ducing such compounds in the laboratory by purely
rhcmical means, savants were busily engaged with
varying success in extracting, purifying, and examining
all manner of products of vegetable and animal origin.
That urea should be rediscovered and extensively stud-
ied in this period was a natural consequence of this gen-
eral turn in the development of chemical science.
I n a paper published by Rouelle le cadet (8) in No-
vember, 1773, the isolation from urine of what was un-
doubtedly an impure specimen of urea is described.
Hilaire Marin Rouelle (1718-79) was the youngest, and
a brother of the more celebrated Guillaume Franpois
Rouelle (1703-70) who was the eldest, of a family of 12
children, born of farming people living at Mathieu, a
village near Caen. The brothers ~ ~ o r k etogether
d in
Paris for many years, Hilaire succeeding eventually to
the post of Demonstrator a t the Jardin du Roi on his
brother's retirement due to ill health in 1768. Little is
known of Rouelle le jeune except that,, unlike his very
spectacular brother (&, $61, he was a quiet unassuming
man. I n his memoir entitled"0bservations on Human
Urine and Its Comparison with the Urine of a Cow and
a Horse" (8), he described the extraction of an impure
specimen of urea, forming the alcohol-soluble portion
of the evaporated urine residue. He referred to it as
the "saponaceous ext,ract of urine (matidre savonneuse),"
in contrast to the alcohol-insoluble matidre eztrae-
tive. The former, he noted, was present in far
greater abundance and crystallized like salts, but at-
tracted moisture and was therefore difficult to obtain
solid. On heating, it yielded much more than half its
weight of ammonia, a little oil, and sal ammoniac.
He regarded this matidre savonneuse as the end
product of the numerous chemical changes of the nu-
tritive vegetable matter during digestion and circula-
tion in the body. Though not the first to isolate urea,
Rouelle le cadet may justly be credited XI-ithits first, if
imperfect, "analysis" and proof of its high nitrogen con-
tent.
About 20 years later, a significant. improvement in
the isolation of urea from urine, namely its precipita-
tion as the sparingly soluble crystalline nitrate, mas in-
dependently discovered by W. Cruickshank (27) in
England, and Fourcroy and Vauquelin (28) in France.
William Cruickshank,' who was appointed surgeon in
the Royal Artillery in 1794 and chemist to the Ordnance
Department in 1804, was collaborating at the time with
the Surgeon-Gencral, Dr. Rollo, at the Royal Artillery
Hospital at Woolwich, London. The results of their
joint study of the disease diabetes mellitus mere pub-
lished in Rollo's book "Cases of the Diabetes Mellitus"
'William Cruickshank, the author of a numher of papers on
chemical subjects, has o f t e n been confused w-ith William Cum-
herland Cnlick8hank, F.R.S., (1745-1800) r h o worked with
William Hunter in his Great Windmill Streat Srhool of Anatomy.
London
VOLUME 33, NO. 9, SEPTEMBER, 1956
(87), in the preface of which the author credits Cruick-
shank mith all the chemical work that had been carried
out. This included the chemical examination of the
urine of the patients under Rollo's care and the dis-
covery of urea nitrate, described in the text (27) as fol-
lows:
Treated with t v o or three times its weight of nitric acid, the
animal extractive matter affords its weight of shining scales re-
sembling acid of borax, their figure being apparently that of Hat
~.homhoids. .. . although they evaporated in white amok" when
exposed to a moderate heat, yet when more strongly ignited
they burned with a reddish flame and a kind of detonation simi-
lar to the nitrate of ammonis.
FOURCROY AND VAUQUELIN'S RESEARCHES
At about the same time, Fourcroy and Vauqnelin
(28) referred to the white shining cryst,als t,hat are pre-
cipitated most unexpectedly on addition of nitric acid
to the alcoholic extract of urine evaporated to t,h? con-
sistency of a sirup. On heating, the crystals melted,
swelled up, and yielded much oil and ammonis, lcaving
practically no residue. Fourcroy and Vauquelin were
puzzled that an "animal substance" should combine
with an acid, forming with it a crystalline body as if a
base, yet behaving quite unlike a base in all other re-
spects. Neither the British nor the French investi-
gators, however, reconverted the nitrate to urea.
