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T H E JOURNAL OF I N D U S T R I A L A N D EiYGIiVEERING C H E J I I S T R Y .
which, as tests show, becomes more pronounced in the presence of moisture. 7 . Carbon dioxide from the air, while i t may aid in seasoning, is not essential, as shown b y several series of tests. 8. That increasing the fineness of any particular sample of unsound cement improves its quality in this respect. 9. With the toregoing data, it appears that the theory of free lime as the sole cause of unsoundness is not well founded. I O . Expansion may be due principally to physical strains in the coarser particles. 1 1 . Any theory of expansion on a purely physical basis seems inadequate, inasmuch as pats may frequently remain in boiling water several hours or more before destructive expansion becomes manifest. If i t were merely the different rates of expansion, one would expect the rupture to take place shortly after the boiling begins. 12. With the data in hand a t present, a possible theory presents itself as follows: Seasoning of a n unsound cement consists of decrepitation of the coarser particles, caused by or accelerated b y heat and moisture, and that the moisture need not be in sufficient quantities to hydrate the free lime, but merely t o render the coarser particles sufficiently fine t o permit hydration before the set has taken place. 13. Le Chatelier claimed tri-calcium silicate to be the essential constituent of Portland cement and free lime as the agent destructive to soundness. Unger obtained vitrified tri-calcium silicate which disintegrated (seasoned), yet hardened well, while a fused tri-calcium silcate was unsound. This would indicate t h a t if free lime is present in Portland cement, it is in the glassy unground particles. 14. 0. Schott denied the existence of tricalcium silicates, tri-calcium aluminates, and tri-calcium ferrites in Portland cement, yet fused mixtures of these compositions showed the characteristic destructive phenomena found in unsound cements and which he attributed t o free lime. 1 5 . Michaelis claimed burning a t too high temperatures produced unsound cements. Microscopic examinations of clinkers show a different physical structure of that from a rotary kiln and that burned at lower temperatures. The contradictory results obtained by investigators, both of synthetical mixtures and actual clinker, seem to be due t o different degrees of fusion. 16. Shepherd and Rankin have demonstrated the existence of calcium tri-silicate, but the real cause of expansion is yet not conclusively proven. 17. What is needed now, in addition t o the excellent work of the authorities herein mentioned and others unmentioned, is an investigation which will link together our knowledge on purely theoretical constitution of Portland cement clinker and the chemical and physical constitution of a commercial Portland cement, and further show what changes take place in passing from a n unsound to a sound state.
May, 1 9 1 2
THE CHEMISTRY O F ANAESTHETICS, 1V: CHLOROFORM. By CHARLESRASKERVILLEA S D W. A. HAMOR. Received December 13, 1911.
(Continued from the A p r i l No.) 2. T H E
CHAKGES
UNDERGOES
WHICH
WHEN
A
AN.IESTHETIC CURRENT
OF
CHLOROFORM OXYGEN
IS
COKDUCTED THROUGH IT.
Among the anaesthetic mixtures, the combination of Chloroform vapor with oxygen was used shortly after the introduction of chloroform as an anaesthetic, and it has recently been reintroduced into practice by Neudorfer, Kreutzmann, and others. I t is stated b y anaesthetists that oxygen does not antagonize the action of chloroform on the heart or nerve centers, but that it protects the patient from the dangers which result when chloroform is administered while his blood is in a condition of undue venosity' and that it prevents any intercurrent asphyxial condition. Gwathmey has stated positively' that oxygen increases the value of all inhalation anaesthetics as regards life. I t has been maintained, however, that chloroform undergoes alteration in this procedure. Falks attempted t o demonstrate that the passage of oxygen through chloroform4 produces chemical changes in the anaesthetic. He reported that after the passage of oxygen for 2 0 minutes, changes could be recognized in the residual chloroform, in some cases hydrochloric acid and in others an acid with reducing properties5 having been recognized. The quantities produced were found t o be greater the higher the temperature and degree oE illumination. This work is partially contradicted b y the clinical results obtained b y anaesthetists, and b y the observations of Willcox and Collingwood6 on the administration of oxygen bubbled through absolute alcohol.7 In order to determine whether the passage of a current of oxygen through anaesthetic chloroform results in the decomposition of the anaesthetic, 4 ounces of chloroform containing 0 . 7 0 per cent. b y volume of absolute alcohol and 0.035 per cent. by volume of water, but otherwise pure, were placed in the chloroform container of the Gwathmey anaesthetic apparatus (Fig. I ) , and a slow stream of oxygen was conducted through the chloroform for ten and one-half hours, a t the end of which time 3 / / , ounce of chloroform remained. The experiment was conducted under the usual conditions obtaining during administration by the Gwathmey method, b y electric light and a t an average temperature of z o o C. The residue, upon examination, gave the following results: Buxton, Araesthefics, 4th ed., p. 299. Medical Record, October 8th, 1910, p. 616. "On Chloroform-Oxygen Narcosis," see also Ziegncr, Miinch. M e d . Wochenschr., 67, 2585 : and Guarini, Sci. Am.. 90, 24. 3 Deut. M e d . W o c h . , 1902, 862. 4 The purity of this was not described, b u t it was evidently of the grade specified by the German Pharmacopoeia. I Acetic acid, resulting from the oxidation of the alcohol in the chloroform used (?). 8 Brit. M e d . J . , Nov. 5th. 1910. 7 Willcox and Collingwood stated t h a t the administration of oxygen bubbled through absolute alcohol is a marked cardiac stimulant. It is especially important t o note t h a t they found the administration pleasant and non-irritating t o the patient-that it causes no ill-effects t o the lungs or bodily system. 1
2
.
May,
1912
Aldehyde. Sone.
T H E JOURAYAL OF I.VDCISTRIAL A N D E N G I N E E R I N G C H E M I S T R Y . Acidity. Acetic acid present.
Hydrochloric acid. Sulphuric acid test. None. S o free Pronounced reaction. chlorine. Faint reaction for odorous decomposition products and chlorinated decomposition compounds,
Oxygen was then passed through 4 ounces of chloroform containing 0.56 per cent. by volume of absolute alcohol and 0.03 per cent. b y volume of water, b u t otherwise pure, for three and one-half hours, after which time 2 ounces of chloroform remained. The intensity of illumination and temperature conditions were identical with those of the preceding experiment. The chloroform residue contained no free chlorine or hydrogen dioxide; no hydrochloric acid or carbonyl chloride; no acetaldehyde; b u t it showed the following changes: Acetic acid: 0.00045 gram in I O O cc. A marked response with sulphuric acid, intensified on the addition of formalin. Although a faint reaction for chlorinated decomposition products was obtained, the reaction with sulphuric acid was attributed to oxidation products of the alcohol present.
These experiments showed t h a t when chloroform of the present pharmacopoeial strength and purity
363
ounces of chloroform had passed through the water, the experiment was discontinued. The examination of the residue and condensed chloroform showed the following: Acidity (acetic acid): Chloroform used. ..................... Residue in contai Condensed chloro
none. 0.00015 g. in 100 cc,
none.
Sulphuric acid test: Chloroform used. ..................... Residue in container ....... Condensed chloroform
negative. marked reaction. negative.
Therefore, it was concluded t h a t the oxidation products of alcohol are not carried over when the chloroform-oxygen stream is conducted through water, and t h a t these are concentrated in the residue. This applies, of course, only when the conditions usually followed in practice are observed. 3.
T H E DECOMPOSITION O F CHLOROFORM V A P O R UPON E X P O S U R E TO GAS LIGHT, ETC., DURING ADMINIS-
t. a,
TRATION.
The occurrence of untoward symptoms during the administration of chloroform in rooms in which gas is burning,' or where there are other varieties of naked flames,S or strong electric light,^ has been frequently reported; consequently, it has been urged t h a t surgical operations be not performed by gaslight.4 As t o just what products are formed, there is a difference of opinion. Itersons considered t h a t there occurred a combination of the chloroform vapor with the combustion gases, whereas Hartmann6 and Waddelow7 observed an odor of chlorine, Von Langenbeck considered t h a t " chlorocarbonic acid " was formed, and Breaudat found hydrochloric acid and an acrid oil. At all events, when a mixture of chloroform vapor and air is decomposed b y a flame, irritating compounds are formed.s 4. T H E
EFFECT
OF
AGITATIOh-
UPON
ANAESTHETIC
CHLOROFORM.
