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diff --git a/old/67736-0.txt b/old/67736-0.txt deleted file mode 100644 index decea6e..0000000 --- a/old/67736-0.txt +++ /dev/null @@ -1,1434 +0,0 @@ -The Project Gutenberg eBook of The Chemical Constituents of Piper -Methysticum; The Chemical Constituents of the Active Principle of the -Ava Root, by Alice Augusta Ball - -This eBook is for the use of anyone anywhere in the United States and -most other parts of the world at no cost and with almost no restrictions -whatsoever. You may copy it, give it away or re-use it under the terms -of the Project Gutenberg License included with this eBook or online at -www.gutenberg.org. If you are not located in the United States, you -will have to check the laws of the country where you are located before -using this eBook. - -Title: The Chemical Constituents of Piper Methysticum; The Chemical - Constituents of the Active Principle of the Ava Root - -Author: Alice Augusta Ball - -Release Date: March 29, 2022 [eBook #67736] - -Language: English - -Produced by: Mary Glenn Krause, Les Galloway and the Online Distributed - Proofreading Team at https://www.pgdp.net (The University - of Hawaiʻi at Mānoa) - -*** START OF THE PROJECT GUTENBERG EBOOK THE CHEMICAL CONSTITUENTS OF -PIPER METHYSTICUM; THE CHEMICAL CONSTITUENTS OF THE ACTIVE PRINCIPLE OF -THE AVA ROOT *** - - Transcriber’s Notes - -Obvious typographical errors have been silently corrected. All other -spelling and punctuation remains unchanged. In particular the author -uses Kavahin for what is now normally referred to as Kavain. - -Italics are represented thus _italic_. - - - - - THESIS - - presented for the degree of - - MASTER OF SCIENCE - - at - - THE COLLEGE OF HAWAII - - JUNE 1915 - - by - - ALICE A. BALL. - - - - -The Thesis, herewith, on “The Chemical Constituents of the Active -Principle of the Ava Root” by Alice A. Ball, clearly demonstrates her -ability to do original work and to present her results in logical form. -Approved. - -[Illustration: J. F. Illingworth] - - Chair of the Committee on - Advanced Degrees. - - College of Hawaii, - May 14, 1915. - - - - - THE CHEMICAL CONSTITUENTS - - OF - - PIPER METHYSTICUM - - OR - - THE CHEMICAL CONSTITUENTS - - OF THE ACTIVE PRINCIPLE - - OF THE AVA ROOT. - - - - - _INDEX._ - - - Page - - 1. Historical 1 - - 2. Method of Extraction 7 - - 3. Method of Separation of the Resins 9 - - 4. Various Metallic Salts of the Resinous Acids 12 - - 5. The Total Resins 13 - - 6. The Barium Acid 15 - - 7. Oxidation Products of the Barium Acids 21 - - 8. The Iron Acids 28 - - 9. Oxidation of the Iron Acids and - the Free Acids 33 - - 10. Alcohol Radicals 34 - - 11. Methysticin and Methysticinic Acid 36 - - 12. Physiological Action 38 - - 13. Conclusion 43 - - - - - _HISTORICAL._ - - -“Among the customs peculiar to the inhabitants of the South Pacific -Islands, perhaps the most noted is that of the preparation and drinking -of a narcotic beverage called _ava_, _kava_, or _yakona_. Much of -its notoriety arises from the repulsive way in which it is sometimes -made. Aside from this, it is characteristic of a certain oceanic -area, and seems to be as strikingly limited to this area as is the -stick-and-groove method of making fire. The custom, is not confined -to one ethnic stock, many notices in literature showing that both -Papuans and Polynesians practise it. In many of the islands the Liquor -is concocted by chewing the root of the Macropiper methysticum, or -long pepper, ejecting the comminuted mass into a bowl, adding water, -straining out the pulp, and drinking the fluid. In other localities it -is made by simply grating the root and adding water. - -“The plant from which kava is made is a shrub of the natural order -Piperaceae. It is about six feet high with stems ranging from an inch -to an inch and a half in thickness; the leaves are cordate and from -four to eight inches long. This family is the source of the pepper -of commerce and contains several species that are of medicinal and -commercial importance. - -In making kava, the root and base of the stem is used. The roots -usually weigh from two to four pounds, though sometimes as much as -22 pounds. Several varieties are distinguished by the natives; for -instance, in Tahiti there is a yellow variety called _Marea_; another, -which becomes pink on exposure to the air, is called _avini-ute_. - -“Chewed when freshly gathered, the root first tastes sweet and -aromatic, then bitter, acrid and pungent. It provokes abundant -secretion of saliva and in a few seconds occasions a sensation of -burning on the tongue. The root contains about fifty percent of starch, -a little pale-yellow essential oil, two percent of an acrid resin, and -one percent of the neutral crystalline principle methysticin, called -kavahin. To the latter principle we must attribute the toxic qualities -of the kava preparation. The resin and the kavahin are insoluble in -water, but are soluble in saliva and the gastric juices. - -“In Samoa, the ava root is grated or chewed, then soaked, the woody -pulp strained off, and the fluid drunk. The root is used either dry or -green. The flavor of the liquid is at first like that of soapsuds, but -immediately afterward a pleasant aromatic taste is imparted, faintly -bitter, as in quinine. In Samoa, ava drinking is the accompaniment of -all meetings of the men. - -“Kava is at first stimulating, but the effect of an excess resembles -that of opium, producing a drowsy drunkenness, lasting for two hours. -The inebriate is usually peaceable, but sometimes is irritated by -noises, which is attributed by natives to the use of kava grown in -moist ground. The results of excess are skin disease, emaciation, and -general decrepitude. The peculiar whiteness of the skin caused by kava -drinking is said to be sought after in some islands as a sign that its -possessor is wealthy enough to devote his time to its acquirement. - -“There is some misapprehension in regard to whether the liquid -undergoes fermentation before it is consumed, but it is positively -known that there can be no fermentation, for the liquor is drunk -immediately after the addition of water to the macerated root. Kava -that is prepared by chewing is said to be more palatable, which -is perhaps due to the conversion of the starch into a fermentable -substance by the ptyalin of the saliva.”