During the next few years, Fourcroy and Vauquelin,
two of the leading scientist,^ in the field of animal
chemistry, subjected the chief urinary constituent to
the most exhaustive and detailed study. I t is ohvious
from their early writings that the material used in their
initial investigations mas far from pure, but they suc-
ceeded in establishing correctly the more obvious prop-
erties of this substance. The accuracy and value of
their findings increased as their technique of isolating
urea was improved.
I n their paper of 1798 (15) full analyses of fresh and
putrefied urine emphasized the change in composition
accompanying fermentation. Urea was referred to as
"the special urinary constituent," present in greatest
abundance, mhich causes urine, evaporated to a sirup,
to crystallize, and yield crystals on addition of nitric
acid. I t was still incorrect,ly regarded to give urine its
characteristic odor, color, taste, and ability to undergo
spontaneous change into ammonia and carbon dioxide.
Fourcroy and Vauquelin also remarked on the power of
urea of reversing the crystalline form (from cubic to
octahedral and vice versa) of sodium chloride and am-
monium chloride, respectively. A similar observation
had in fact been made as early as 1783 by Rome
de 1'Isle (89) who recorded the formation of octahedral
sodium chloride in the presence of urine without, how-
ever, tracing t,his change to any particular constituent
of urine. The clue which had led Rome de 1'Isle to this
discovery was his acquaintance mith Rouelle, as is ob-
vious from the following passage (89) takeq, from his
hook:
A solution of sea-salt left to evaporate spontaneously in the
laboratory of M. Rouelle, examined sfter 5 years, had formed
hoth at the surface of thc liquid and at the bottom of the vessel,
octahedral crystals an regular as those of alum. I have kept
some of his er,vstsls as specimens in my oollect,ion. Thcre is
reason to believe that this ~oa-szltcemo from txines mod by XI.
Iior~ellefor extraction oi microcosmic d t ; for, on pouring fresh
nt.ine into a solution of very pure scit-salt, this salt, instead of
assuming the cubic form that it had before, el~\rstallisesin octs-
Iredra as regular as those of alum, without, hoivever, undwgoing
any rhange in taste or in its other properticc.
Figure 3. The Royal A r t i l l e r y Hospital, Woolwish. The Scene a%
C r u i c k s h a n k ' s Activities a t the Time of His Discovery of Ure. Nitrate
In their paper of 1799, Fourcroy and Vauquelin (10)
detailed their method of isolating the "special urinary
constituent," which they considered to he a substance
of such importance t o the animal economy to warrant
special designation. They thcrefore proposed the
name "uri?el' which mould readily call to mind the an-
atomical structures a.nd physiological functions as-
sociated with the fluid from which it was derived.
Fourcroy and Vauquelin's method of isolating urea
mas still essentially the same as that used by Rouelle,
and their product was probably no purer than such
early preparations. Fresh urine mas evaporated to a
sirup, mhich on cooling set to a crystalline mass;
treatment with alcohol, in vhich the mineral salts were
insoluble, gave an extract which was concentrated to a
sirupy liquor. On cooling, this deposited a hromnish-
yellow crystalline solid consisting of impure urea.
Owing to the presence of impurities, the detailed de-
scription of the action on urea of heat, water, acids,
alkalies, and chlorine is inaccurate. However, among
the wealth of descriptive detail important facts begin
t o emerge, including the formation of ammonium carho-
nate on heating urea; its hydrolysis to ammonium car-
bonate by water, dilute acids, and particularly, strong
alkalies; and finally, t,he slow, though incomplete oxi-
dation of urea by chlorine into equal volumes of nitro-
gen and carbon dioxide.
Much progress had been made hy 1808 when Four-
croy and Vauquelin (SO) were able to describe the prep-
aration and properties of much purer urea. This mas
obtained by being first isolated as the sparingly soluble
nitrate from which free urea was liberated, in aqueous
456
solut,ion, by neutralization mith potassium carbonate.