FIG.1.
is administered in conjunction with oxygen, no decomposition of the chloroform occurs, and t h a t the oxidation of the alcohol present would not give rise to products which mould affect the results of anaesthesis, provided the vapors are passed through water which absorbs the oxidation products. The results obtained also support the views previously expressed with regard t o the oxidation of anaesthetic chloroform. I n order t o ascertain whether the oxidation products of alcohol are removed b y passage through water' and whether any oxidation products responding to the test with sulphuric acid are carried over b y the vapor of the chloroform, the following experiment was performed: Oxygen was passed through 3 1 / ~ounces of chloroform containing I per cent. of 9 j per cent. alcohol, but otherwise pure, for four and one-half hours, the oxygen-chloroform vapor being conducted through four ounces of water kept a t 2 0 ' C. The resulting chloroform vapor was condensed, and after 13/( 1 Such a procedure is followed when the Gwathmey apparatus is used in practice.
Tunnicliffes concludes
t h a t when chloroform is
One of the earliest references to the decomposition of chloroform by exposed flames is in the China Med. Missionary J . . Dec., 1888, 160. Iterson, Fischer, and Zweifel drew attention t o this decomposition in 1889. and in t h a t year Patterson narrated personal experiences (Pracfifioner,42, 418). See also, Lancet. March 12th, 1898; Bzrminqham .ited. Rev., August, 1892; but especially, Schumburg, Apoth.-Ztg., 13. 7 5 8 ; Gerlinger, Ibid., 17, 314; and Eisenlohr and Fermi, Ber., 1892, 5 8 5 . Soubeiran and Liebig had observed t h a t a mixture of chloroform and alcohol. in equal measures. burns with a smoky flame and pungent odor. According t o Ramsay and Young (Jahresber., 1886, 628). the vapor of chloroform, when passed through a red-hot tube, yields hexachlorbenzene (CoCI,), perchlorethane (C2Cle). and some perchlorqthylenc (C,CL). Lob (2. Elekfrochsm., 7, 903) reported t h a t when a wire was heated t o redness by an electric current in the vapor of boiling chloroform, hydrochloric acid and tetrachlorethylene were the principal products of decomposition a t comparatively low temperatures, hexachlorbenzene and hexachlorethane and chlorine appearing also a t higher temperatures. The tetrachlorethylene is probably formed by polymerization of dichlormethylene, the primary product of the pyropenetic decomposition. 2 Oil lamps and candles (Waddelow, Pharm. J . , 141 6 , 324). 3 Buxton (Anaesfhefks,1907, p. 180) states that he observed that chloroform decomposes when a powerful electric lamp is held over the inhaler. Cf. Schoorl and Van den Berg, Pharm. Weekblad, 43, 47, who show that air is necessary for such decomposition. E . 0 . . by Von Langenbeck (see Pharm. Z t g . . April 6 , 1889, 221). 5 Ibid. 6 Ibid. 7 LOG.cit. See also, Wardleworth, Pharm. J . , 141 14, 376. 8 Lancet, 1899, i, 1728; Therap. Gaz., 1899, 601: Breaudat's Dict. Physiologie. Cf. Rags ky, J . p r a k f . Chem., 48, 170. 9 J . Roy. A r m y Med. Corps, 2 , No. 4, 459. 1
T H E J O U R N A L OF I N D U S T R I A L A N D EKGIlYEERIA-G C H E M I S T R Y .
364
initially pure, except for added alcohol, it remains free from “ pharmacological deterioration ” under the ordinary conditions of military transport, providing that the bottles are kept closely stoppered and protected from strong light. The authors subjected unopened, brown glass bottles of the following anaesthetic chldroforms to intermittent agitation for 206 hours in a Spiegelberg shaking apparatus, in such a way that considerable mechanical shock was imparted to the chloroform: I . A three-ounce bottle of chloroform manufactured from acetone, containing 0.5 per cent. by volume of absolute alcohol and 0 . 0 2 5 per cent. by volume of water, but otherwise pure and of full pharmacopoeial grade. 2 . A two-ounce bottle of chloroform manufactured from acetone, containing 0.8 per cent. by volume of absolute alcohol and 0 . 0 5 per cent. by volume of water, but containing a trace of extractive matter from the cork stopper. 3. A two-ounce bottle of chloroform containing 0.97 per cent. by volume of absolute alcohol and about 0.05 per cent. of water. but otherwise pure. 4. A two-ounce bottle of chloroform manufactured from acetone, containing 0 . 7 per cent. by volume of absolute alcohol and about 0.04 per cent. of water, but otherwise pure. All of these samples were well stoppered and were, in every respect, identical with chloroform as i t is supplied to the trade. The samples numbered 2 , 3, and 4 contained more air space than No. I , this being especially marked in the case of Nos. 3 and 4. When the samples were examined after agitation for 206 hours, the following results were obtained: Hydrochloric acid Odorous or chlorides: , decomchlorine and position hydrogen Sulphuric products. Sample. Acidity. dioxide. acid test. None Pronounced 1. . . None reaction 2. .. . ‘‘ Pronounced reaction 3. 0.00045 g. “ Decided reacetic in action‘ 100 cc. 4. 0.0004 g. “ Marked reaction? acetic in 100 cc.
.. . . . . . . . .. . .
Chlorinated decomposition compounds. Very faint reaction None Faint r e action
From these experiments, the following conclusions were drawn: I. When anaesthetic chloroform is subjected to agitation accompanied by mechanical shock, the alcohol present undergoes oxidation, the extent of this being dependent upon the amount of air present, the nature of the agitation, especially its violence and length, and the light exposure. The above experiments were all made in daylight a t 2 0 ’ C. 2 . Impurities decomposable by sulphuric acid are formed under such conditions, these resulting both from oxidation of the alcohol and, when unprotected cork stoppers are used, from the extraction of resinous 1 The cork stopperzof this container was capped with tin, hence no extraction could occur. 2 As in l.
May, 1912
matters from the stopper or luting. “Chlorinated decomposition compounds ” may form, although we are inclined to attribute the response had for their presence to oxidation products of alcohol in this case. Since these conclusions apply to anaesthetic chloroform of the present United States Pharmacopoeia degree of purity and strength, care should be exercised when such chloroform is shipped for considerable distances, or is kept a t sea, that a minimum amount of air is present; in case glass-stoppered bottles are not used, that the cork stopper is capped to prevent extraction and shrinkage ; and that the succussion to which chloroform is likely to be subjected, is neither of an intense nor protracted nature.1 5. T H E P R E S E R V A T I O N O F C H L O R O F O R M . ( a ) Preservation with Alcohol. As early as 1857 i t was pointed out b p Squibba that an addition of alcohol to chloroform was the best means of preventing decomposition ; i t appears that the practice, one which he considered of importance, originated with him some years previously. Squibb observed that chloroform of the density above 1.497 had a marked tendency to decompose, and that the decomposition became inevitable above 1.498. Therefore, he suggested reduction in specific gravity to 1.49 or a t least 1.494, by the addition of ethyl alcohol. Later3 Squibb stated that his experience was that “pure” chloroform to which 0.625 per cent.. of alcohol had been added might be kept for ten years in groundstoppered bottles of amber glass without a trace of decomposition. In 1863, David Brown, of the British firm of J . F. Macfarlan & Co., finding that samples of chloroform which rapidly decomposed were invariably of the density 1.50, while those which kept well were of slightly lower density, suspected that the small proportion of alcohol present in the last-mentioned was the cause of the preservation. Ever since this time, it has been the British custom to reduce chloroform to the density 1.497 or thereabout, which procedure, it has been maintained,4 has given satisfaction and is a necessary one. Shortly after the observations of Brown, Maisch,s after a series of experiments on the action of light on chloroform, arrived a t the following conclusions: In order to preserve “pure” chloroform of the specific gravity 1.49, it should be kept totally excluded from the light; and to keep chloroform in the daylight, it should be reduced in specific gravity by the addition of about two fluidrachms of 95 per cent. alcohol to one avoirdupois pound of chloroform of the density 1 See P a r t 6 of this section, where the Storage of chloroform is discussed. Further reference to the subject of extraction will be made when the T e s t wzth Sulphuric Acid is referred to. 2 Paper read before the hTew York Academy of Medicine in that year: see Ani. Med. iifmzth., July, 1857. a EQhemerir, 4, 1431. 4 Fee Dott, Pharm. J . . [3] 16, i03. Also, Clark, Ibid., [3] 12, 740. Symes and Mason (Ibzd.. 8, 893) also testified t h a t small quantities of alcohol considerably enhance the keeping qualities of chloroform. Brown (Ibid. 26, 865) was of the opinion that the specific gravity of chloroform should not be under 1.497 a t I S o C. Such chloroform contains 0.25 per cent. of alcohol and, according to Brown, if kept out of the sunlight and otherwise properly stored, may be kept many years. 6 Proc. A m . Pharm. Assn., 1867.
