No.1165.

DECEMBER 27, 1845.

LECTURESON

ORGANIC CHEMISTRY: DELIVERED DURING THE WINTER SESSION, 1844-45, IN THE

University of Giessen.BY JUSTUS LIEBIG, M.D., PH. D., F.R.S., M.R.I.A.

Professor of Chemistry in the University of Giessen.

BENZILIC ACID.-BROPiOBEtiZOIC ACID. - HIPPURIC ACID, ITSNATURE, PROPERTIES, AND SOURCES.-HIPPURATES.

GENTLEMEN,—I told you, towards the conclusion of my lastlecture, that the action of alkalies upon benzile converts thelatter substance into

BENZILIC ACID.

This remarkable acid may be produced by adding to a solutionof hydrate of potass in alcohol, a sufficient amount of benzile toleave but a very slight alkaline reaction in the fluid, boiling themixture subsequently, until a precipitate ceases to form in it,upon addition of water, and evaporating finally, to dryness inthe water-bath. The residue is a mixture of benzilate of potasswith free potass; it is to be left exposed to the atmosphere,to allow the free potass to absorb carbonic acid. When the wholeof the free potass is converted into carbonate, the mass is tobe reduced to powder, and the latter subsequently extractedwith alcohol, when the carbonate of potass will be left as ’’

a residue. The fluid is filtered off from the latter, and the ifiltrate subsequently decolored by means of animal charcoal,if necessary. The clear filtrate yields, upon subsequent eva-poration, colourless crystals of benzilate of potass. If thesolution of this salt be mixed with boiling hydrochloric acid,brilliant crystalline needles of Benzilic Acid will be depositedupon cooling.

Benzilic acid is with difficulty soluble in cold, but dissolves morereadily in hot water; it is inodorous, but possessed of an acidbitter taste.- It fuses at 2480; upon the application of a moreintense heat it turns red, and evolves carmine-red fumes, ex-haling, at the same time, a peculiar odour. Benzilic acid and thebenzilates manifest a characteristic deportment with concentratedsulphuric acid-viz., they impart to this acid a fine deep carmine-red tint, which disappears again upon diluting the mixture withwater.The analysis which I made of this acid led to the formula-

- C28 Hm Os + H 0and this formula was subsequently confirmed by Zinin’s analysisof several of the benzilates. This chemist analyzed (in the Giessenlaboratory) the benzilates of potass, lrad, and silver ; the twolatter salts are obtained as difficultly soluble precipitates, when asolution of benzilate of potass is mixed respectively with acetateof lead, or nitrate of silver.The composition of these salts is as follows :-

Benzilate of potass ............ C28 Hy?5 K 0" lead ............ C2" Ul 05 Pb 0" silver. ....... CI3 Hil 05 Hg 0

The mode of formation of benzilic acid is extremely simple ; twoequivalents of water are, by the action of the potass, made toaccede to the elements of benzile.

Jknzilic acid possesses a certain historical interest since it wasthe first acid which was found to be produced by the simple acces-sion of water to the elements of a neutral substance; severaltransformations of a similar kind have been observed since.We have still to examine, in this place, another compound

belonging to the stilbeiie series, and to which chemists haveassigned the inappropriate name of

BR0IIOBy·_B’ZOLC ACID.

This acid was first discovered by Peligot. It is produced whendry benzoate of silver is exposed to the vupour of bromine: thebest way of producing this acid is to place the dry benzoate of Isilver at the bottom of a glass vessel provided with a stopperor cap, in which a tube filled with bromine is suspended. Thefumes of bromine, which escape at the common temperature,are absorbed with avidity by the benzoate of silver; the decom-position may be considered completed as soon as red fumesbecome visible. INo. 1165.

Bromobenzoic acid and bromide of silver are formed in thisprocess: the former of these two substances is subsequently sepa-rated from the latter, by treating the whole mass with ether, andevaporating the etheric solution, when the new acid will separatein the form of a brown liquid, which speedily solidifies. To obtainthe bromobenzoic acid in a state of purity, it is subsequentlycombined with potass, the solution of the potass salt is decoloredby means of animal charcoal, and the pure acid finally sepa-rated by means of hydrochloric acid.

Pure bromobenzoic acid appears as a colourless crystallinemass, which fuses at 212°, and sublimes at 482°. It is insolublein water, but dissolves readily in alcohol and ether.The analysis of this acid has led to the empirical formula of-

(since one equivalent of bromobenzoic acid combines with twoequivalents of metallic oxide.)This formula explains the mode in which the new acid is

armed : two equivalents of oxide of silver yield up their oxygento the anhydrous benzoic acid, and are converted into bromide ofsilver, whilst, at the same time, one equivalent of the hydrogenof the benzoic acid is replaced by bromine.