Evaporation to dryness followed by extraction of the
residue xith alcohol a t 10" effected separation of the
urea from the potassium nitrate. The product, which
separated on careful evaporation of the alcoholic solu-
tion, consisted of hard transparent square plates or
prisms, or quadrilateral leaves, "with a tast,e resem-
bling fresh nuts," and left scarcely any trace of residue
on ignition. An account of this important work pres-
ent,ly found its way into Thenard's "Treatise of
Chemistry" (Sf). A re-zxamination of the action of
heat on urea now gave more precise results than had
been recorded by the same authors eight years before.
I n addit,ion to t,he formation of ammonium carbonate,
they observed (SO) a distinct crust-like sublimate con-
sisting of a sparingly solnble weak acid (cyanuric acid).
Fourcroy and Vauquelin regarded this as uric acid, a
very understandable error, as Wohler (32) rema.rked,
considering the state of knowledge a t the time. The
French workers also observed that distillation of uric
acid afforded besides ammonium carbonate a sublimate
very like nrea from its form, color, fresh taste, solu-
bility iu water, and, above all, its precipit.ation from
solution by nit,ric acid. Although they were unable to
prove their views ronrlusively, their results mere fully
confirmed by Wohler (52) some 20 years later. Four-
croy and Vauqnelin are therefore t,he first to have ob-
tained nrea by a purely chemical reaction. if only from
anot,her compound of animal origin.
ANALYSIS OF UREA
Fourcroy and Vauquelin's procedure of isolating urea
mas shortly aft,erwards further improved by Prout (3.9)
who was probably the first to prepare the compound in
the pnre state. William Prout, F.R.S., though best
known for his hypothesis concerning t,he atomic
I In a thesis, presented to the Faculty of M e d i m e of the
II
I British contemporary.
figure 4. william proat (1785-1850)
JOURNAL O F CHEMICAL EDUCATION
meights of the elements, carried out numerous iuvesti-
gations of a pioneer character in physiological chem-
istry. After neutralizing the nitric acid of urea nitrate
with potassium rarbonate, Prout allowed the potas-
sium nitrate to crystallize out and thus it could be re-
moved. The nrea filtrat,es mere then purified mith :I
large quantity of charcoal and gently evaporated to dry-
ness, t,he residue mtracted with boiling alcohol in the
usual way, and the product finally recrystallized two or
three times from thc same solvent. Since in his pub-
lication Pront claims t,o have made his results public in
lectures three years before, the date of the first isolation
of pure urea may he taken as 1814.
Prout. sholred that his pnre urea was not decomposed
by boiling water. I t romhined wit,h a number of metal-
lib oxides, the grayish rompound with silver oxide det-
onating on ignit,ion. Like nit,rir arid, oxalic acid
afforded a sparingly soluble crystalline salt, later e n -
ployed by Berzelius (54) as yet another convenient,
means of isolat,ing urea from urine. But the most re-
markable part of Prout's work mas his astonishingly
arcurat,e analysis; he obtained a percentage composi-
tion of urea almost ident,ical mith that calculated from
its formula (cf. Table 1). Pront performed the com-
hust,ions using copper oxide a s the oxidizing agent.
He emphasized the need for the great,est rare in measur-
ing t,he water formed and nit.rogen evolved, and for this
purpose made his onm plat,inum weights and calibrated
the graduat,ions of his nit,rometer. He paid great at-
tention t,o the removal of moist,ure, drying all substances
in a vacuum over sulfuric arid before use in the an-
alysis.
In 1817, a successful analysis of an organic compound
was naturally an achievement of a high order. That,
reliable result,s were not always the rule is sho\vn by a
passage in the xvritings of t,he great Berzelius, whose
obvious impatience a t the state of affairs is reflect,ed in
the following observations:
There is often, in organic analysis, a tempt,ation to base ral-
culations on imperfect experiments. If such calculations are later
confirmed by those u-ho have made greater efforta to obtain
trustworthy results, one can claim to have fird performed this
determination; if not confirmed, :t mmll crtw is soon forgotten
(3.5).