M a y , 1911
T H E JOL-RA17,4LOF I S D L * S T R I A L A S D En’GIA\7EERIAYG C H E J I I S T R Y .
1.492. Maisch found that when chloroform had been reduced in specific gravity t3 1.475 or less, the presence of several drops of water in the bottle would not induce the liberation of “chlorine” after an exposure of two weelis in direct sunlight. He considered t h a t this amount of alcohol (about forty drops in one fluid ounce) would not be objectionable when the chloroform was used a s an anaesthetic. The preservation of chloroform with ethyl alcohol has also been insisted upon b y German. and French2 authorities. I n fact, it may be said that the addition of alcohol, in amounts varying from 0 . 2 j-1.00 per cent., has been generally favored and that such a n addition is universally practiced.3 The amounts of alcohol stated as permissible in the various official chloroforms intended for anaesthetic purposes are as follows: Belgium, . . . . . . . . . . . . . . . . Denmark. ....................
...
................
1 . O per cent. 1 . O per cent. 0,005 part by weight.
. . . . . . . . . . . . . . . . 0 , sper cent. Sweden . . . . . . . . . . . . . . . . . . . . . . 0.5-1.0 per cent. . . . . . . . . 1 , O per cent. absolute. Switzerland. . . . . . . . . . 0.6-1 . O per cent. Cnited States
The B r i t i s h Pharmacopoeia does not define the quantity of alcohol permitted, b u t specifies t h a t the chloroform be worked t o the density 1.490-1.495.4 The amounts allowed in the anaesthetic chloroforms of countries other than those mentioned above, may be determined from the specified densities;s thus, in Holland and Russia, a mere trace of alcohol is permitted at the outside limit.6 However, it should be mentioned that, although thk addition of small amounts of alcohol to chloroform has been pharmaceutically recognized as necessary, several have expressed a negative opinion.’ 1 Hager (Year-Book of Pharm., 1870, 119) recommended the addition of 0.75-1.0 per cent. of alcohol, and stated t h a t it served as a preservative for any definite period. According t o Schact and Biltz (Pharm. J . , 1895, 1005). an addition of alcohol amounting t o one part in four hundred of chloroform ( 0 . 2 5 per cent.) is sufficient to prevent recognizable decomposition for one month or longer: with double miit amount (0.5 per cent.). decomposition is prevented for nearly a year; and with 1 per cent. for many years. \Ve may say, however, t h a t these are only average statements, liable to variation in both directions, according t o the effects produced by the varying intensity of light, and only being applicable t o chlorofonn properly stored and contained in bottles having a minimum amount o f air present. 2 Regnauld ( J . Pharm. Chim., [SI 10) foond t h a t alcohols have a preservative action on chloroform, toluol being m m t effective. Behal and Francois [J. Pharm. Chim., 6 , 417 (1897)l considered t h a t the addition of a small amount of alcohol as a preservative should be permitted. 3 I n this connection, see Brztish Pharn~acogoeia, 1886, 109; Jolles. Chem. Ztg., 11. 786. 4 In 1878, British manufacturers reduced the chloroform of density 1.597-1.500 by the addition of about 1 per cent. of absolute alcohol. The Bvitzsh Pharmacogoeia of this time allowed chloroform of the density 1.49, thereby admitting the addition or presence of such a n amount of alcohol as some claimed would be prejudicial t o administration. The United States P / ~ a r n a c p ~ o e zallowed a chloroform of the density 1.480, and, as a result, the American chloroform was regarded b y some as adulterated and quantities were imported a t this time. 6 See Table I1 under Sgecific Grazity. 8 .Is a matter of fact, however, the anaesthetic chloroform used in these countries contains a t least 0.25 per cent. of absolute alcohol, according t o our determinations of the density and quantitative cstimations of the alcohol present. 7 Du Bois-Reymond (Sci. A m . Sugpl.. No. 839. P. 13413) considered t h a t alcohol was of no use when impurities were present and was unnecessary when the chloroform was pure. Helbing and Passmore (Hdbinq’s Pharm. Record, March. 1892) concluded from the few experiments which they made on the decomposing influence of sunlight, t h a t the value of the addition
365
MialheI even regarded the presence of absolute alcohol in chloroform as deleterious. The authors haye demonstrated in Part I of this section that ethyl alcohol retards the decomposition of pure chloroform and t h a t pure chloroform readily decomposes into Oxidation products of a deleterious nature-in fact, it becomes toxic---unless so preserved. Those who hold a contrary opinion have evidently failed to conduct experiments under conditions con-, ducivp t o oxidation and have misunderstood the function of alcohol, as well as other preservatives, in the oxidation process. The value of having pure anaesthetic chloroforni for use and the importance of its proper storage cannot be gainsaid-in fact, these conditions are conceded as necessary ones by those who have had occasion t o inquire into the changes which chloroform undergoes when carelessly stored or kept for long periods; but we are convinced t h a t the presence of pure alcohol in pure chloroform is both a precaution and a necessity, and t h a t small amounts of alcohol in no way interfere with the physiological action of chloroform.
( b ) Presertiative Agents Other thaw Alcohol. Inorganic Preservatives.--BoettgerZ found t h a t chloroform which had undergone decomposition by exposure t o sunlight might be purified b y agitation with sodium hydroxide, and stated that when chloroform was placed in contact with sodium hydroxide i t might be preserved indefinitely. Newman and Ramsay3 recommended a similar treatment, namely, the use of lime, both for purification of decomposed chloroform and as a preservative. Brown,4 however, found t h a t the method of Newman and Ramsay was unsatisfactory. Allains stated that although the addition of alcohol or ether t o chloroform somewhat retarded the formation of carbonyl chloride and hydrochloric acid, it did not altogether prevent it. He learned t h a t sulphur, purified by digesting for 24 hours with ammonia and then carefully washed and dried, would effectually prevent the decomposition of chloroform.6 Temoin7 reported t h a t chloroform, to which 0.4 per cent. of sulphur had been added, underwent no alteration on keeping, even when exposed t o light. L)ott,8 considering t h a t oxygen was essential t o the decomposition of chloroform b y light and t h a t chlorine was always present at the earlier stages of the alteration, of absolute alcohol t o pure chloroform was questionable. All of these investigators assumed t h a t the chloroform which they termed “pure” contained no alcohol. 1 Pharm. J., 7, 345. Mialhe found t h a t chloroform acquired caustic properties when mixed with a small quantity of absolute alcohol, and concluded t h a t chloroform used in medical practice which caused vesication of the lips and nostrils contained a certain quantity of anhydrous alcohol. the presence of which was suspected by Soubeiran and Gerdy. Mialhe thought that the alcohol might act by combining with and coagulating the albuminous fluids of the body. 2 Bull. de Therag., May 15, 1864. 3 Lancet, Jan. 23, 1897. Pharm. J . , 61, 669; Mon. sci., 6.3, 423. Chem. Z t g . , 19, 310. 8 I n a sample saturated with sulphur, after exposure t o sunlight for four months, no impurities could be detected and the sample produced a “normal anaesthesia.” 7 Pharm. Centralh., 46, 872 ; Chem. and Drug., 64, 973. 8 Pharm. J., [4] 2, 249.