Bromobenzoic acid, when expelled from its potass salt by astrong acid, assumes two equivalents of water, and forms thusthe crystallized acid. The rational formula of bromobenzoic acid]K nndonbtRdIv

and this acid is evidently a product derived from the same acidfrom which nitrostilbenic acid springs, and which is as yet un-known to us.

I will now briefly recapitulate the various substances whichmay be considered to form the stilbene series:-

IIIPPURIC ACID.

The examination of hippuric acid forms a natural sequel to

that of the benzoyle compounds, since this acid may be readilyconverted into benzoic acid, and was, for a length of time, lookedupon as benzolic acid. Hippuric acid occurs in the urine of allanimalsliving upon mixed food, and is present also in the urineof man, but is more particularly contained in a considerable pro-portion in the urine of the graminivora.To obtain hippuric acid, fresh urine of horses or of cows is

concentrated over a gentle fire, and (since hippuric acid does notexist in the urine in a free state, but in combination with a base,such as ammonia, soda, &c.,) subsequently mixed with hydro-chloric acid until it acquires a fee’L 13- acid re-action. The fluid

deposits, after the lapse of some time, crystals of impure hippuricacid. Great care must be taken in this process to prevent theebullition of the urine, since this would cause the conversion ofthe whole of the hippuric acid into benzoic acid. Putrid urinelikewise contains simply benzoic acid, instead of hippuric acid.The impure crystals are usually’ purified by transmitting chlorinegas through the boiling-hot solution, or by mixing the latter witha small portion of hydrochloric acid, and adding, subsequently,

2 c

690

chloride of lime, until the acid is obtained inodorous and colourless.Animal charcoal is retained with great pertinacity by hippuricacid, and is accordingly not well adapted to purify this acid. Avery excellent and economical way of effecting the purificationof hippuric acid, is to boil the impure crystals with milk oflime, to filter the solution, (which is now already, in a great mea-sure, freed from the contaminating colouring matter, &c.,) andto precipitate the filtrate subsequently with carbonate of potass;the carbonate of lime, which separates upon this, carries downthe last traces of impurities; the hippuric acid is then isolatedfrom the potass salt by means of hydrochloric acid, and finallyrecrystallized, when it may be looked upon as perfectly pure.

Hippuric acid crystallizes in long transparent quadrilateralprisms of a mixed acid and bitter taste. The action of heat con-verts these crystals into an oily liquid, which, upon cooling, re-solidifies to a crystalline mass. Hippuric acid, when subjectedto dry distillation, is decomposed; benzoic acid and benzoate ofammonia pass over, in conjunction with a brown oily liquid,

’’

which smells of Tonca beans, and contains, probably, benzonitrile,.(a product of the decomposition of benzoate of ammonia, whichyou will recollect from one of the preceding lectures.)

Hippuric acid is difficultly soluble in cold, but dissolves morereadily in hot water. It is soluble in alcohol, and likewise, al-though more sparingly, in ether.The analysis of hippuric acid led me to the formula-

CIs Hg N 06 = CIS Hs N Os + H 0which formula was subsequently confirmed by Peligot andDumas.The salts of hippuric acid have recently been investigated in

the Giessen laboratory by Schwarz.Hippuric acid forms with the alkalies, acid and neutral salts.Neutral hippurate of potass is produced by dissolving hippuric

acid in carbonate of potass. It forms crystalline, convolutedlaminse. These crystals are soluble in water and alcohol, andhave the following composition :-

The two atoms of water escape at 212°. -

Acid hippurate of pot ass is produced by dissolving an excess ofhippuric acid in carbonate of potass. It forms broad crystallinescales, shining like satin; their composition is expressed by theformula-

2 C18 H8 N O5 + H 0 + K 0 + 2 aq.Hippuric acid forms with ammonia an acid salt of analogous

composition with the acid potass salt. This acid ammoniacalsalt is invariably produced upon evaporating hippuric acid withammonia, even though the latter substance be present greatly inexcess. The acid hippurate of ammonia is soluble in water andalcohol, but very sparingly soluble in ether.

The compounds of hippuric acid with the alkaline earths areproduced by boiling the acid with an excess of the recently pre- I

-cipitated carbonates of the earths, and removing subsequently the Iexcess of the dissolved earths by transmitting a stream of car-bonic acid through the solution : all these compounds are solublein water, and crystallizable; they all contain one equivalent ofhippuric acid to one equivalent of metallic oxide. Their compo-sition differs simply inasmuch as the barytes salt contains oneequivalent of water, whilst the lime salt contains three, and thestrontia salt five equivalents of water.

