(Par. 18, act of 1913, 25 per cent ad valorem.)

GENERAL INFORMATION.

Description.--Guaiacol is the monomethyl ether (C,H,O2 or C.H(OH) (OCH,)) of ortho-dihydroxybenzene (pyrocatechin) obtained from wood-tar creosote or prepared synthetically. Creosote and its compounds and phenol are closely allied in action.

Synonyms. Ortho-dioxybenzene-methyl ester; methyl-orthodioxy benzene; methyl-pyrocatechin; catechol-monomethyl-ether.

Preparation. Guaiacol may be obtained by fractional distillation of beechwood-tar creosote. The fraction passing over between 200° and 205° C. is treated with ammonia and fractionated again. The lower boiling fraction is dissolved in ether and treated with an alcoholic solution of potassium hydroxid. Potassium-guaiacol separates out. This is washed with ether and crystallized from alcohol, and the guaiacol obtained by treatment with dilute sulphuric acid.

Several processes have been proposed for the synthesis of guaiacol. It may be formed, together with potassium sulphate and water, by heating a molecular mixture of pyrocatechin, potassium hydroxide, and potassium methylsulphate. Guaiacol is removed by solution in alcohol or petroleum-ether and purified by recrystallization. By another method sodium, pyrocatechin, and methyl iodide are heated in methyl alcohol, treated with sodium hydroxide solution and filtered. Guaiacol is liberated from the resulting combination by treatment with hydrochloric acid, distilled, and crystallized.

Compounds and derivatives. These form a rather numerous class, over 20 being briefly described in the U. S. Standard Dispensatory (1916) to which reference may be made for their names, synonymy and uses. A large number are more extensively discussed in a series of articles by F. G. Ehlert in the Pharmaceutical Review, 1901-2. In general these products are of German origin, of a proprietary type, and have been introduced in the endeavor to present the valuable properties of guaiacol in a tasteless or less irritant form, or to combine the virtues of guaiacol with those of some other medicinal agent. In general their uses are those of guaiacol. Of these numerous substances, guaiacol carbonate only has received official recognition; also, it is the only guaiacol product specifically mentioned in the act of 1913.

Guaiacol carbonate may be formed by passing phosgene gas (carbonyl chloride) into guaiacol dissolved in caustic soda solution. Guaiacol carbonate separates out and sodium chloride remains in solution. The carbonate is washed with caustic soda solution, and crystallized from alcohol. It was introduced under the name of Duotal by a German firm; the United States patent has expired. Benzosol, or guaiacol benzoate; guaiamar, or guaiacolglycerylester; monotol, or guaiacol methylglycolate; styracol, or guaiacol cinnamate; guaiacol-salol or salicylate of guaiacol are noted in New and Non-Official Remedies, 1917. All but guaiamar are of German origin; the United States patents on benzosol and guaiamar have expired; that on monotol expires in 1923. The name "styracol"

is protected by trade-mark, but the substance appears not to be patented.

Uses. The uses of guaiacol are similar to those of creosote, its parent substance. It is used in the treatment of pulmonary tuberculosis; it diminishes the cough, but has no specific action on the tubercle bacillus. It has also been used as an antipyretic in fevers, but is apt to produce collapse. It is locally employed in ointments in skin diseases for its anesthetic and antiseptic effects. Guaiacol, and more particularly guaiacol carbonate, are used as intestinal antiseptics. The only official preparation of guaiacol is the petroxylin. Guaiacol carbonate-Imports for consumption-Revenue.

rate.

Pounds.

Per cent.

1,637

$2,645

6,907

11, 125

$661 2,781

$1.62

1.61

469

1,160

290

2.47

200

6, 458

1,614

32.29

9,517

75, 671

25

25

25

$1.70-$1.80

1.70-1.80

1.70-1.80

1.70-1.80

1 Six months ending June 30, 1920.

Guaiacol, liquid-Prices per pound, wholesale, New York, spot.

[From Cil, Paint, and Drug Reporter.]

1.70-1.80

July, 1916.

13.75

(For laws from 1883 to 1909, see Chloral hydrate, supra.)