366
T H E J O U R N A L OF I N D U S T R I A L A N D E N G I N E E R I N G C H E M I S T R Y .
regarded it as probable that sulphur acted as a reducing agent, and that any substance slightly soluble in chloroform and readily oxidizable would likewise act as a preservative. Experiments with morphine, gallotannic acid, and hypophosphorous acid confirmed this view. Organic Preservatives.--Masson* found that poppyseed oil exerted a marked preservative action on chloro.form. A specimen containing 0.1 per cent. was exposed t o direct sunlight for 2 I days, a t the end of which time there was no decomposition; and one with 0.2 per cent. of the oil, kept in ordinary light, showed no decomposition in three years. From Masson’s own observations on the preservative powers of alcohol,* one would conclude that he considered it perfectly satisfactory. Breteaus devised a method for the prevention of the alteration of chloroform in the air and light, and of indicating finally the decomposition, which consisted in adding to the chloroform from 5-10 thousandths parts of one of the following bodies: pith of elder, cork or coniferae; and 3-5 thousandths parts of guaiacol, ionone, spermaceti, cholesterol, terpineol, citronellic acid, geranic acid, etc. He stated that the elder pith might be impregnated with a solution of a material colorless in chloroform, and dry, this material, as congo red, undergoing a change of tint under the influence of the decomposition products of chloroform. Congo red was stated to be very desirable, since it turns blue, and gradually decomposes, when the alteration is decided. Later Breteau mentioned the following substances as preservatives of chloroform in addition to those just mentioned: ethyl alcohol and ethyl ether, nitrobenzene, methyl and amyl salicylates, thymol and coniferin. As “ indicators, ” he stated that cellulin and gelatin might be used in addition to dyestuffs, and that the “ indicator” might also consist of a dyestuff which changes color in the presence of the decomposition products of chloroform.4 Still later he stated t h a t the “indicator” might be interposed between the chloroform and the stopper of the container, or might be fixed to the stopper, or might even form the stopper. Cinnamic acid and inositemono-methyl ether were added to the list of preservative agents.5 Breteau and Woog6 have published the results obtained by using the preservatives and “ indicators ” devised by Breteau. They found that by the use of 2-4 parts per 1000 of oil of turpentine,7 purified spermaceti, menthol, terpineol, citronellol, geraniol, amyl and methyl salicylates, guaiacol, thymol, safrol, ionone, or methyl-protocatechuic aldehyde, chloroform J . Pharm. Chim., [6] 9, 568. Masson considered t h a t the preservative action of alcohol on chloroform was demonstrated by the condition by the samples a t the Phurmacie Cenfrale in 1899, where specimens containing only 0.1 per cent. and exposed in yellow glass bottles in a window t o diffused light. were found t o have kept “perfectly” after standing for ten years. a French Patent 353,858, 1905. 4 First Addition t o French Patent 353,858, 1905, dated June 20, 1905. Second Addition t o French Patent 353,858, 1905, dated Nov. 18. 2
’
1905.
Comfit. rend., 143, 1193. The use of oil of turpentine as a preservative of the chlorides of carbon has been patented by Pichon and Truchelut (French Patent 402,235 of 8
7
1909).
,
May, 1912
could be preserved in white glass bottles in diffused light. I t was also learned that a number of “indicators ” showed the acidity of chloroform undergoing incipient decomposition before it was sufficiently developed to affect silver nitrate.’ There can be no question of the value of some, if not all, of the preservatives proposed by Breteau, but, so far as the authors are able to learn, his method of preservation has not been adopted by manufacturers of anaesthetic chloroform, mainly owing to the fact no doubt that the value of ethyl alcohol is established. Preservation i n an I n e r t Gas.-Mouneyrat” devised a method for the prevention of the decomposition of chloroform, involving storage in special apparatus in an atmosphere of nitrogen.3 This method might serve for the storage of samples of pure chloroform. (t) Role of Alcohol i n the Preservation of Chloroform. Schacht and Riltz4 found that not only did an addition of ethyl alcohol arrest decomposition t h a t had already commenced, but that it would, with sufficient agitation, remove the “free chlorine” that had been eliminated, as well as the carbonyl chloride formed. They found that the amount of alcohol requisite for that purpose depended upon the extent to which decomposition had advanced, and hence they concluded that the length of time during which alcohol would protect chloroform would always be proportionate to the amount of alcohol added, According to this view, so soon as the amount of alcohol is consumed, b y the joint action of the “free chlorine” and the carbonyl chloride directly resulting from the decomposition of chloroform, the products of the change that has gone on up t o that point without injuriobs consequences become all a t once recognizable, just as if the alteration had suddenly commenced. At that point, Schacht and Biltz found that the presence of “free chlorine” and carbonyl chloride, the “ initial products of the decomposition, ” could be detected. To account for the presence of hydrochloric acid, Schacht and Bi!tz state that since hydrochloric acid will also have been formed by the subsequent reaction of the “free chlorine” with alcohol, that acid will also become recognizable as soon as the last trace of alcohol disappears, although it will a t first ‘be dissolve& by the alcohol present. In the opinion of Schacht and Riltz, these successive changes afford an explanation of the fact that chloroform containing alcohol will, in the first instance, evolve hydrochloric acid, 1 Rreteau and Woog stated t h a t an elder pith disc dyed lightly with congo red and left in the bottle of chloroform would serve to,indicate decomposition by a change in color t o blue. Since congo red is very sensitive and is insoluble in chloroform, such a procedure may be followed and t h e method may prove t o be advantageous in hospitals, etc. 2 French Patent 370.991, 1906. 3 Mouneyrat found t h a t decomposition was prevented by storing chloroform in closed bottles, e. g., siphons, under a pressure of pure nitrogen gas.and he described a special container which might be filled and emptied for use in an inverted position. The neck of the bottle is fitted with a screw valve: when i t is required to Ell the bottle, the air is exhausted by a vacuum pump and pure nitrogen is admitted. This process is repeated several times, until every trace of oxygen has been expelled. The bottle, still i n the inverted position, is then placed in connection with a supply of chloroform, which is drawn through the valve, owing to the v;tcuum which exists in the bottle, When partly full, the valve is closed, the bottle ip brought t o an upright position, and pure nitrogen is forced in a t a pressure of 3 4 , atmospheres. .. . . , , 4 Pharm. j.,1893, 1005.
.
May, 1912
T H E J O U R N A L OF I N D U S T R I A L ‘ A N D E N G I N E E R I N G C H E M I S T R Y .
367
originating indirectly from the reaction of ‘ I chlorine ” harmless products with “ chlorine ” and carbonyl with alcohol, and soon afterwards “free chlorine” chloride, while Adrian was of the opinion that alcohol and carbonyl chloride, originating directly from the combined with the “free chlorine, ” forming finally trichloraldehyde. Schacht and Biltz did not, so far decomposition of chloroform.1 Brown,Z commenting on the views of Schacht and as their investigations indicate, examine exposed Biltz, in which these chemists attributed the pre- anaesthetic chloroform to learn whether oxidation servative action of alcohol on chloroform to the for- products of alcohol were present ; and Adrian, although mation of harmless products by the action of the he apparently found acetaldehyde, misinterpreted primary decomposition products on alcohol, quoted the nature of the oxidation process, considering that experiments t o show that “free chlorine ” and carbonyl chloroform decomposed in the presence of alcohol. chloride might be readily detected in chloroform before Since we have shown that free chlorine is not a prithe added alcohol had been consumed; and further mary product of the oxidation of pure chloroform, that such chloroform yielded only a very faint reaction and that no alteration of the chloroform itself occurs with silver nitrate, a t the time when a very marked while sufficient alcohol is present to be itself oxidized, one was obtained with zinc iodide and starch. He con- the explanations offered by these investigators are cluded, therefore, that the preservative action of not satisfactory. We do not deny that free chlorine alcohol‘must be ascribed to some other cause; and and carbonyl chloride may be eliminated from dethat it was folly to attempt to arrest decomposition in composed pure chloroform b y the addition of, and fact, we have found t h a t chloroform altogether by the excessive addition of agitation with, alcohol-in carbonyl chloride may be thus partially, a t least, alcohol. it is also likely that chlorinated deSince Adrian3 also considered that the products of removed-and the decomposition of pure chloroform are carbonyl rivatives of the oxidation products of alcohol may chloride, water, and chlorine, and then carbon di- form after the chloroform itself commences to oxidize; oxide and hydrochloric acid, it was natural that he but we have shown that the chloroform itself is not should hold a similar view of the function of alcohol subject t o decomposition while alcohol is present, and in preservation. Adrian found that the presence of that the primary products of the oxidation of anaesalcohol did not, strictly speaking, prevent the de- thetic chloroform are the oxidation products of the composition of pure chloroform; but that i t retarded alcohol present. The objection of Brown t o the it, and “fixes the nascent chlorine, ” forming, instead view of Schacht and Biltz may be explained b y the of free hydrochloric acid and toxic carbonyl chloride, .fact that oxidation products of alcohol give certain other chlorine derivatives which are harmless to the alcohol reactions ; for example, the iodoform test of animal organism. According to him, the first phase Lieben and the chromic acid test, considered as indicof this reaction is that of “free chlorine” on alcohol, ative of the presence of alcohol by Brown, show the presence of acetaldehyde in chloroform. The explaas represented b y nations advanced by Schacht and Biltz and also b y C,H,OH C1, = CH,.CHO 2HCl. Adrian, t o account for the presence of hydrochloric The acetaldehyde thus formed has a great affinity for acid in anaesthetic chloroform after the alcohol preschlorine, giving acetals more or less chlorinated until ent had been consumed, may be accounted for by t h e finally, by successive stages, trichloraldehyde, fact that they considered that chlorine, and not CCl,.CHO, is formed. The hydrochloric acid liberated hydrochloric acid, is a primary product of the oxidaduring these reactions, according t o Adrian, combines tion of pure chloroform; this is not in accord with our also with the alcohol, forming esters, providing the experience. alcohol is in excess; if not, it is found as free acid. The authors are firmly convinced that the experiAdrian found that in two years pure chloroform would mental evidence supplied in Part I of this section liberate 0.034 per cent. of free chlorine, and from offers a correct explanation of the decomposition of 0.011-o.or5 per cent. in six months; therefore, he pure chloroform and of the changes which occur concluded t h a t the addition of one part of alcohol in when anaesthetic chloroform is oxidized, and t h a t one-thousand of chloroform was sufficient to ensure this is fully substantiated by the results tabulated preservation. He also considered that sulphur and and discussed in Parts 2 and 4. These results showed almond oil doubtless acted in a similar manner b y that the explanations of the function of alcohol and “fixing” the “nascent chlorine” as i t was liberated. of other preservatives in retarding the decomposition Thus i t will be seen that Schacht and Biltz and also of chloroform were incorrect, and therefore the authors -4drian believed that chloroform itself decomposed were obliged t o take a totally different view of the in the presence of alcohol, although Adrian admitted role of alcohol in this oxidation process. that the decomposition was retarded by alcohol. ( d ) The Authors’ Theory of the M e c h a n i s m of PreserSchacht and Biltz thought that alcohol acted by forming vation. * On the other hand, Schacht and Biltz Considered that the decomStadlmayr’ considers that alcohol acts as a “cataposition of pure chloroform commenced by giving rise to carbonyl chloride, lytic retarding agent, ” thereby delaying the dewater, and chlorine, and then carbon dioxide and hydrochloric acid, at once; this view was also held by Brown. composition of chloroform. Undoubtedly i t modifies 2 Pharn. J . , 1893, 321. the reaction velocity of the oxidation, of which de3 J. Pharm. Chim., 18, 5 . Cf. the similar view of Benrath (Ann., 382, portment we have analogous cases, 222L who maintains that alcohol does not “protect” chloroform from de-
+
+
composition, but simply renders carbonyl chloride harmless.