[1] - - [1]—By Walter Hough—Reprinted from Smithsonian Miscellaneous - Collections—No. 1472—August 1904. “Kava Drinking as Practised by the - Papuans and Polynesians.” - -“In 1779 Captain King, R. N., who followed Captain Cook to the Islands, -describes the case of a priest as follows ‘a little old man of an -emaciated figure, his eyes exceedingly sore and red, and his body -covered with a white leprous scurf, the effects of an immoderate use -of ava.’ He also says, ‘The chiefs suffer dreadful effects from the -immoderate use of ava. Those who are most affected by it had their -bodies covered with a white scurf, their eyes red and inflamed, their -limbs emaciated, their whole frame trembling and accompanied with a -disability to raise the head.’”[2] - -[2] “Leprosy Prize Essays,” 2nd series by Thompson and Cantile, 1897. - -F. A. Griel, makes the following statement in a foot note. “The mixture -is a subnarcotic, and if drunk by European sailors produces highly -nauseous effects. If frequently taken a dry burning heat is produced -all over the body, the eyes become red, skin peels off in flakes -and then degenerates into leprous ulcers or the whole body becomes -emaciated and wastes away.”[3] - -[3] Miquel, Systema Piperacearum. - -Numerous attempts have been made to isolate the active chemical -constituent or constituents. As early as 1844 Morson discovered an -active principal _Kawine_. This is a greenish-yellow, strongly aromatic -and acrid resin. This was again studied by Cuzant in 1860. - -Gobley isolated from kava root a crystalline principle (analogous to -piperin), _methysticin_, or _kavahin_, which is without odor and taste -and is probably inert.[4] In 1886 Lewin separated the resin into two -resins, of which the Beta resin is greasy and of a reddish-brown color, -appearing in mass almost black. This is less active than the alpha -resin which is yellowish brown, has the characteristic odor of the -drug, is freely soluble in alcohol, and placed upon the tongue produces -a burning sensation followed by local anaesthesia.[5] - - [4] J. P. C. Jan. 1860. - - [5] A. J. P. 1886, 450. - -A volatile oil has been found in the root.[6] - - [6] J. P. C. March 1862. - -Lavialle claimed to have obtained an alkaloid, _Kavaine_.[7] - - [7] L’Union Pharm. Jan. 1889. - -The following statement was found in “Watts Chemical Dictionary”, -“Kawain—a crystalline resin occurring along with methysticin in -kawa-kawa, It is not a glucoside. On oxidation it yields benzoic -acid.[8] - - [8] Gobley, J. Ph. (3) 37, 19. - -The following statement appears in the Encyclopedia Britannica. -“There appears to be little doubt that the active principle in this -beverage is a poison of an alkaloidal nature. It seems likely that -this substance is not present as such (i.e. as a free alkaloid) in the -plant, but that it exists in the form of a glucoside, and that by the -process of chewing, this glucoside is split up by one of the ferments -in the saliva and the free alkaloid and sugar is formed”. - -Arthur Bossingham[9] communicates the results of a chemical examination -of Kava-kava. Besides the crystalline body, methysticin, which has -already been described by others, he was able to isolate and identify -three resins, one soluble in 5% solution of potassium carbonate, the -second insoluble in this, but soluble in 5% solution of caustic potash, -while the third was insoluble in both of these alkaline solvents, The -ash amounts to 2.495% of the air dried root, and contained besides mere -traces of Fe, Mn, mainly Calcium, Sodium and Potassium.[10] - - [9] Proc. A. Ph. A. 1898, 564. - - [10] Proc. Wisc. Pharm. Assos. 1898, 53, 55. - - - - - _METHOD OF EXTRACTION._ - - -The fresh rhizome was chopped up and then ground up by means of a -meat chopper. In the preliminary work the material was dried in a -vacuum oven at a temperature not exceeding forty degrees Centigrade. -In the later work the material was rapidly dried in the sun. This -operation required about two days time. After being thoroughly dried, -the material was finely powdered, and then extracted with ether. The -following continuous extraction apparatus was used. Due to the extreme -rapidity with which the ether evaporated, it was necessary to surround -the coils with ice so as to keep the condensers cold. - -[Illustration: Diagram of apparatus] - - - - - _METHOD OF SEPARATION OF THE RESINS._ - - -After the removal of the crystalline methysticin from the extract, the -following method of separation of the resinous products was used. - -The free acids were removed by shaking the total resins successively -with solutions of one percent ammonium carbonate, one percent -sodium carbonate and one percent sodium hydroxide. The acids thus -removed were recovered by treating the alkaline solution with dilute -hydrochloric acid and shaking out with ether. The three acids were not -markedly different in their physical properties. They possessed the -characteristic odor of the crude drug, were viscous, brown in color -and did not solidify at minus ten degrees Centigrade. These free acids -constitute about five percent of the total resins. - -The remainder of the extract was treated with alcoholic potassium -hydroxide and saponified by heating the solution to about eighty -degrees for fifteen minutes. After the alcohol was removed by -distillation a small quantity of water was added. This resulting -solution was then extracted with