Prout's results are exrellent, judged by any stand-
ards, and could hardly be bettered by skilled sperialists
working with modern equipment today. His &and-
ard as an experimenter is further appreriat,ed by a
comparison of his results I\-ith t,hose of BBrard ($61,
published about the same t,ime (see also Thenard (37)).
University of Montpdlier, BBrard had set out to cxtend
-
the knowledize of animal rhemistrv. hv " analvz~nc
" several
of the most important animal substanres, inrlnding
urea and urir arid. Like Prout, he employed Gay-
Lussac's method of completely oxidizing the organic
eompound with copper oxide; in arruracy, horwver,
his results (rf. Table 1) fell rather short of those of his
Prout (35) also analyzed urea nitrate: he believed
VOLUME 33, NO. 9, SEPTEMBER, 1956
that a knowledge of its compositiou might prove useful
clinically in estimating urea in given specimens of
urine as the spariugly soluble nitrate. He first deter-
mined the amount of calcium carbouate dissolved by
the nitric acid from a known weight of urea nitrate,
and confirmed his findings by establishing the weight of
urea uitrate formed from a given quautity of urea. Ex-
perimeuts of this uature could naturally not be ex-
pected to provide very exa.ct figures (see Table 2). It
is perhaps a little curious that an experimenter of
Prout's caliber should choose to give results in such a
case to two decimal places.
Brief reference is pertinent at this point to an early
attempt to analyze urea. I11 their extensive studies,
Fourcroy and Vauquelin (10) bad carried out quantita-
tive thermal decompositions of urea and endeavored to
calculate its composition from the amouuts of ammonia,
carbon dioxide, and water (all of knowu composition)
\\.hi141f ~ r n i ~f hdr i~lfinit,r(~
I . O I I S ~ ~ufI Ithe
~ I pynJ.vsis
I~S
produrts. 'l'his ili~dcquntr ttvl~niquc? ttewsjitlitinr:
cumbersome calculatio~~s and somewhat arbitrary cor-
rections to allow for the presence of impurities gave
figures for the perceutage composition that were in-
evitably highly inaccurate. Even so, they enabled
Fourcroy aud Vauquelin to express the opinion that
urea is the most nitrogeneous of all animal substances.
I n 1820, Proust (SS), famous for his discovery and de-
fense of the law of constaut proportions and for much
brilliant work in all branches of chemical science, sub-
stituted lead for potassium carbonate iu the isolation-
process of urea. It appears that he was unaware of
Prout's work, in spite of the appearauce of its French
tramlation in the important Annales (SS), since be
refers only to Fourcroy aud Vauquelin's earlier papers.
He attributed the deliquesceut uature of their product
to its contaminatiou mith salts (sodium chloride, and
the acetate, bensoate, and chloride of ammonia);
these tend to dissolve during the alcoholic extraction if
the solvent is heated too strongly or is not perfectly
dry. A brown resinous substance contained in urine
is also partially alcohol soluble and hence liable to con-
tamiuate the urea. According t o Proust, lead car-
bonate has a strong affinity for this resinous material
and is therefore particularly suitable for its removal.
Proust accordingly warmed aqueous urea nitrate with
lead carbonate until effervescence ceased; most of the
lead nitrate was then removed after filtration and
partial evaporatiou of the filtrate, the last traces of lead
being eliminated mith hydrogen sulfide. The usual
treatment then afforded pure colorless crystals of
urea.
I n 1829, Heury (39) was charged with the task of pro-
ducing larger quantities of urea for the Hospital of St.
Antoine, Paris, for testing its value as a therapeutic
agent against diabetes, a purpose for which needless to
say, it proved unsuccessful. Thus far all methods of
isolating urea from urine had heen based on its direct
separation, either free or as a sparingly soluble salt, the
other constituents remaining behind in the filtrates.
Henry (39) on the other hand, solved the problem by
TABLE 1
Composition of Urea
Prerwsl
Foaveroy and Bd~ard Pmul end Dumas
V a u q ~ ~ e l i(10)
n (3fi. 37)* ($3) (43) Cnlculaled
" T h e figures quoted have been recelculated from Bhrd'e
original data. The percentages given by this investigator were
incorrect because of erroneous equivalent weights used in the
original cnlc~llxtions.
precipitatiug all other constituents with basic lead
acetate, leaving urea in the filtrate from vhich it was
readily obtained by the usual methods. Berzelius (34),
who cousidered urea oxalate to he the most convenient
intermediate affording purest urea, qnestioned Henry's
claim of having obtained superior yields by his method,
but couceded that it afforded urea most cheaply on the
large scale. This aspert assumed importance as urea
began to find favor as a diuretic (34).