COURT AND TREASURY DECISIONS.

Guaiacol carbonate was held dutiable as a nonalcoholic and not as an alcoholic medicinal preparation under the act of 1909, on the authority of United States v. Hoffman-La Roche Chemical Works (1 Ct. Cust. Appls., 276), which, however, turned upon a jurisdictional question. In re Amermann, T. D. 31524. And under the act of 1897 (United States v. Lehn, 2 Ct. Cust. Appls., 59, of 1911). (For classification under prior acts see Chloral hydrate, supra.)

THYMOL.

[Par. 18, dutiable at 25 per cent ad valorem.]

GENERAL INFORMATION.

Thymol belongs to that class of chemical compounds known as phenols and occurs in the volatile oil of Thymus vulgaris Linne (Fam. Labiatae) and in some other volatile oils.

Substitutes. Phenol may be employed as an internal or external antiseptic, but is irritating and of higher toxicity. A number of proprietary disinfectants are used for similar purposes. As a substitute for thymol in hookworm disease, oil of chenopodium has lately attracted favorable attention, as has chloroform in veterinary practice.

Carvacrol, a substance closely allied to thymol, occurring in the oils of Monarda fistulosei L., Origanum dubium Boiss (Cypress origanum), O. onites L., (Smyrna origanum), Satureia hortensis L. and S. montana L., (white thyme) has recently been suggested in England as substitute for thymol in antiseptic use. The oil of cypress origanum is a commercial commodity, 4,200 pounds, valued at £980, being exported to the United Kingdom in 1913. 82.5 per cent of this oil is carvacrol, and preparations of origanum oil under the name of "Perfumed Formosyls" have been prepared for medical use in Great Britain.

Uses.-Thymol is official in the principal pharmacopoeias. It was introduced into medicine as a substitute for phenol, and in action stands midway between this and oil of turpentine. As an antiseptic it is more powerful and permanent than phenol, and much less poisonous, but its insolubility in water, its high price, and its odor, which is extremely attractive to flies, prevent its general use for this purpose. Thymol is employed as a gargle or spray in throat affections and as an ointment in skin disease. Its chief internal application is in hookworm disease; it is almost a specific against the parasite. It has been employed as an intestinal antiseptic in typhoid and other bacterial disease of the intestines.

It is frequently used as an antiseptic ingredient of dentifrices. Official salt. Thymol iodide (Aristol, dithymol diiodide) is obtained by the addition of an iodine-potassium iodide solution to thymol in a solution of sodium hydroxide. It possesses in part the antiseptic properties of both thymol and iodine, and is used as a substitute for lodoform, being less efficient in most connections, and is used when the odor of iodoform would be objectionable.

Unofficial salts.-Thymol carbonate, or thymo tal, is an efficient vermicide, and useful in hookworm disease.

Thymol salicylate of salithymol, thymacetin, and thymoform are less important derivatives.

Production.-Thymol is a constituent of the essential oils of several plants, the most worthy of note being Thymus vulgaris L., Monarda punctata L. (fam. Labiatae) and Carum copticum Benth & Hook. f. (fam. Umbelliferae). Commercial supplies of thymol have come almost wholly from the latter plant. Thymol from Thymus vulgaris (Thyme) has recently been offered in England, but the product is said not to fulfill pharmacopoeial requirements, the reason given being that, under present excise requirements, thymol can not be crystallized in England from pure alcohol. Production of thymol from Monarda punctata L. (Horsemint) is still in the experimental stage, and will be further noted under "Competitive Conditions."

The seed of Carum copticum (also known as Carum ajowan, Ptycholis coptica, P. ajowan), known commonly as ajowan, is derived from a herbaceous plant closely related to caraway, cultivated throughout India, especially in Bengal, and growing also in Egypt, Persia, and Afghanistan. It has been introduced into Europe, but commercial supplies have come wholly from India. Oil exists in all parts of the plant, but only that of the seed contains thymol in commercial quantities (45-55 per cent as against 1 per cent in the oil of the plant aside from the seed). The oil is obtained by steam distillation and distilled to drive off the more volatile constituents (Cymene, etc.). The residue (above 200° C.) is treated with sodium hydroxide solution, which takes up the thymol, which is precipitated as an oily layer by the addition of hydrochloric acid. Thymol crystallizes out on cooling, and may be purified by clarifying and recrystallization from alcohol. It may also be obtained by fractional distillation and crystallization, or by refrigeration of ajowan oil. The details of the German commercial processes are trade secrets. Before the war German firms had practically no outside competition, and recent efforts by English chemists to produce an equally valuable product do not appear to have been wholly successful.