ether to remove the alcohol radical or -radicals and the unsaponifiable material from the saponified product. -The ether extract was saved to be used in the work on the alcohol -radicals. The aqueous portion was evaporated to a semi-solid mass. -Carbon dioxide was passed over this mass for about fifteen minutes -to change any excess of potassium hydroxide to potassium carbonate. -Alcohol (95%) was then added to precipitate the carbonate. The -carbonate was then filtered off and water added to the filtrate. - -To the clear filtrate a solution of barium chloride was added. -Immediately a dense thick cream yellow precipitate formed. Barium -chloride was added in excess. The barium salt was filtered off by -means of a suction pump and the precipitate washed with water. The -filtrate was treated with a few drops more of barium chloride so as to -be sure that an excess had been added, which was proven if no further -precipitate formed. To this clear filtrate an excess of a solution of -ferric chloride was added. Immediately a thick heavy precipitate of the -iron salt came down, which was filtered off by means of a suction pump -and the precipitate washed with water. - -The barium precipitate was treated with dilute hydrochloric acid and -heated to boiling to decompose the barium resinate, and to liberate -the free resin acid. The liberated acid was a brown resin of a thin -consistency and had a characteristic odor. This acid was removed by -shaking out with ether. The ethereal solution was dried with anhydrous -sodium sulphate, filtered, and the ether removed by distillation. The -last traces of ether were removed by heating the resin acids in a -vacuum oven at sixty five degrees Centigrade. This resinous acid is the -acid spoken hereafter in this paper as the BARIUM ACID. - -The iron precipitate was treated with dilute sulphuric acid (ferric -chloride is soluble in ether and ferric sulphate is not) and heated to -boiling to decompose the iron resinate. The acid when liberated had a -strong characteristic aromatic odor. It was extracted with ether in the -same manner as the barium acid. This resinous acid is the acid spoken -of in this paper as the IRON ACID. - -The resinous extract left after the removal of the crystalline -methysticin is spoken of as the TOTAL RESINS. - -The resin acids removed by the preliminary shaking out with the various -aqueous alkalies are spoken of as the TOTAL FREE ACIDS. - - - - - _THE VARIOUS METALLIC SALTS OF THE RESINOUS ACIDS._ - - -After obtaining the potassium salts of the acids and having freed -the same from the excess of the potassium hydroxide and potassium -carbonate, the possibilities of the formation of different metallic -salts were tried. - -The soluble salts of the following metals yielded precipitates:— - - Manganese - Barium - Cobalt - Silver - Mercury - Iron - Zinc - Copper - Calcium - Lead - -The following metallic salts gave a complete precipitation:— - - Silver - Iron (ferric) - Manganese - -Since the barium and iron (ferric) salts gave the best means of -separation, they were used to separate the resins. - - - - - _THE TOTAL RESINS._ - - -The total resins were brown in color, thick syrupy consistency and -possessed the characteristic odor of the drug. - -A molecular weight determination was made in the same manner as with -the Barium acids, and the following data obtained. - - - Wt. of pipette before 18.7660 - Wt. of pipette after 14.7160 - Wt. of resin used 4.0500 - Temperature before 3.52 - Temperature after 3.71 - Change in temperature .18 - Volume 37 cc. - Constant for solvent 3280 - Approximate molecular weight 2000 - -Combustions were made and the following data obtained. - - Wt. of boat 3.4722 3.4720 - Wt. of boat and resin 3.6355 3.6220 - Wt. of resin .1633 .1500 - - Sulphuric acid tube 79.1051 79.3865 - Tube plus water 79.2073 79.4770 - Water .1022 .0905 - Hydrogen equivalent .01136 .01006 - - KOH bulb 49.4316 50.8720 - Bulb plus carbon dioxide 49.8350 51.2430 - Carbon dioxide .4034 .3710 - Carbon equivalent .12102 .1010 - - Percent Carbon 67.31% 67.3 - Percent Hydrogen 6.9 % 6.7 - Percent Oxygen 26.8 % 27.0 - -The total resins when placed on the end of the tongue produced a marked -stinging sensation followed by a local anaesthesia. After the first -stinging was produced the sensation was rather pleasant. The local -anaesthesia persisted a long time, giving a sensation much the same as -that produced by cocaine. The barium and iron acids also produced this -local anaesthesia, but the initial stinging sensation was much more -pronounced, which was probably due to the acid nature of the substance. - - - - - _THE BARIUM ACID._ - - -The resinous material used and spoken of as the “Barium Acid” is -the material prepared and so named as given under the “Method of -Separation”. - -PHYSICAL PROPERTIES:—Dark reddish brown in color, syrupy in consistency -and has a characteristic odor; heavier than water; soluble in benzol, -ether, alcohol and acetone, but insoluble in petroleum ether and water. - -This resin constitutes about sixty percent of the total ester resins; -i.e. the resins left after the free acids have been removed with -aqueous potassium hydroxide. - -An analysis of the barium salt obtained by precipitation from the -potassium soap was made and the following data obtained:— - - Wt. of substance used 1.1715 .5860 - Wt. of barium sulphate .4430 .2205 - Barium equivalent .2606 .1298 - Percent barium 22.2% 22.1% - -The following method was used in making the above analysis. The weighed -material was ignited in a platinum crucible by gently heating until the -combustible gases formed were given off. The crucible was then more -strongly heated to completely burn off the carbonaceous material left. -The residue was extracted with nitric acid and the barium precipitated -as the sulphate with dilute sulphuric acid, and the weight of the -barium sulphate determined. - -Expressed