Z.anpew. C h m . , 23, 1547.
368
’
T H E /O€J&A’AL~OFI N D U S T R I A L AND R 4 1 - G I A Y E E R I S GCHEMISTRY.
The retardation of the Oxidation of phosphorus b y the vapor of organic compounds is well-known,q as is also the retardation of the formation of ammonium carbonate by alcohol vapor;* but there is a remarkably similar case of retardation of oxidation by means of organic compounds, namely, in the oxidation of sodium sulphite. Bigelow3 has found that if a solution of sodium sulphite is oxidized by drawing through i t a current of atmospheric air, the velocity of the oxidation is greatly reduced by the presence of small quantities of alcohol, etc. Here also the influence of the retarding agent is found to be additive. From Bigelow’s investigation it may be concluded that the influence of the retarding “catalyst” is not on the dissolution velocity of oxygen, but on the reaction velocity. The only reason, however, that Bigelow gave for terming the retardation of the speed of oxidation a “catalytic action” was that considerable retardation was caused b y small amounts of substance. I n no case did he present evidence to demonstrate t h a t the retarding substance remains unchanged or that a small amount of i t will suffice to effect the retardation of the reaction for any considerable period of time. All the substances which he found retarded the oxidation of sodium sulphite (primary and secondary alcohols, polyatomic alcohols, phenol, aniline, ether, acetaldehyde, benzaldehyde, benzene, turpentine, etc.) were, if we consider the organic retarding agents alone, non-oxidizing agents ; and the substances which did not retard were not reducing agents or but very poor ones. Therefore, it appears that the retardation of the oxidation, in this case a t least, is ascribable to the reducing power of the substances added. Such a view’ is’ strengthened in part by the investigations of Young,t who found t h a t the presence of relatively small quantities of “poisonous substances, ” especially alkaloids, reduced the rate of the oxidation of solutions of stannous chloride by means of free oxygen; and who later5 presented evidence tending to lead to the conclusion that oxidations by means of free oxygen are subject to inhibition b y small quantities 06 foreign substances, that probably all organic substances possess inhibitive action, and that this effect is not instantaneous but develops somewhat slowly with t h e oxidation of the solution. I n these investigations, as in that of Rigelow, i t was not determined whether or not the inhibiting agent remained unchanged, but the principal fact brought out-namely, that the inhibitive effect develops with the oxidation of the solution-shows that here we have a case of so-called “negative catalysis” and that the inhibitory action is a chemical one. This view is supported by the work of Titoff,6 who learned that mannite acts as a “negative catalyst ” in the oxidation of aqueous solutions of sodium sulphite, and that the 1 Berthellot, J . de I’EcoZe Polyt., 3, 2 7 4 ; Graham, Quart. J. Sci.. 6, 83; Davy, Edinb. Phzl. J . , 15, 48; Centnerszwer, Z . physzk. Chem., 16, 1. 2 Van’t Hoff, Studwn, 1896, p. 36. 8 2.physik. Chem., 26, 493. 4 J . A m Chem. Soc., 28, 140. Ibui., 24, 326. a 2.bhyszk. Chem., 46, 641.
‘
May, 1912
retardation is proportional to the amount of mannite present. I From the preceding me may draw the following conclusions : I t is well established that certain organic compounds exert a retarding influence on the reaction velocity of oxidation processes The retardation-at least in the cases considered-is due to the reducing power of the organic compounds, and consequently the inhibitive action is a chemical one. The retardation is proportional to the amount of inhibitor present. Since i t has been shown that the oxidation of chloroform is retarded b y the presence of alcohol, for example, and that the period of retardation is dependent upon the amount of alcohol present ; z and particularly since we have demonstrated that the decom osition of chloroform itself is prevented so long as oxidation of any alcohol present proceeds, we offer the following explanation of the preservation of chloroform. T h e preserzatizle action of alcohol is due to the combination of the “retarder” w i t h certain of the reactiizg substames ; and a n y substance soluble in chlorojorm and readily oxzdizable will exert a n inhibitory effect on the oxidation of chloroforiii itsel). All compounds which have been fou?zd to serve as preservatives of chloroform are reducing agents,- and the eftect i s only due to their capacity f o r owdation. I n the case of alcohol, inhibition develops w i t h oxidation and retardatzon results until the oxidation of the i d i b i t o r reaches a m a x i m u m . T h u s , when chlorojoriiz is ‘‘ preserved” w i t h alcohol, the preservative i s gradually corisumed and zs eventually totally destroyed, after which the decomposition of the chlorofornz itself proceeds as in the case of pure chloroform, w i t h the exceptiou that chlorznated derivatires of the oxidatioG products of alcohol m a y result.
8.
6.
THE
STORAGE
OF
AXAESTHETIC
CHLOROFORX.
Chloroform required for anaesthetic purposes should always be furnished in vials, bottles or dropper-ampoules of anactinic glass containing about the quantity sufficient for one narcosis, and a t the most not more than can be used within several days. A two-ounce bottle is of sufficient size, and the use of a fresh bottle of this capacity which has been properly stored is an assurance that the anaesthetic has not become contaminated. Kevertheless, the user should always assure himself of the good faith of the manufacturer. If, however, for any particular reason chloroform is ordered in a large container, e. g., in hospitals, i t is advisable, immediately after opening i t , t o subdivide the entire remaining contents into two-ounce bottles, taking care to fill the small bottles completely. It is important to see that the bottles are completely free from water, and empty bottles should not be refilled without thoroughly cleansing and drying them. I n no case should chloroform be gradually withdrawn in small quantities from large bottles or 1 Cupric sulphate causes the oxidation to proceed with a measurable velocity, thereby accelerating the mam reaction, but when mannite 18 present, the positive catalyst is destroyed by chemlcal unlon with the retarder 2 Reference IS had only to the components1of Mure anaesthetic chloroform.