Notwithstanding the diversity of published methods
of isolating urea from urine and the minute directions
given in almost every paper, Wohler (58) was still able
in 1829 to add the fruits of his experience to the general
store of knowledge. It is iuteresting to note that
in this investigation, concerned mith the thermal de-
romposition of urea and published well after his urea
synthesis, Wohler chose to isolate his starting material
from urine. Recognizing the complete destrnrtion of
urea caused by nitrous acid, he stressed the need of us-
ing nitric acid free from nitrous acid in the preparation
of ura nitrate. He employed barium rarbouate to
liberate free urea therefrom, and emphasized the im-
portance of extracting the evaporated salt mixture with
alcohol a t ordinary temperatures even though this re-
quired much more solvent, since in the presence of
urea a good deal of mineral salt appeared to pass into
the alcohol at its boiling point. I n iuvestigating the
pyrolysis of urea, Wohler was the first to note its melt-
ing point, but reported it to lie near 120'. From the
context it is clear, however, that this physical property
of urea was observed only incidentally; it was ob-
viously not yet the general practice to determine melt-
ing points accurately as a criterion of the purity of or-
ganic compounds.
UREA AND CHEMICAL PHYSIOLOGY
The period which witnessed the progress made in the
isolation of urea and the study of its chemical prop-
erties also saw the first contributions to the knowledge
TABLE 2
Comoosition of Urea Nitrate (Pmut (33))
Found Calndaled
Ures 52.63 48.70
Nitric acid 47.37 51.20
458 JOURNAL OF CHEMICAL EDUCATION

of its function in the living body. This was of course first pure specimen in 1817. At the same time, there is
not surprising in view of the medical background, al- already discernible that ever increasing momentum, so
ready alluded to, of many of the chemical investigators familiar to us today, with which science progresses. The
of those times. Already before the end of the eight- few and modest memoirs published before 1800 are fol-
eenth century, nrea and uric acid, the chief organic eon- lowed, after the turn of the century, by a mounting nnm-
stituents of nrine, were suspected to be the end products ber of researches of rapidly increasing accuracy and sci-
of nitrogen metabolism (8). The chemical study of entific value. Reading these early papers, we cannot
these compounds and their concentration in the body fail t o admire the genius and perseverance of those
fluids was considered of the highest consequence to the early men of science whose work provided such a firm
progress of both physiology and medicine. This view, foundation for their successors. Presently, in little
together with repeated admonitions to practicing doc- more than a decade, urea was destined to play a part in
tors to pay more heed t o chemical discoveries, was ex- the history of science that marked the birth of modern
pressed with increasing emphasis in the successive organic chemistry.
memoirs of Fourcroy and Vanquelin and in the writings
of many of their contemporaries. ACKNOWLEDGMENT
BBrard (867, after analyzing many animal sub- I t is a pleasure to acknowledge t,he courtesy and nn-
stances, was of the opinion that "since urea a,nd uric failing help given a t all times by the staffs of the
acid are the most azotised of all animal substances, the Libraries of the British Museum, the Royal Society,
secretion of urine appears to have for its object the the Chemical Society, the Royal Colleges of Physicians
separation of the excess azote from the blood." This and Surgeons, and the Wellcome Historical Medical
vas born out by repeated observations that the urea Library and Museum, all of London, England.
content of urine appeared to he directly related to the
protein (and hence nitrogen) content of the diet. LITERATURE CITED
Cantau (do), for example, demonstrated the presence (1) CAMP~IGNE, E., J. CHEM.EDUC.,32, 403 (1955).
of urea in the excrements of carnivorous birds al- (2) HOFMANN, A. W., Ber., 15, 3127 (1882).
t,hough urea is normally absent from those of the (3) MCKIE,D., Nature, 153, 608 (1944).