as the ACID NUMBER, or the number of milligrams of potassium -hydroxide required to neutralize the free acids in one gram of the -substance, the following data was obtained:— - - Barium equivalent .2606 .1298 - Barium expressed as KOH equiv. .2131 .1062 - Wt. of material used 1.1715 .5860 - Milligrams of KOH per gram 181.9 181.3 - ACID NUMBER 181.9 181.3 - -The following gives the ACID NUMBER obtained by direct titration of -the barium acid; in “A”, barium hydroxide was used and in “B”, sodium -hydroxide was used. - -A small quantity of the material was dissolved in a sufficient quantity -of neutralized alcohol to give a liquid of a light yellow color, -Phenolphthalein was used as the indicator, and the alkali was added -until a red color was produced. - - “A” “B” - - Wt. of substance .6160 .2345 - Cc. of alkalie 4.54 1.75 - KOH equiv. per gram 41.40 41.90 - Acid number 41.40 41.90 - -On evaporating a portion of the alcohol from the material left after -titrating with the sodium hydroxide, and adding water to obtain an -aqueous solution of the sodium salt, an emulsion was formed, and on -standing globules of the free resinous acid separated. From the data -thus obtained, it can readily be seen that the acid or acids which -constitute the BARIUM ACID must have a number of carboxyl groups and -form a different series of salts by precipitation than by direct -titration. The salt or salts formed by direct titration, although -neutral to phenolthalein may be acid in structure. This is further -shown by the fact that the potassium salts produced by direct titration -are readily hydrolyzed. The acid number obtained by the precipitation -of the barium salt may be called the COMBINING VALUE, and the acid -number obtained by titration the TITRATION VALUE. - -A number of molecular weight determinations were made on the free -barium acid. McCoy’s Boiling Point Apparatus was used and Merk’s benzol -(free from thiophene) was used as the solvent. A weighing pipette with -a bulb was used to introduce the material, the bulb being weighed -before the material was introduced into the apparatus, and afterwards, -the difference being the weight of the material used. - - Wt. of pipette (before) 16.3670 14.8895 - Wt. of pipette (after) 14.8895 12.4610 - Wt. of material used 1.5225 2.4285 - Original temperature 3.53 3.53 - Final temperature 3.60 3.62-3 - Change in temperature .07 .09 - Volume of solution 37 cc 43.5 cc - Constant for solvent 3280 3280 - Approx. Molecular Wt. 2000 2100 or 1800 - -Combustions were made using the barium acids. By qualitative tests it -was found that the acids contained only carbon, hydrogen and oxygen. -The following gives the results of the combustions. - - Wt. of boat 2.8402 2.8402 - Wt. of boat and resin 3.0500 3.0250 - Wt. of resin .2098 .1848 - Wt. of H2SO4 tube 78.0250 78.1415 - Wt. of tube plus water 78.1520 78.2550 - Wt. of water .1270 .1135 - Hydrogen equiv. .0143 .0126 - - Wt. of KOH bulb 48.8140 51.7095 - Wt. of bulb plus CO2 49.3800 52.2085 - Wt. of CO2 .5660 .4990 - Carbon equiv. .1543 .1361 - - Percent Hydrogen 78.5% 73.6% - Percent Carbon 6.8% 6.8% - Percent Oxygen 19.7% 19.6% - -An attempt was made to make the potassium salts of the barium acids by -saponification with alcoholic potash. A small quantity of the acid was -treated with an excess of ten percent alcoholic potash and heated to -eighty degrees Centigrade to complete the saponification. Instead of -the formation of the potassium salts, a thick dark brown solid, gummy -mass separated. On cooling it solidified to a brittle solid which had -all the physical properties of a true resin. This solid is soluble -in ether, chloroform and benzol, slightly soluble in alcohol and -insoluble in petroleum ether and water. It burns without the formation -of an ash. Evidently, this brittle material is a condensation product -of the original barium acid. - - - - - _OXIDATION PRODUCTS OF THE BARIUM ACIDS._ - - -A small amount of the Barium acids was sealed with concentrated nitric -acid in a hard glass tube and heated in a bomb furnace for an hour -and a half at 115 to 120 degrees Centigrade. On cooling a yellow -solid separated. Qualitative tests showed that this oxidation product -contained no nitrogen, combined with sodium hydroxide readily, is -soluble in hot water, slightly soluble in cold water, easily soluble in -ether, alcohol and benzol and slightly soluble in carbon tetrachloride. -It decolorizes alkaline permanganate but does not decolorize bromine -water. - -That there are a number of intermediate products formed and that -nitration also takes place during the formation of these intermediate -products is shown by the following. A small quantity of the acids were -placed in a test tube and covered with concentrated nitric acid. This -was suspended in an H2SO4 bath and a thermometer inserted so as to -observe the temperature. On being gently warmed the nitric acid and -the resin began to react with a rapid evolution of carbon dioxide and -oxides of nitrogen. As soon as the reaction had modified and before the -temperature rose above one hundred degrees Centigrade, a small amount -was removed and added to water. Some of the solid acid was formed and -also a number of globules of oil and there was a strong persistent odor -of nitrobenzene. The original test tube was heated to about one hundred -and twenty degrees centigrade and a small portion again removed. There -was more of the solid material formed and the odor was similar to -vanillin or coumarin or cinnamic aldehyde. The test tube was again -tested when the temperature had reached one hundred and thirty five -degrees Centigrade. There was no aromatic odor and a large amount of -the solid formed. When viewed under the microscope the substance had -the appearance of curled threads. - -When the barium acids were treated with the standard nitrating mixture, -a solid was obtained which showed