May, 1912
T H E J O U R N A L OF I N D U S T R I A L A N D EA‘GINEERISG C H E M I S T R Y .
carboys. When it is found necessary t o store anaesthetic chloroform, i t should always be kept in a cool, dark place, in well-filled, or, better still, completely filled, tightly+ stoppered bottles of anactinic glass.1 Contai,zers.-It has been shown2 that colorless glass protects chloroform less thbn red or yellow glass, and in practice brown glass bottles are now exclusively used.3 Chloroform should not be kept in black bottles, because it is difficult t o learn when these are perfectly clean and dry. If colorless bottles are used for any reason, these should be provided with an opaque covering and kept in a dark place. All glass containers should be made of high-grade glass,? which should show no alkaline reaction when the bottle is filled with distilled water containing several drops of phenolphthalein solution and heated a t 100’ C. for six hours. A qdestion of importance in the trade is, “ W h a t marked advantage have glass bottles over soldered tins?” The question of keeping anaesthetic chloroform in tin containers has been a much agitated one in the Federal K a r Department, and within the last ten years this Department has decided in favor of the tin container. The opinion of the authors is that glass containers are t o be preferred, since any foreign matters present may be readily observed and the bottles then cleaned. In the case of tins, greater care must be exercised t o ensure a non-contaminated chloroform, especially since some of the flux used in soldering may be accidentally introduced and thus impart an acid reaction to the chloroform. As mentioned previously, hydrochloric acid accelerates the decompositon of chloroform. Since i t has been stated that spirit containing 95-96 per cent. b y volume of ethyl alcohol is perfectly indifferent to tin, and tin and tinned metals are absolutely unattacked b y 90 per cent. denatured spirit, the tinned metals only being corroded where the tin layer is broken,s one would conclude that , acid-free chloroform,6 containing the usual amounts of alcohol and water, would also be without action on tin, providing i t is stored in tin containers, having no broken or scratched surface, very carefully capped, and with a minimum amount of air. In order t o determine this, a five-pound sample of chloroform containing 0.84 per cent. b y volume of absolute alcohol and approximately 0 . o j per cent. of water, which had been stored in a tin container, sealed, for sixteen months, was examined for the presence of tin. This sample 1 “On t h e Storage of Anaesthetic Chloroform,” see also Bull. Pharm., 20, 215; ,Valional Dispe?tsators. 1887, p . 439; and Merck’s Annual Refiort, 16, 42. 2See P a r t I of this section; cf. Madsen, Phnrm. J.;[4] 18, 747. 3 All of the manufacturers of chloroform in this country use brown glass (“anactinic”) bottles. Of the eight different makes of German chloroform examined by the authors, only two u.ere contained in colorless bottles. 4 “On the Action of Alkalies op Chloroform,” see Rerthelot, Bull. soc. chim., [2] 29, 4 ; AndrC. Comfil. r e n d . . 102, 553; de St. Martin, Ibid., 106, 492; Mossler, Mon.atsh.. 29, 573. It appears t o be well established t h a t potassium hydroxide in alcoholic solution will slowly decompose chloroform. 6 Heinzelmann, Z . Sbwifusind., 27, 399. Malmejac, however, [ J . Phavm. Chtm., 13, 169 (1901)] found t h a t a small amount of tin goes into solution in 95’ alcohol after six months. “On the Action of Hydrochloric Acid in Chloroform on Tin,” see Patten, J . Phys. Chem.. 7 , 161, who found t h a t the dry solutions acted upon t h e metal less violently than upon Tinc or aluminum, b u t more violently than o n lead.
369
left a residue non-volatile a t 100’ C. amounting to o . o z z o gram per liter, but none remained upon ignition and no tin could be detected in the sample. The examination of a sample of anaesthetic chloroform which had been kept in a sealed tin for six years also showed that no tin had been dissolved. In both cases, however, oxidation of the alcohol present had occurred, although no d’ecomposition products of chloroform were present. We have b$en informed b y a prominent manufacturer of chloroform that he has “demonstrated t h a t moist chloroform in the presence of a metal will slowly form traces of CH,CI,, and . . . . probably . . . . that i t is possible t o distil pure, dry chloroform in a metal container and produce a decomposition, as shown b y Cu, = C,Cl,+ the following formula: 4CHC1, Cu,Cl,. This reaction, however, takes 2CH,C1, place so slowly that i t would never be noticed except in the handling of a material on which superlative efforts have been expended for years in order to get the last extreme of purity. ” Moreover, .‘‘ all chloroform contains traces of CH,Cl,.” In view of this, therefore, i t would seem that there is another reason for preference in the matter of container. I n this connection, i t should also be mentioned that i t is probable that all metals which show anomalous anodic conductivity are likely to develop free hydrogen dioxide in contact with water and oxygen.1 Stoppers f o r Glass Containers.-The PharwacoFoeia of the L:+zited States formerly required the use of “glassstoppered ” bottles, but subsequently changed this to “ well-stoppered ” bottles, thus allowing the use of cork-stoppers, a practice which has become general in this country,2 owing to the consequent reduction 1 in cost. The objections which have been urged against the employment of cork stoppers are two in number: first, the chloroform penetrates the cork after some time, especially during the agitation incidental t o shipment, causing shrinkage and consequent leakage ; and second, organic matter is extracted from the cork.3 To obviate these difficulties, certain manufacturers have adopted the plan of covering the bottom of the corks with tin foil,s a procedure which has been found t o be satisfactory, while others use a paper or parchment covering.5
+
+
Barnes and Shearer, J . Phys. Chent.. 12, 155, 468. However, hydrogen dioxide is not formed on shaking finely divided zinc, magnesium or aluminum with water when all traces of free oxygen are excluded (Kernbaum, Comfit. rend., 152. 1668). 2 I n Germany, however, glass-stoppered hottles are used by prominent producers of anaesthetic chloroform (Kahlbaum; de Haen; Jferck; A,-G. fur Anilin-Fabrikation). Consequently it was found difficult t o meet the sulphuric acid test prescribed by the Pharmacopoeia. Cf., however, A m . J . Pharm., 1868, 289. At present such a protection is used by three American firms. Since adopting this plan, these firms state t h a t no complaints regarding leakage or conformity t o t h e sulphuiic acid test have been received. When metal coverings are used on the stoppers of chloroform containers, they should be made rather of thin sheet metal, than of foil, since we have found t h a t tin-foil becomes broken or displaced, and often separates from t h e stopper when i t is withdrawn from the bottle. Failure t o do this has been t h e cause of some complaint. If t h e plan mentioned is followed, t h e use of glass-stoppered bottles will not be found necessary, even though the t r a d e should become willing t o pay t h e advanced price for such packages. Such a plan has been adopted by one American firm and three German producers.
370
T H E J O U R N A L OF I N D U S T R I A L A N D E N G I N E E R I N G C H E 3 4 I S T R Y .
May,
1912
Allain‘ and Masson) have recommended that when chloroform is kept in cork-stoppered bottles, a lute of “bichromate gelatin” should be used to prevent leakage. This is totally unnecessary when a proper stopper isused, and the employment of lutings on the stoppers has led t o many differences between the manufacturer and consumer in the past.3 Only one of the many samples of anaesthetic chloroform examined by the authors was contained in a bottle having a luted cork stopper, and in this case, although the chloroform itself was pure, considerable of the resinous matter had been extracted, and, as a result, the chloroform failed to comply with the sulphuric acid test, which, as will be shown later, is one of great importance.