(4) WALDEN, P., Natwwi~senschaften,16, 835 (1928).
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leopards, and panthers, remarked on the unusually (7) VAN HELMONT, J. B., "Van Helmont's Works," translated
high urea content,, often reaching 13 per cent. One into English by J. CHANDLER, London, 1664.
(8) ROUELLE, H. (LECADET), J. m a . L y n , 40,451 (1773).
cannot help but observe that scientists were eer- (9) BACKER, H. J., Ned. Tfjdsehr.Geneesk., 1943, 1274.
tainly no less venturesome in the choice of the subject (10) FOURCROY, A. F. DE, AND L. N. VAUQUELIN, Ann. rhim.
for t,heir investigations 120 years ago than they are (Paris), 32,80 (1799).
t,oday. That urea resnks from the oxidative degrada- (11) BOERHAAVE, H., "Elementa Chemisre quse Anniversario
tion of proteins was finally proved, in uitro, by BB- Labore Doeuit, m Pubhcis, ete." (with the author's
autograph), Leyden, 1732.
c.hamp (42) in 185G. He succeeded in isolating urea by (12) BoERHAAYE, V d . 11, pp. 317-8 (Process 98). BOERHAAYE,
oxidizing egg albumin, serum albumin, blood fibrin, "Elementa Chemiae," English translation by T. DAI.-
and glntin with potassium permanganate, provided LOWE, Vol. 11, London, 1735, p. 220 (Process 98).
that the medium was kept neutral or only faintly alka- BOERHAAVE, "Elements. Chemiae," Spurious Work,
English translation by P. SHAWAND E. CHAMBERS,
line, a condition that was essential to prevent the de- London, 1727, p. 193 (Process 87).
struction of the urea as it was formed. 113) BOERHAAVE. "Elementa Chemiae auae Anniversario Lahore
In 1822, Pr6vost and Dumas (45) demonstrated the Docuit, id Publicis, etc.," Vol. I; pp. 66-7. BOERHAAVE,
presence of nrea in the blood; their careful proof of its "Elements. Chemiae," English translation by DALMWE,
identity with urea from nrine included an elementary (14) BERZELIUS,Vol. I, p. 42.
J. J., "Lehrhuch der Chemie," Vol. 9, 1840,
analysis of their specimen (for results, cf. Table 1). p. 435.
By a comparison of the composition of the blood of (15) F ~ U R C R AND O Y VAUQUELIN, Mdmires de l'lnstitul Nationale
dogs, eats, and rabbits before and after nephrectomy, des Sciences,
.- ~ - 4 , 363 (1803); Ann. ehim. (Paris), 31, 48
they concluded that the kidneys are organs whose fune- (1798).
BORELLI,L'hista're et des mdmoires de L'Aeademie des
tion, like that of the skin, is purely to provide an elim- Sciences, T . 2,51(1688).
inating surface, a theory earlier put forward by Rollo L E ~ R YN., , L'hiatoire et des mdmolres de 1'Academie de
(27). The exact site of the formation of nrea was still Sciences, Mdm., 1707, 22, 33, 35; L'histoiw et des m4m-
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GEOFFROY, E. F., L'histoil-e et de8 mbmoires de L'Aeademie
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indication that the liver is involved in its formation. HELLOT,J., L'histoire et des mhoircs de I'Aeademie drs
Scienees, Mdm., 1737, 342.
CONCLUSION MARGRAFF, A. S., L'histoire et des mdmmres de L'Academie des
The early history of urea provides a vivid impression Sciences, Hist., 1751, 142.
SCHEELE, C. W., "The Chemical Essays of Charles William
of the slow and difficultbeginnings of chemical science: Scheele, Translated from the Transactions of the Acad-
the best part of a century elapsed between the first iso- emy of Science, Stockholm," by T. BEDDOES,London,
lat,ion of urea and the preparation and analysis of the 1786.
VOLUME 33, NO. 9, SEPTEMBER, 1956 459

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(39) HENRY(FILS),J . de P h a m e i e , 15, 161 (1829).
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