The hippurates of the protoxide of cobalt and peroxide of nickelare likewise produced by treating the corresponding carbonates ofthe two oxides with hippuric acid. Both these salts are crystal-lizable, and contain five equivalents of water.

Hippurate of copper crystallizes spontaneously in small rhombicprisms, from a mixture of sulphate of copper with hippurate ofpotass. It contains three equivalents of water.

Compounds of hippuric acid with oxide of lead.-Upon mixingneutral acetate of lead with a cold solution of hippurate ofpotass, a white curdy precipitate is formed, which is difficultlysoluble in boiling water, and crystallizes from this solution uponcooling, in fine needles of silky lustre. The composition of thesecrystals is- -

C, H, N 0, Pb 0 + 2 aq.The hippurate of lead forms sometimes, also, large quadri-

lateral tabular crystals, which contain one atom of water morethan the needles. The water of crystallization escapes at 212°.

Hippurate of silver is produced by mixing solution of nitrate ofsilver with hippurate of potass; this salt separates likewise in theform of a curdy precipitate, which dissolves in a large portion ofwater, upon boiling, and crystallizes subsequently from this solu-tion in fine needles of silky lustre. Hippurate of silver is re-markable, inasmuch as it contains one equivalent of water ofcrystallization, which is rather unusual with salts of silver.

Hippuric acid combines likewise with oxide of ethyle.The investigation of formobenzoilic acid-which substance, you

will recollect, from one of the preceding lectures-has given rise toseveral investigations, having for their object the attainment of amore minute and correct insight into the constitution of hippuricacid. The latter acid was supposed to be of a binary composition,like formobenzoilic acid, and this supposition accordingly led tothestudy of the deportment which hippuric acid manifests with thosesame agents that had led to such important results in the case ofmandelic acid.

Pelouze was the first to enter upon the investigation of thissubject. This chemist boiled a solution of hippuric acid in con-junction with peroxide of manganese and dilute sulphuric acid ;a considerable amount of carbonic acid was evolved in this pro-cess, and the filtered fluid deposited, upon cooling, a copiousamount of crystals of benzoic acid, whilst sulphate of ammoniaremained in the solution. Pelouze interpreted the results of hisexperiment to this effect, that he looked upon hippuric acid as adoubly conjugate acid, consisting, in his opinion, of hydruret ofbenzoyle, formic acid, and hydrocyanic acid. According to thisview, hippuric acid might be looked upon as acid, to which theelements of one equivalent of hydrocyanic acid have acceded.

The benzoic acid produced from hippuric acid by oxidizingagents, would accordingly appear to be derived from the hydruretof benzoyle, whilst the carbonic acid which is evolved in the

process may be supposed to be furnished by the formic acidpartly pre-existing in the hippuric acid, and partly produced inconjunction with ammonia, from the hydrocyanic acid.

It is impossible to deny that this view of Pelouze has a certainprobability in its favour; however, even disregarding altogetherthe fact, that all endeavours of producing hippuric acid artificially,like formobenzoilic acid, have hitherto failed, it is certainly verystrange that an acid supposed to be formed by the combination oftwo simple acids, should, nevertheless, combine only with one equi-valent of base instead of acquiring the properties of a bibasicacid, as one would be naturally led to expect.

’ These reflections induced Dr. Fehling, who was at that timepursuing his chemical labours in the Giessen laboratory, to re-investigate the deportment of hippuric acid with oxidizing agents.He selected for this purpose, peroxide of lead, which affords thisdouble advantage, that its action is not too energetic, and that itmay readily be separated again.When hippuric acid is boiled with the brown peroxide of lead,

a portion of the acid forms hippurate of lead, whilst another por-tion is decomposed with evolution of carbonic acid. The hippuricacid is then to be separated from the oxide of lead, by cautiouslyadding sulphuric acid to the mixture ; the fluid is filtered off fromthe sulphate of lead, and the filtrate again heated with a freshportion of peroxide of lead, when hippurate of lead will again beformed, and a further quantity of hippuric acid will be decom-posed. The hippuric acid is now again separated from the hip-purate of lead, by means of sulphuric acid, and the whole processrepeated. In this manner the operator will finally succeed inobtaining a perfectly neutral fluid, free from the slightest ad-mixture of lead, and which, upon evaporation, yields white,spear-like crystals. The analysis of this substance led to the for-mula,

C14 II, N 0, = C,, Hs O2 N H2which is exactly the formula of benzamide: and the chemicaldeportment of these crystals is, in fact, exactly like that of ben-zamide, although they do not resemble the latter substance in ex-ternal appearance. These crystals are converted into benzoic acidand ammonia, when boiled in conjunction with acids or alka-l:es.