Excess alcohol ; Acetone ; Methyl alcohol ; Carbon tetrachloride : Tetrachlorethylene, hexachlorethane, etc. ; Aldehydes, chloral ; Amyl, propyl, and butyl alcohols and compounds; Ether;I Acids (sulphuric, hydrochloric, formic, acetic) ; Metallic chlorides; Ethyl chloride; Ethylene chloride ; Ethylidene chloride ;a Ethyl acetate; Oils ( ‘ I empyreumatic, ” “pyrogenous, ” “ chlorinated ”) ;3 VII. The Impurities of Anaesthetic Chloroform. Fixed and extractive matter.3 I . C H E M I C A L CONSIDERATIONS. B. For the oxidation products of chloroform and I n conducting an examination of anaesthetic chloroform with the view of ascertaining its suitability for alcohol; in other words, i t must be ascertained if the the production of anaesthesia, one must test:? chloroform has been properly stored. The possible A. For impurities which the chloroform brings impurities of this class are as follows: Acetaldehyde ; with it from the manufacturer. These are usually Acetic acid, formic acid;4 the so-called ‘‘ organic impurities, ” which are found Carbonyl chloride ; in considerable amounts in a chloroform which has Hydrochloric acid ; been made from poorly rectified spirit, acetone, or Hydrogen dioxide ; carbon tetrachloride (the sources), if impure chemicals Chlorine ; have been employed in the manufacture or subseChlorinated derivatives of alcohol oxidation prodquent rectification and purification, or if the chloroucts. form has not been properly purified. These impurities, even though some may not be of much imThe detection and, where necessary, the estimation portance from a physiological standpoint, must still of the impurities embodied in these two classes, will be given attention, since an impure chloroform is be discussed in succeeding sections of this paper. more likely to become altered through oxidation 2. I’ H Y S I 0 LO G I C A L C 0 N S I D E RAT10 NS . during storage, notwithstanding the fact that pure Huchards has said: “ Pure chloroform, well given ethyl alcohol has been added. So far as we have been to a patient prepared for it, almost never kills.” able to learn, the adulteration of anaesthetic chloroform is not practiced n0~?’,5and crude chloroform is Serious results have occurred from the use of anaesnot often sold as chloroform of anaesthetic grade.6 thetic chloroform containing foreign substances, and although the grades a t present sold as chloroform for To summarize, the possible impurities of this class anaesthesia hardly contain impurities which can be are as follows: held responsible per se for deaths which have occurred Excess water; during narcosis, yet the presence of these may pro1 J . Pharm. Chim., [ 3 ] 9, 571. duce some, a t least, of the disagreeable after-effects 2 Ihid., [ 6 ] 9, 568. According t o hlasson, the “bichromate gelatin” so often noticeable following the administration of 100: distilled water, 300 ; glycerin, is thus composed: Solution A-gelatin, 10. Solution B-potassium dichromate, 20; distilled water, 200. Two some chloroform. Consequently, anaesthetic chloroparts by weight of the first are mixed with one part by weight of the second, form should comply with the most rigid tests,6 and the both previously being warmed; the mixture should be kept a t 55-60’ on preparation which conforms with these requirements a water bath during use. 3 Some of these will be referred t o when the Test with Sulphuric Acid and a t the same time is comparatively less likely to is discussed. decomposition than others also answering the same 4 This summarization is given in order t h a t the reader will observe the tests, should a t all times be preferred to a cheaper propriety of all consumers of chloroform of assuring themselves, by examination, t h a t the chloroform they purchase and use or dispense is pure, notbut less stable grade. According to the investiga-
withstanding the fact t h a t , as a rule, chloroform of inferior grade, frequently encountered about 1880 (see Perrin, Pharm. J . , [31 9, 614; and Championniere, Ibid., 131 12, 6 2 3 ) . especially in France, is now rarely represented as being of anaesthetic grade. This is largely due t o the stringency of many of the pharmacopoeias, but is in part t o be ascribed t o the experience and integrity of the manufacturers. It sometimes happens, however, t h a t chloroform is declared t o be impure, by surgeons following a fatality from i t s use in particular. when this is not the case. For a n example, see the experiences of Blum, Pharm. J . , 141 19, 103. “On the Organic Impurities of Chloroform,” see Stadlmayr, Pharm. P m t . 43. 418. Cf., however, Baird (Proc. Mass. Pharm. A s s n . , 1906, 591, who examined six samples of chloroform in 1904, and found one “adulterated.” 6 B u t this appears t o have been practiced as late as 1885 in this country, since Davenport ( A m . J . Pharm., [4] 16, 111) reported t h a t fourteen out of fifteen samples of chloroform examined by him in t h a t year were the crude article.
1 From 1865-1875, ether was considered as one of the general contaminants of chloroform. 2 About 1880, ethylidene chloride was regarded as a general impurity of chloroform. 3 See Tests for Odor and Residue. 4 According t o Benrath ( A n n . , 389, 2 2 2 ) , chloroform in aqueous suspension or aqueous alcoholic solution is oxidized t o formic acid or its decomposition products when cxposed t o ultra-violet light. J . des Pratuicns, May 31, 1902. 6 The pharmacopoeial tests are, in general, insufficient, and samples of chloroform may comply with the tests prescribed by various pharmacopoeias and yet important differences may be shown to exist among them by means of other tests. These facts have been brought out by Langgaard (Therap. Monatsh;, May, 1902), and the opinions and results obtained by the authors will be given in subsequent sections of this paper.
T H E J O U R N A L OF I N D U S T R I A L A N D E N G I N E E R I N G C H E M I S T R Y .
May, 1912
tions of Feigl ancl Meier,I the customary chemical examination of a sample of anaesthetic chloroform is not conclusive, but requires confirmation by biological tests. Most important, however, is clinical experience. In regard to the fatal results which have been obtained in practice following the use of chloroform vapor for the induction of anaesthesia, a considerable percentage of cases, especially those where death has ensued immediately upon first inspiration, may not be due to the action of chloroform a t all.2 However, Simpson3 enumerates a number of cases antedating the general introduction of anaesthesia which may be classed as chloroform deaths.4” I n all indubitable cases the nature of the chloroform administered certainly plays an essential role ; this fact is supported b y convincing evidence, even though the percentage of deaths caused b y chloroform administered during operations is unaccountably different in different years, times, and places.5 We can attribute the existing diversity of opinion on the subject only to the degrees of purity of the anaesthetic used, the different modes of administration, the varying lengths of the time of the anaesthesia, the varying severity of the operation, and the state of the patient. According t o almost all authorities, the first danger from the use of chloroform consists in a n interruption of respiration$ and it has been said that only after the observation of the pulse had superseded that of respiration did chloroform deaths become more frequent.‘ Experience has therefore clearly shown that every obstacle to respiration must be removed; the presence of irritating contaminants in the anaesthetic must, as a consequence, be guarded against.8 In France, Sedillot,P who laid the greatest stress on the purest chloroform, did not have to record a single death; but in nine-tenths of all the chloroform deaths on record, not a word is said in regard to the degree of purity of the anaesthetic employed, and consequently a n important factor for forming an opinion is entirely excluded.10 Hence the published statistics are not t o be relied upon. ‘ I
1 Biochem. Z., 1906, 316. Feigl and Meier marked out the bloodpressure curves on a drum by means of a kymograph; healthy dogs were made to inhale equal quantities of chloroform of different makes through a tracheal canula. The results obtained showed t h a t the different brands of chloroform, although they appeared almost identical by the chemical tests, differed considerably in their liability t o cause a diminution in blood pressure and t o cause arrthythmia of the pulse-beat. 2 See, in this connection, Nussbaum. H a n d b . d . Allg. u . Spec. C h i r . , 1867, 6 1 2 ; Lawrie, Lancet, 1890, i, 149. 3 Brit. M e d . J . , 1870, i, 199. .I Sansom (Chlorofornz, London, 1865) p u t the average mortality a t 0.75 per 10,000; Richardson ( M e d . Tinies and Gaz., 18701, a t 2.8: and Morgan ( M e d . Soc. V a . , 1872), a t 3.4. One of u s (C. B.) in conjunction with Dr. J . T. Gwathmey is securing complete d a t a from every hospital in the United States. 6 Metcalfe ( T r a n s . S Y . A c a d . M e d . . 1. 145) stated in 1850 t h a t his experience, extending then t o 800 administrations, went t o substantiate the fact t h a t the use of impure chloroform causes headache, nausea, and bronchial irritation. 7 Hewitt, Proc. Roy. M e d . and Chir. Soc., 890. 8 Occhini ( P h a r m . J . , [3] 8, 988) came to the conclusion t h a t the tolerance of chlorofonn could be assured by the preventive use of ammoniacal inhalations. Although chloroform and ammonia have a mutually antagonistic action of the heart, according t o Ringer (Practitioner, 1881, 191, such a method is unnecessary if pure chloroform of anaesthetic grade is properly administered t o a patient prepared for it. 9 B u l l . soc. Chir., 7, 1881. Dr. Hunter McGuire, surgeon 10 Some exceptions may be noted here. in the Confederate Army during the Civil War, one time remarked t h a t
37=