the presence of nitrogen when the -standard test was applied. - -After the preliminary tests were made, the following method of -preparation was used. Two or three grams of the barium acids were -introduced into a hard glass tube of about thirty centimeters in length -and fifteen or twenty cubic centimeters of concentrated nitric acid -added. The reaction which is very vigorous at first was regulated by -keeping the tube under running water. After this vigorous action was -over the tube was placed in a sulphuric acid bath, and the temperature -gradually increased until it had reached one hundred and twenty five -degrees Centigrade, at which temperature it was kept for about five -hours. It was necessary to add a small quantities of nitric acid from -time to time to make up the loss by evaporation. When the oxidation -was completed the product was poured into water and then heated to -boiling. The resulting solution was filtered and the filtrate allowed -to cool. On standing a quantity of a pale yellow substance separated. -The following data gives the percent yield of this oxidation product. - - Wt. of container 6.7220 - Wt. of container and substance 7.5920 - Wt. of substance .8700 - Wt. of oxidation product .1240 - Percent yield 14% - -The oxidation product was dried by placing it in a vacuum over -sulphuric acid for several days. The neutralization equivalent of this -crude oxidation product was 157. - - Wt. of substance used .0502 - Number Cc. of NaOH N/10 3.2 cc. - Neutralization equivalent 157 - -The oxidation product was heated on a watch crystal and the sublimate -allowed to collect on a funnel. The first sublimate gave a melting -point of 109 degrees Centigrade. - -Combustions were made on this sublimate with the following results. - - (1) C 66% - H 4.7% - - (2) C 65.7% - H 4.8% - - (3) C 65.15% - H 4.8% - - (4) C 65.8% - H 4.85% - -The neutralization equivalent was obtained by titrating an alcoholic -solution of the sublimate with standard sodium hydroxide. The following -results were obtained on two different lots of the sublimed oxidation -product. - - Wt. of substance .09 .1006 - Cc. of alkali N/10 7 cc 7.9cc - Neutralization equiv. 128.6 127.3 - -Using a third sample the neutralization equivalent was obtained from -the analysis of the silver salt. The silver salt was formed by adding -silver nitrate solution to a carefully neutralized solution of the -sublimate. The insoluble silver salt was filtered off, washed with -water to remove the excess of silver nitrate, and dried in a vacuum -over sulphuric acid for several days. A weighed quantity of the silver -salt was ignited in a platinum crucible and the residue of metallic -silver was weighed. The following data were obtained using material -from the same sample for each analysis. - - Wt. of dish 12.8825 12.8826 - Wt. of dish and substance 13.0060 13.1310 - Wt. of substance .1235 .2484 - Wt. of dish and silver 12.9400 12.9980 - Wt. of silver .0575 .1154 - Neutralization equiv. 125 125.3 - -Using the same sample, a neutralization equivalent was obtained by -titration with standard NaOH. - - Wt. of substance .0912 - N/10 NaOH 7.25cc - Neutralization equiv. 125.8 - -The above data shows that the sublimate is a mixture. No empirical -formula can be calculated from the combustions, and different samples -give different neutralization equivalents although the duplicate -determinations on the same sample showed good agreement thus -demonstrating the reliability of the methods. - -By fractional sublimation it was possible to obtain fractions with -different melting points. The first sublimate melted sharply at 109 -degrees. From the last fraction it was possible to separate some -crystals that melt at 200 degrees Centigrade. These might possibly be -p-acetyl-benzoic acid, as its properties of solubility, crystalline -form, its melting point and power of sublimation agree with those of -p-acetyl-benzoic acid. - -Those crystals that appeared identical with benzoic acid were placed -in a melting point tube, and some known benzoic acid (from toluol) -was placed in another tube. These two tubes were placed in the same -sulphuric acid container and their melting points taken at the same -time. They melted at the same temperature. - -The sublimate had a very pleasant aromatic odor resembling benzoin. -It gave no coloration with ferric chloride, thus eliminating a large -group of aromatic compounds. Some of the crystals were found to be -identical with benzoic acid when examined under the microscope. -The characteristic odor of methyl benzoate was produced when a -small quantity of the crystals were heated with methyl alcohol and -concentrated sulphuric acid. On treating some of the carefully -neutralized product with ferric chloride solution, a flesh colored -precipitate was formed. It agreed closely in its analysis with the -precipitate formed with known benzoic acid. - -The filtrate left after the removal of the iron precipitate was -acidified and extracted with ether, and the ether removed by -evaporation. The resulting substance decolorized alkaline permanganate -solution, but did not decolorize bromine water. When the leaflet -needles that melt at 200 degrees were mechanically removed from the -original sublimate, the substance left after precipitating with ferric -chloride melted at 109 degrees. When these crystals were not removed, -the melting point of this material was not definite, but was over a -range of five degrees, from 110 to 115 degrees Centigrade. - -The oxidation product contains at least three distinct substances, -benzoic acid, a substance melting at 200 degrees and—which is probably -p-acetyl benzoic acid and a third substance melting at 110 degrees. - - - - - _THE IRON ACIDS._ - - -The resinous material used and spoken of as the IRON ACIDS is the -material prepared and so named under the “Method of Separation”. - -PHYSICAL PROPERTIES:—Transparent