This experiment may lead us to assume the pre-existence ofbenzamide in hippuric acid, in the same manner as we con-sidered urea to pre-exist in uric acid, and as we looked upon uricacid as a compound of urea with an hypothetical acid, (urilic acid,)so in like manner, may hippuric acid be considered as a com-pound of benzamide with an acid, which latter is decomposed into

carbonic acid and water, by the action of the peroxide of lead,whilst the benzamide remains unaltered. Now what kind of acidis this hypothetical acid which is thus combined with benzamide ?

Let us subtract one equivalent of benzamide from the elementsof hippuric acid:

691

there will remain an acid of the formula

C4 H 0 H 0We have in organic chemistry two acids of this composition-

viz., fumaric acid and aconitic acid. Whether the one or theother of these two acids has in reality any share in the formationof hippuric acid, is a question which further investigationsmay perhaps decide ; it is not impossible but that the acidmight be discovered, were the requisite examinations madewith sufficiently large quantities of the urine of horses. I havealready told you, that putrid urine contains benzoic acid instead ofhippuric acid ; the investigation in question here, might perhapslikewise show the manner in which this transformation of thehippuric acid into benzoic acid takes place.The presence of hippuric acid was formerly supposed to be

confined to the urine of horses, cows, and the graminivora ingeneral; I found this acid, however, recently, in the urine of manwho lives upon mixed vegetable and animal diet; hippuric acidis contained in the urine of man in the same proportion as theuric acid, and you may easily convince yourselves of its presence,even though you make the experiment upon a comparativelysmall portion of fresh urine.For this purpose, you have simply to evaporate fresh urine, in

the water-bath, to the consistence of syrup, to add subsequentlyhydrochloric acid, and to agitate the mixture when cold with anequal volume of ether, in which menstruum the hippuric acid issoluble. The separation of the etheric solution from the rest of thefluid ensues, however, but very tardily, and with great difficulty,since the ether remains distributed in the frothy liquid. To remedythis inconvenience, add to the liquid about the twentieth part ofits volume of alcohol, when the froth will immediately disappear,and the fluid will separate into two layers, the lower of whichcontains alcohol, urea, and the soluble salts of the urine, whilstthe upper consists of the etheric solution of the hippuric acid ;you decant this upper layer by means of a syphon, and agitatethe decanted fluid with some water, which will at once removethe alcohol and the urea which still continues in admixture withthe hippuric acid. The thus purified etheric solution yields, uponevaporation, long prismatic crystals of hippuric acid, whichusually appear brown, but may be readily purified by recrystalli-zation, and treating with animal charcoal, or better still, withchloride of lime.The proportion of hippuric acid present in the urine of man in

a state of perfect health, is equal to that of the uric acid. Thereare many diseases, however, which increase the quantity of thehippuric acid considerably, so that its proportion, in someinstances, equals, or even exceeds, that in which it exists inthe urine of the horse. Dr. Pettenkofer has recently com-municated to me the case of a young girl, in the hospital atWurzburg, who was labouring under chorea, and whose urinecontained so large a proportion of hippuric acid as to enablehim to obtain it in some quantity. This abnormal amountof hippuric acid decreased subsequently, in proportion to thegradual improvement in the health of the patient, and theurine contained at last simply the normal quantity of hippuricacid.

It follows from the above account of the constitution of

hippuric acid, that this acid contains a benzoyle compound,and this has been further confirmed by some recent obser-vations, which have shown that hippuric acid may, in fact,be produced from a benzoyle compound in the animal

organism. Dr. Ure administered benzoic acid to a patient,in the supposition that this acid dissolves the sedimentsof urine, and more especially uric acid. Upon subsequentexamination of the urine, no benzoic acid was found, but acopious amount of hippuric acid instead. This transformation ofbenzoic acid into hippuric acid, by the animal organism, hasbeen subsequently confirmed by a great many chemists, andamong others by Mr. Garrod, in England, and by Dr. Keller, ofProfessor Wohler’s laboratory, and likewise in the Giessen la-boratory.