Dubois-ReymondI appeared to have experimentally demonstrated that impure chloroform is dangerous. Therefore, to the rules for administering chloroform so often given, he considered t h a t one omitted by all but Sedillot and hisschool should be added, namely: That the quality of the chloroform be carefullyexamined, and only the very best procurable be employed for anaesthesia. There can be no question but that Dubois-Reymond obtained results which indicated rather a difference of degree than of kind between the action of pure and impure anaesthetic chloroform. He insisted that the impurities acted as cardiac depressants;l but, as was noted a t the time,^ it does not appear that by their removal pure anaesthetic chloroform4 ceases t o hamper circulation.5 That the impurities are ordichloroform had been administered 40,000 times in his corps alone without a single death, and he attributed the result largely to the splendid grade of chloroform which the Union Army had supplied him (almost all the chloroform used by the Confederate Army was captured from the Federals, although some of English manufacture came through a blockade). The results of an examination of a sample of chloroform of this period will be given later in this paper. In 1882, Preston ( P h a r m . J . , [31 12, 982) recorded t h a t there had occurred 53 deaths in 152,260 administrations, and t h a t in these 53 cases the impure chloroform had something t o do with the fatal results. Atthill (Brzt. M e d . J., 1892, i, 110) stated t h a t he had administered chloroform in over 2000 cases and considered t h a t i t is essential for its safe use t h a t the chlorofonn be pure; he mentioned t h a t the chloroform in general use a t t h a t time was often impure. Chisolm (Sci. Am. SwbPI., No. 642, 10259). who had in 1888 a record of 10,000 cases of general anaesthesia with chloroform and no deaths, recorded his experiences, hut made no mention whatsoever of the purity of the chloroform used. 1 Brit. M e d . J . , 1892, i , 209. * The report of the Ilyderabad Commission shows t h a t deaths from chloroform are more frequently due t o its checking the power of respiration than t o the arrest of the heart’s action; see, in this connection, Lancet, 1890, i, 149,421, 486, 1140, 1369; 1890, ii, 3 5 6 ; B r i t . M e d . J . , 1891, ii, 1080, 1121. Indeed, Lawrie states (Chloroform, 1901, 15) t h a t the doctrine t h a t chloroform has no direct action on the heart must be considered as finally established. This is supported by the results of the biochemical observations of Feigl and .Meier (Biochem. Z.,1906, 3161, u.ho concluded t h a t narcotic doses of pure chloroform have little or no action on blood pressure, the heart, or the circulatory system in general; and t h a t these effects, when observed. are usually due to the accompanying impurities in commercial alcohol. Some observations, however, seem t o indicate t h a t chloroform has an action on the circulatory system, although in these cases the purity of the anaesthetic was not always considered. Cf., for example, Filehne and Biberfeld, 2. f . exper. Path. u. Therag., 3, 171 (1906); these investigators discuss the advisability of adding volatile analeptics t o chloroform t o prevent the reduction of blood pressure. .Also, 13usquet and Pachon (Concpt. rend. soc. biol., 66, 90) reported fibrillation of guinea-pig’s heart under the influence of chloroform. Schaefer and Scharlieb (Proc. PhwioZ. Soc.. 1903, 17) have insisted on the specific nature of the action of chloroform on cardiac muscles. Bmbley and Martin ( J . Physiol., 32, 147) have found t h a t the action of chloroform in the blood in such quantities as may occur with inhalation of 1-3 per cent. of vapor in air, paralyzes the neuro-muscular mechanism of the blood vessels. Tissot (Compt. rend., 142, 234) reported t h a t more than 70 mg. of chloroform per 100 cc. of arterial blood often causes death. I t appears t h a t chloroform forms a loose combination with haemoglobin; for a discussion of the physical chemistry of anaesthesia, wherein this is discussed, see Moore and Roaf, Thomfison, Yates a n d Johnst o n Lab. R e g f . . Liievpool, 1905-6, 151-94. \Taller (.Vatwe, 76, 403) “tested purified chloroform against the concentratcd residue of its impurities, and found the former to be more powerful than the latter;” he did not, however, lay any stress upon the fact t h a t anaesthetic chloroform can be of variable quality. Tunnicliffe ( P h a r m . J . , [4] IS, 515) subjected samples of anaesthetic chlorofoim t o mechanical shaking for several days, then exposed them for a considerable time to direct July sunlight, and finally allowed them to evaporate in the laboratory t o one-half bulk; the residual portion did not differ at all from pure chloroform in its toxic action on cardiac muscle (!). B r i t . M e d . J . . 1892, i , 236. “Chloroform Pictet” was taken as the example. See above and also Charteris and MacLennan, Brit. M e d . J . . 1892, i, 679, who believed t h a t differently manufactured chloroform, although conforming t o the tests specified by the B r i t i s h Pharmacofioeia, might have different actions, and that possibly some of the dangers were due t o the employment of impure chloroform.
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T H E J O U R N A L OF IA’DUSTRIAL A N D E,YGIiZ‘EERIA-G CHELVZISTRY.
narily very slight, Dubois-Reymond admitted, but he contended that, although really infinitesimal in quantity, they act strongly in chloroform solution. From his experimental investigations and deductions, we learn that there are undoubted impurities which are able to intensify and hasten the lethal properties of chloroform, but we cannot definitely assert just what these are. We know, however, what the general likely impurities of anaesthetic chloroform are ; and if proper precautions are taken t o guard against their presence, untowaFd symptoms should not follow the proper administration of anaesthetic chloroform. I n succeeding sections of this paper, tests to which such chloroform should comply will be given. ( T o be continued in the June N o . ) TESTING METHODS OF RUBBER CONTENTS IN RAW AND VULCANIZED RUBBER. B y W. A. DIJCCA. Received January 5 , 1912.
Two distinct chemical compounds of the rubber molecule have been the subject of extensive investigation during the last ten years, regarding a possible usefulness for a direct determination of caoutchouc in a given sample of raw or of manufactured rubberthe nitrosites or nitrosates as nitrogen compounds, and a compound with bromine as tetrabromide. Harries deserves the credit of being the first one t o make a n attempt in the direction of a distinctly defined nitrogen compound. Almost simultaneously with C. 0. Weber, he began a study of the action of nitrous acid gases upon solutions of rubber in benzole. Weber, who unfortunately did not live to finish his experiments, worked with nitrogen dioxide, developed b y heating nitrate of lead. He obtained, or a t least claimed to have obtained, an addition product of two molecules of NO, to one molecule of rubber of the formula C,,H,,N,O, in a polymeric form. The compound would have t o be classed as a nitrosate. Harries on the other hand applied N,O,, generated from nitric acid and arsenic trioxide. He stated that b y varying the conditions he was able to separate three distinct compounds of a nitrosite character which he called nitrosites ( a ) , ( b ) , and (c). I t is not the purpose of this paper to enter into a detailed discussion of these well known classical investigations, but the true composition of the compounds obtained in the reactions is of the utmost importance for the estimation of pure caoutchouc in a given sample of rubber. I, therefore, feel justified in giving a short review of the more important results reached b y different authors and a t different times. Harries’ three nitrosites are as follows: Nitrosite a, C,,H,,N,O,, is formed b y a six-hour action of dry N,O, upon a I per cent. solution of rubber. 8 , formed when dry N,O, Nitrosite b , C l O H l 5 ~ , Ois gas is passed from two to three days through a suspension of nitrosite a in benzole. Nitrosite c, CloH15X30,, is precipitated from a I per cent. rubber solution in benzole b y the action of wet N,O, gases.
May,
1912
His first statements were later modified in some respects by Harries himself. The ultimate product of the action of N,O, gas upon I per cent. solutions of rubber in benzole was claimed to be uniformly nitrosite c , provided the reaction were allowed t o go on for a sufficiently long time. Contrary to his first report, he gave as the best way t o prepare this compound the use of K 2 0 , gas thoroughly dried over phosphorus pentoxide. These results naturally induced Harries t o apply the new compound for a n analytical determination of caoutchouc. He obtained a satisfactory result on a sample of an uncured rubber compound, but did not make any attempts to develop the method any further, as this would hardly be within the scope of his work as a college professor, and should rather be accomplished b y a technical man. His work in this direction was taken u p where he had left it b y a number of investigators; they practically all reached different conclusions based on various results. The most exhaustive study of the subject was undertaken by Alexander with rather surprising results, not in accordance with Harries’ observations. The action of N,03 was shown to go much further than had been observed b y either Weber or Harries. His method of precipitating the nitrosites from the rubber solution differed from Harries’ method in so far as he generated nitrous acid anhydride from starch and 80 per cent. nitric acid. The formula of the final product was given as C,H,,N,O,, containing one carbon atom less than the original rubber molecule. This fact was explained by the oxidation of one of the two methyl groups of the caoutchouc molecule to carbonic acid gas, while the other one is supposedly oxidized only to the carboxyl group COOH.
C-CH,-CH,-CH
I/
HC-CH,-CH,-C-CH,
----f
/I CO, H 0,K-C-CH,-CH,-CH I
It
o,N-~-cH,-cH,-C--COOH
H That this explanation is possible from a theoretical standpoint is open to discussion. I n support of his theory Alexander mentioned his observation of carbonic acid gas during the reaction. He certainly made a very thorough study of the matter, both theoretically and practically, and his analytical results are hardly to be doubted. On the other hand Gottlob, who undertook a careful re-examination of Harries’ experiments, comes t o the conclusion that their results were correct beyond any doubt and that he could confirm them in all respects. In his opinion, Alexander obtained different results only b y not closely following Harries’ method in every detail. We conclude from these contradicting statements, that it is, t o say the least, very difficult to obtain