Thymol has been produced to some extent from ajowan seed in the United States, although in normal times supplies have usually been imported. In recent years several American plants have been found to yield a considerable amount of thymol and production has been experimentally undertaken by the United States Department of Agriculture, by several experimental stations, and commercial firms. The present commercial status has not been investigated.

Previous to the war Germany had a virtual monopoly of the manufacture of thymol, which was produced by more or less secret processes from ajowan seed imported from India. The product was also manufactured by synthesis. In other European countries efforts have been made with some success to prepare thymol from other plants. A factory has also been established by the British Government in India. Its product has apparently been absorbed by British governmental agencies.

Synthesis of thymol.--Several methods have been proposed for the synthesis of thymol. The chief organic compounds from which it may be derived are cumidine, paracymol, menthone, buchu camphor (diosphenol) dimethyloxystyrol, and metacreasotic acid methyl ester. In general it may be said that these compounds are fully as expensive ast thymol under normal conditions, and the processes by which thymol is derived from them are also expensive as well as complicated. While it has sometimes been hinted that synthetic processes were in use

in German factories, the large German imports of ajowan seed and the normal price of thymol leave room for doubt as to whether such processes are of commercial importance.

A synopsis of synthetic processes and references to original litera-ture may be found in Abderhalden (see Bibliography).

Thymol was first used in India; a crude product has been prepared there to some extent for oriental consumption, but scarcely for European and American commerce.

The oil of thyme contains 20-30 per cent and that of horsemint as much as 60 per cent thymol.

The price of ajowan seed, and therefore of thymol, normally depends on sanitary conditions in India, being highest during epidemicsof plague, cholera, etc.

Imports. Imports prior to 1914 are not listed. For the years. 1914-1918 an average annual amount of 12,199 pounds, valued at $33,136, is reported. During this period the commodity has yielded an annual average revenue of $8,334. A large increase in importsis noted in 1918.

Prices. Import values per pound for 1914-1918 range between $1.30 and $7.81. American wholesale prices for 1912-1918 vary between $1.40 and $18 per pound.

War disturbances. The production of thymol before the war was,. as has been noted, in effect, a German monopoly. With the severance of the German supply thymol went practically out of the market. Thymol shortage was felt particularly in England, and efforts at production were made without apparently conspicuous success. A factory subsidized by the British Government is said to have been established in India, but its product apparently is wholly devoted to the needs of the British Government in India and elsewhere. substitutes elsewhere noted have been largely developed under the stimulus of war necessities. Various pine oils are now largely used as disinfectants, and these also may be considered thymol substitutes. or rivals in certain connections.

The

Competitive conditions.-No attempt to grow the ajowan plant in America has been noted. The horsemint (Monarda punctata), which occurs as a common weed in the sandy lands of central Florida, yields 0.12 to 0.20 per cent of a volatile oil whose thymol content ranges from 56 to 62 per cent. Hood reviews investigations made. by the Bureau of Plant Industry, United States Department of Agriculture, as to the commercial possibilities of this plant. Promising results were obtained in cultivation of the plant and production of thymol on a small scale. Seed was gathered from wild plants; selection of types promised well in developing a strain of horsemint above the average in thymol content. The plant grew well (in Florida) and its cultivation was inexpensive. A plantation should last five years. Estimating the selling price of thymol at $2 per pound the writer shows an annual profit of about $16 per acre per year in the five-year period. He believes that the production of horsemint for thymol might be profitable in connection with other oil-yielding plants for which a distilling apparatus is required.

The production of thyme for thymol would probably not be commercially feasible in America.