Dr. Keller took, in the evening, about half an ounce of benzoicacid, from which he did not suffer the slightest inconvenience,and which caused simply a slight nocturnal perspiration. In themorning urine, this benzoic acid was found in the form of hip-puric acid, which separated in crystals upon the addition ofhydrochloric acid to the evaporated urine. It has since beendiscovered that cinnamic acid (which is remarkable for the greatfacility with which it is converted into benzoic acid by oxygen)is likewise transformed in the animal organism into hippuricacid.

I The aliments which constitute the food of man contain nobenzoic acid, as far, at least, as the investigations which havehitherto been made on this subject enable us to judge: thisurine of the cow contains invariably a large proportion ofhippuric acid, no matter whether the animal be fed upon hay orupon beet-roots: now the investigations which have been madeof the constitution of beet-roots, tend to prove that this

vegetable contains no benzoic acid; it follows, accordingly, thatthis acid must be looked upon as a product of the organism,the elements of which are furnished by the non-nitrogenousaliments. It is obvious that these aliments must undergo a wholeseries of transformations, in consequence of which they assumeat last a constitution similar to that of benzoic acid, which latter,combining with a nitrogenous compound produced by the organ-ism, is finally converted into hippuric acid.The transformation of benzoic acid into hippuric acid in the

organism, seems to throw some light upon the manner in whichmany of the remedies derived from the vegetable kingdom,and which themselves are products of the vital process, effect thecure of abnormal states in the animal economy. Is it not highlyprobable that these remedies may, by their chemical constitution,be directly adapted to perform in the organism that part whichthe aliments have ceased to perform, owing to some organ orother refusing the co-operation which is necessary to convertthem into the appropriate form?

CONTRIBUTIONS TO CLINICAL MEDICINE.BY JOHN TAYLOR, M.D.,

PROFESSOR OF CLINICAL MEDICINE IN UNIVERSITY COLLEGE, ANDPHYSICIAN TO UNIVERSITY COLLEGE HOSPITAL, LONDON.

PERICARDITIS.

CASE 21.-A boy, aged 10, admitted, after several attacks of acuterheumatism, with great enlargement of the heart, and disease ofthe mitral valve. Subsequently there supervened acute pericar-ditis, double pneumonia, pleurisy of the right side, and slight rheu-matism in the knees. Death. Remarks. Signs of hypertrophyand mitral valve disease. Causes of wide diffusion of mitralmurmur, and of the jerking character of the pulse. Pericarditisrevealed only by the physical signs; temporary suspension of it.Chamcters of the friction sound atJirst uncertain; it existedwith, but was modified 6, M/’MM in the pericardium. Differencesbetween the dulness of hypert1’Ophy at, d of pericarditis. Vibra-tory tremor at the apex arising from valvul(t2- disease, and at thebase from pericarditis; it co-existed with serous effusion, andceased before the friction sound. Undulatory movement inde-pendent of adhesion of the pericardium, or of l!ffusion of serumwithin its cavity. Pain trifling and transient; complications;pneumonia ; its diagnosis absence ofpain and of expectoration.Sympathetic phenomena. Ortliopnwa independent of pericardialeMS/OM. Latent pleurisy. (Edema and albuminuria withoutrenal disease. Causes. Rheumatic pericarditis and pneumonia,with very trifling affection of the limbs. Treatment. Apprecia-tion of the effects qf calomel.

«’ILLIAM H-, aged ten, admitted Wednesday, May 7th, 1845.A somewhat puny boy, of sanguine temperament and fair com-plexion ; accustomed to go to school; always had plenty of goodfood and clothing. His mother died in January last, at the ageof twenty-eight, of disease of the heart. Has never enjoyed verygood health. Has had several severe attacks of acute rheumatism,accompanied by palpitations of the heart; the last occurredtwelve months ago, and confined him to bed for a month. Hehas been getting much thinner since the death of his mother inJanuary. ,

For the last three months has complained of pains in the limbs,and shortness of breath, especially felt when at play, or whengoing np stairs. Three weeks ago he had pain in the right sideof the chest, followed, after two or three days, by pain in the leftside, and between the shoulders; he was also troubled with acough, and palpitations of the heart. On May 5th, he was takento the Burton-Crescent Dispensary, and was ordered by Dr.Stewart six leeches over the heart, and some aperient medicine.On the 6th, he was seen by Dr. Ballard, who sent him to thehospital on the 7th. Has not been confined to bed.On admission, impulse of the heart very strong, heaving, and

felt over a much larger space than natural. A vibratory tremoris felt by the hand applied over the heart. Dulness on percussionover a large space ; superiorly, it is complete as high as the fourthrib on the left side, and incomplete up to the third rib. Thereis a loud, prolonged, bellows murmur with the systole of theheart ; its greatest intensity is over the apex ; it is very loud at