and reddish brown in color, oily in -consistency and has a characteristic tea like odor, heavier than water, -freely soluble in benzol, ether, alcohol and acetone, but insoluble in -petroleum ether and water. - -This resin constitutes about eighteen percent of the total ester resins. - -By qualitative tests it was shown that the acids contained only carbon, -hydrogen and oxygen. Combustions made on the iron acids gave the -following results. - - Wt. of boat 2.6950 2.6950 - Wt. of boat and substance 2.8470 2.8495 - Wt. of substance .1520 .1545 - - KOH bulb 50.9620 51.0805 - Bulb and CO2 51.3370 51.4610 - Wt. of CO2 .3750 .3805 - Carbon equivalent .1023 .10376 - Sulphuric acid tube 76.2448 76.3450 - Tube and water 76.3400 76.4453 - Wt. of water .0952 .1003 - Hydrogen equiv. .0106 .01114 - - Percent Carbon 67.3% 67.2% - Percent hydrogen 7.0% 7.2% - Percent Oxygen 25.7% 25.6% - -An analysis of the iron salt obtained by precipitation from the -potassium soap gave the following data. - - Wt. of substance used .2955 .3387 - Wt. of FeSO4 .0445 .0509 - Ferric equiv. .03208 .03676 - Percent Iron 10.85% 10.85% - -The following method was used in making the above analysis. The weighed -material was ignited in a platinum crucible by gently heating until the -combustible gases formed were given off. The crucible was then strongly -heated until the carbonaceous material was completely burned off. The -residue was weighed and the percentage of iron determined. - -Expressed as the ACID NUMBER, or the number of milligrams of KOH -required to neutralize the free acids in one gram of the substance, -the following data was obtained. - - Ferric equivalent .03208 .03676 - Fe expressed as KOH equiv. .0965 .1107 - Wt. of material used .2955 .3387 - Mg. of KOH per gram 326.6 326.7 - Acid number 326.6 326.7 - -The following gives the ACID NUMBER obtained by direct titration of the -Iron acid. The method is the same as that used in getting the titration -value of the Barium acid. - - Wt. of substance .2450 .2472 - Cc of alkalie 2.2 2.3 - KOH equiv. .01232 .01288 - KOH equiv. per gram 53.87 52. - -An attempt was made to saponify some of the iron acid, but it was -impossible. The alcohol was partially distilled off, and the acid -freed by making the mass acid with sulphuric acid, and shaking out -with ether. The ether was distilled off, but the remaining acid had -different physical properties from the acid with which the experiment -was started. It was lighter in color, and solidified at zero degrees. -At room temperature it was almost solid. On ignition it left no ash. -This probably is a polymerization product of the original acid. - -Since many organic acids whose salts cannot be prepared by the ordinary -methods can be prepared by passing dry ammonia gas through a solution -of the acid in anhydrous ether, this method was tried with the iron -acid. The iron acid was dissolved in anhydrous ether, and the dry -ammonia gas was bubbled through this ether solution. At first no change -was noted, but after several minutes there was a flocculent thready -precipitate formed which was light brown in color. The experiment was -repeated. At first the precipitate was a very light brown, but after -forming it quickly darkened. After standing a few hours the flocculent -precipitate changed to a sticky brown mass. This same change was -produced immediately if the precipitate was exposed to the air. The -resulting mass had no odor of ammonia. - -The flocculent precipitate formed at first was probably the ammonium -salt of the iron acid, which like most ammonium salts, it was -precipitated due to its insolubility in ether. Due to the ease of -hydrolysis this salt immediately decomposed to the acid and ammonia -when traces of moisture were present. - - - - - _OXIDATION OF THE IRON ACIDS AND THE FREE ACIDS._ - - -When the iron acids were oxidized in the same manner as the barium -acids the amount of the oxidation product formed was about one fourth -of that produced with an equal amount of the barium acids. The time -necessary to completely oxidize the iron acids was much less then -required for the barium acids. On sublimation the iron acid gave a -product melting at 110 degrees Centigrade and is probably identical -with the one formed from the barium acids. The iron acid also yielded a -sublimate melting at 208 degrees C. - -The free acids when oxidized in a like manner gave as one of the -products a low melting crystalline compound that contained nitrogen. - -The iron acid although related to the barium acid as shown by the -formation of a common oxidation product is different in structure as -shown by the difference in the amount of the oxidation product formed -and the time to complete the oxidation. - - - - - _THE ALCOHOL RADICALS AND UNSAPONIFIABLE MATERIAL._ - - -The material that was shaken out with ether after the saponification -consists of the unsaponifiable material and the alcohol radicals of the -acids produced by saponification. - -On allowing the ether to evaporate from this material, feathery -needles separated. These were removed by means of a suction pump and -recrystallized from hot acetone. The melting point of this product was -122-125 degrees Centigrade. The precipitate was dissolved in benzol and -allowed to slowly crystallize. It formed long prismatic needles with -melting point of 130 degrees Centigrade. When heated with concentrated -sulphuric acid, a brown green fluorescent solution was produced. - -The remaining material was steam distilled, and the distillate -extracted with ether to remove the oil. The ether was dried with -anhydrous sodium carbonate, the solution filtered and the ether removed -by distillation. The oil that remained was light yellow, specific -gravity less than that of water, and possessed a very characteristic -odor resembling that of musk. The material left after the steam -distillation was cooled and shaken out with ether. The ethereal -solution was dried with anhydrous sodium sulphate and the ether -removed by distillation. The resulting mass was a dark brown resin -without any characteristic odor, solidifying at zero degrees. - -The crystalline product with a melting point of 130 degrees and the -essential oil are evidently the alcohols formed through saponification -of the resin esters. The crystalline product could be readily separated -from the resinous material because of its slight solubility in -acetone. Since this product was not precipitated when the unsaponified -resin esters were treated with acetone and because it did not make -its appearance until after the process of saponification, it is -quite probable it is a product of saponification. The essential oil -can be detected in extremely small amounts due to its penetrating -characteristic odor. Before the process of saponification it could not -be detected, but as soon as saponification took place the odor was very -marked. From this it is quite evident that this oil is a product of -saponification. - -The dark brown resinous mass that remained may be either an alcoholic -resin formed through the hydrolysis of the ester resins or it may -be a resin belonging to the class known as resenes[11] which resist -saponification. - -[11] Com. Organic Analysis. Allen Vol. II, 146. - - - - - _METHYSTICIN AND METHYSTICINIC ACID._ - - -The crystalline product obtained from the ether extract was -recrystallized several times from absolute alcohol to remove all -traces of any resinous material. It had a melting point of 122-123. -It therefore was not pure methysticin, which has a melting point of -138-139 degrees. On examining this product under the microscope it -was found to contain two distinct forms of crystals, long needles and -prismatic plates. Some free methysticinic acid, melting point 180 -was examined under the microscope and found to consist entirely of -prismatic plates. Therefore the original crystalline body contains some -methysticinic acid. - -Some of the original precipitate was crystallized once from absolute -alcohol and thoroughly dried. This was used for the following data to -determine the percent of free methysticinic acid in the crystalline -product. A weighed amount of the crystalline product was dissolved in -carefully neutralized alcohol, and titrated with tenth normal NaOH, -using phenolthalein as the indicator. - - Wt. of substance used .2590 - NaOH N/10 .5 cc - % methysticinic acid. - -The potassium salts of the various resin acids formed by the -saponification of the ester resins should yield a resinous mass syrupy -or oily in consistency when acidified, if it consists entirely of the -two groups of acids spoken of as the iron acids and the barium acids. -Also the weight of the barium acids plus the weight of the iron acids -should nearly equal the weight of the ester resins, if these are the -only two acids, because the alcohol radicals constitute not more than -two percent of the ester resins. But when the total potassium salts -were acidified the product formed contained a crystalline substance -in addition to the resinous acids. This crystalline substance was -separated from the resinous acids by means of their difference in -solubility in ether. On recrystallization from absolute alcohol, -it had a melting point of 179 degrees Centigrade. It is therefore -methysticinic acid. This acid constitutes about twenty percent of the -total acids from the ester resins because the barium and iron acids -constitute only about seventy five percent. - -This methysticinic acid cannot be entirely formed by hydrolysis of -methysticin which was incompletely removed from the resinous material. -The methysticinic acid existed either combined with some other alcohol -than methyl alcohol or was combined with one of the resin alcohol -radicals. - - - - - _PHYSIOLOGICAL ACTION._ - - -Due to the impossibility of preparing the alkali salts of the barium -and iron acids so as to be positive that the resulting preparations -completely represented the barium and iron acids, and due to the -insolubility of the acids and the total resins in solvents from -which they would not again be precipitated when introduced into -the circulation, it was found necessary to make an emulsion. The -emulsifying agent used was acacia (gum arabic). It was possible by -careful preparation to make a permanent emulsion that was miscible -with water in all proportions to form a homogeneous mixture. The -animals used were rabbits of about six pounds weight. The injections -were made by Dr. Geo. McCoy, director of the Leprosy Investigation -Station at Kalihi. All the physiological experiments were made at the -bacteriological laboratory at the Leprosy Investigation Station. - -One cubic centimeter of the emulsion of the total resinous extract -(strength 1 in 5) was injected into the ear of a rabbit; the animal -died immediately. Another rabbit was injected in the same manner -with one half cubic centimeter of the same preparation. The animal -immediately stretched out and became rigid, or appeared to be -paralyzed, but after several minutes these symptoms lessened and after -about five minutes the rabbit appeared normal as far as activity was -concerned. As soon as the rabbit had recovered a second injection of -one quarter of a cubic centimeter of the same preparation was injected -in the same manner into the same animal. The same symptoms were -produced and with equal intensity, but ten minutes passed before the -animal again became conscious. For several minutes after recovery the -animal appeared somewhat drowsy and stupid but it soon regained its -former activity. - -One half cubic centimeter of the iron acid emulsion (strength 1 in 7) -was injected into the ear of a rabbit. Immediate paralysis and apparent -anaesthesia set in lasting very pronouncedly for eight minutes. The -rabbit’s head was drawn backwards and its legs stiffened giving -symptoms similar to strychnine poisoning but they did not persist. -When a second injection of one quarter cubic centimeter was given to -the same animal, the same symptoms were produced, the animal remaining -under the influence of the injection for about fifteen minutes. - -The iron acid injection was repeated on another rabbit with the same -pronounced symptoms of strychnine poisoning but the effect lasted only -about ten minutes. - -One half cubic centimeter of the barium acid emulsion (strength 1 in -7) was injected into the ear vein of a rabbit. The animal uttered -several loud cries and after moving several feet it became spastic and -went into a sort of a stupor, beginning to come out of it after ten -minutes. As soon as the animal recovered, a second injection of one -quarter cubic centimeter was made. The animal again uttered loud cries -and then it went into a stupor, but it was not spastic. This lasted -approximately ten minutes. The animal did not completely recover until -about twenty minutes. - -Thinking that the action might be largely mechanical and that the -symptoms produced were from the emulsion itself and not from the effect -of the material that was emulsified, an emulsion of olive oil was used -in a like manner. This olive oil emulsion was made in approximately the -same consistency as the resinous emulsions, and one cubic centimeter -was injected into the ear vein of a rabbit. No visible effects followed -this injection during the one hour’s time the rabbit was under -observation. - -One cubic centimeter intraperitoneal injections of the total resinous -extract emulsion and the same amount of the iron acid emulsion were -made into rabbits. During the three hours the animals were under -observation no symptoms were produced. This may have been due to the -extreme slowness of absorption as compared with the rate of elimination -from the circulation. - -Dr. J. F. Illingworth states as the result of his observations while -in the Fiji Islands that the kava beverage even when taken in large -amounts, does not apparently affect the brain to an extent as to cause -the drinker to appear as if under the influence of alcohol, but he -appears as if the muscles from the hips downward are paralyzed. These -symptoms last for about half an hour, at the end of which time the -person is perfectly able to walk home. - -In general the active constituent of any drug produces a more -pronounced but more fugitive effect than the crude drug itself, and one -might therefore expect more violent reactions from the isolated active -constituents of the Ava then from the crude infusion. Judging from the -negative results obtained from the injection of the olive oil emulsion, -it is probable that the physiological effects described above -following the intravenous injections of the various preparations were -not mechanical but must be ascribed to the action of the constituents -of the Ava. - - - - - _CONCLUSION._ - - -The crystalline product consists, largely of methysticin, the methyl -ester of methysticinic acid. In addition to this there is about five -percent of the free methysticinic acid present. - -The resinous product consists of about five percent of free resinous -acids, which acids can be separated into three different acids or -groups of acids according to their solubility in the different -alkalies. The remaining resinous product is composed of ester resins. -On hydrolysis these esters yield three distinct acids, two resinous -acids and methysticinic acid. The two resinous acids are distinctly -different, both in physical properties and in chemical properties. They -can be sharply separated by means of the difference in solubility of -their barium and iron salts. These acids may be separate individual -substances, or a group of related substances. The barium and iron acids -although different chemically, have some groups in common as shown by -the formation of a common oxidation product. There are at least three -alcohol radicals formed through hydrolysis, a resinous alcohol radical, -a crystalline substance with a melting point of 130 degrees, and a -volatile oil. - -The physiological action of the Ava is due to the ester resins. The two -resinous acids formed through the hydrolysis of these esters seem to be -the two active constituents of the resin ester. - -From the above outlined work it appears that the ava root does not -contain any alkaloidal substance, as none of the constituents were -found to contain nitrogen. - -That the aqueous infusion used by the ava drinkers contains the same -constituents as are extracted by the ether is shown by the following. -An infusion of the ava was made by allowing some of the powdered drug -to remain in contact with water for about twelve hours. The infusion -was then filtered and the filtrate extracted with ether. A resinous -mass remained which from all appearances was identical with the resins -obtained from the ether extract. It also gave the same action when -placed on the tongue as was produced by the resins from the ether -extract. - -*** END OF THE PROJECT GUTENBERG EBOOK THE CHEMICAL CONSTITUENTS OF -PIPER METHYSTICUM; THE CHEMICAL CONSTITUENTS OF THE ACTIVE PRINCIPLE OF -THE AVA ROOT *** - -Updated editions will replace the previous one--the old editions will -be renamed. - -Creating the works from print editions not protected by U.S. copyright -law means that no one owns a United States copyright in these works, -so the Foundation (and you!) can copy and distribute it in the -United States without permission and without paying copyright -royalties. Special rules, set forth in the General Terms of Use part -of this license, apply to copying and distributing Project -Gutenberg-tm electronic works to protect the PROJECT GUTENBERG-tm -concept and trademark. 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