These stresses are known as the principal stresses. The planes on which they act are known as the principal planes, as there are no tangential stresses along these planes. The direction of these. planes is given by the equation

The maximum and minimum tangential shear are given by the equation

The planes along which they act are given by the equation

Somewhat more than two hundred and fifty years ago, in 1638 to be exact, a certain Vice-Queen of Peru was cured of fever by the use of the bark of some trees native of Peru. After her recovery this grateful woman, the Countess of Cinchon, took steps to make known to the world the healing properties of the bark. In Europe, particularly in Spain, the bark now known as the wonderful Cinchona bark in honor of the Countess, came gradually into use as a febrifuge. And as we now think of quinine its most, important medicinal constituent, with its wonderful antiseptic, tonic and febrifugal properties, is it strange that before very many years after its first use the supply of trees was found nearly exhausted?

It was only natural that physicians and others of an inquiring turn of mind should investigate a remedy of such sovereign worth, and so we find that, after many years of experimenting and investigating, it became possible to separate from the bark that intensely

* Contributions from the Havemeyer Laboratories of Columbia University, No. 115.

bitter portion that gives it healing power. Indeed it required nearly two hundred years of use to teach us the presence and nature of the alkaloids in cinchona bark. It was at a comparatively recent date, therefore, 1820, that two investigators, working together, succeeded in isolating two pure alkaloids. From an extract which they had made both cinchonine and quinine were obtained in pure condition. To Pelletier and Caventou belongs the honor of discovering quinine (1, 2).*

Of the twenty-one alkaloids that have thus far been discovered in cinchona bark, without hesitation quinine is selected as the most important.

Let us inquire for a moment why this is. Primarily it is on account of its peculiar and unique therapeutic action. Quinine is considered in the medical profession as almost, if not quite, a specific for fevers of a malarial nature. And we should remember that in all our extensive materia medica there are indeed few specifics.

We are not particularly concerned in this paper with the exact modus operandi by which our alkaloid overcomes the pernicious effects of the parasites causing intermittent fevers; but one theory advanced to explain its action is interesting. It is suggested that quinine is of such a composition as to combine chemically with certain constituents in the make-up of the parasitic organism, result being the death of the organism.

the

A second reason for the important place won by quinine is that it predominates over the accompanying related alkaloids in point of quantity present in the bark. Cinchonine, cinchonidine, and quinidine, which are present in cinchona bark in smaller amounts, are not without effect in intermittent fevers; but fortunately quinine is the most plentiful and at the same time the most effective.

It is somewhat strange, in view of the importance of quinine and the relative unimportance of cinchonine, that we find the composition and chemical structure of quinine less thoroughly investigated than that of cinchonine. Indeed the structure of cinchonine has been worked out with much pains and several graphic formulæ have been proposed for it. Much has been done on quinine as well, although it is apt to be more lightly passed over as "similar to cinchonine," or "probably a paramethoxycinchonine."

In 1838 Liebig proposed the formula, C,H,,NO for the anhy*These numbers refer to the Chronological Bibliography at the close of the article.

drous alkaloid quinine (4, 6). Later, in 1854, Strecker (8, 9), and also Regnault (5) established its correct formula, CH,,N,O, (3). There are no successful efforts to further establish or change the formula recorded immediately after 1854; and only minor points of the constitution were investigated at this time. Now and then for twenty years we find various reactions of quinine noted, but the period from 1878 to the present time covers the greater part of the investigations and nearly all of the important ones.

Quinine may be prepared (14) either amorphous or crystalline, the amorphous being anhydrous and readily changing to the crystalline form with three molecules of water. Anhydrous crystals are also known. Quinine solutions are lævorotary, have an alkaline reaction, a bitter taste, and with ammonia and chlorine water give a characteristic green color; dilute aqueous solutions of its salts, especially of the sulphate, show a blue fluorescence.

The anhydrous amorphous alkaloid has a melting point of 172.8° C., the anhydrous crystals 174.4-175° C., but the trihydrated base melts much lower, at 57° C. Alkalies precipitate the alkaloid from the solutions of its salts, and this property is made use of in its commercial production. The powdered cinchona bark is treated with water and alkali, generally lime, and the free bases, including quinine, are then extracted by means of suitable solvents. Various methods of separating quinine from the other alkaloids are resorted to. It is prepared synthetically by methylation of cupreine (42, 43).

Quinine is soluble in alcohol, ether, and chloroform, but quite insoluble in benzene and water, although imparting its taste to the latter. Indeed the extremely bitter taste of the alkaloid and its salts is one of the most serious drawbacks to its use in medicine. Many attempts have been made to prepare a tasteless quinine compound, or even one with a less disagreeable taste. These necessarily take the form of insoluble compounds. They are, of course, tasteless if insoluble; but, if really insoluble, they are practically inert therapeutically. The demand for tasteless quinine is so pronounced that many fraudulent preparations have been put forth from time to time, some of them free from quinine, as well as from its bitter taste. The tannate, being insoluble, is nearly tasteless. Quinine carbonic ester, with formula given as C,H,N,O,. COOCH, is also practically tasteless. It is dissolved by dilute alkalies, and hence in the alkaline juices of the intestinal tract it

201 23

2

becomes therapeutically available. It is of considerable commercial importance, being especially useful for child medication.

There are several compounds known to literature that are isomeric with the alkaloid (19); and there are also several ways of producing the different isomers. Skraup and others (44, 45, 46, 52, 55, 56) after adding a molecule of a halogen acid, remove the elements of the same acid by means of alkalies; but they recover only a small per cent. of the original quinine. Instead, isoquinine, pseudoquinine, niquine, etc., are obtained. Sulphuric acid or even heat alone converts quinine into its isomers. Thus it was that Pasteur in 1853 produced quinicine, another isomer, by heating the alkaloid to 120° C. in the presence of dilute sulphuric acid (7). It may also be produced by heating with glycerol to 180° C. Skraup, Hesse, and others have studied the isomers and some of their decomposition products (44, 45, 46, 52, 55, 56).

When quinine is treated with bromine or chlorine in the cold, it takes up two atoms of the halogen. An addition product is formed. One molecule of halogen acid is added in a similar manner (39, 44, 51); and these new compounds will add two more molecules of the same or a different (44, 45, 54) halogen acid. A condition of unsaturation, therefore, exists in the alkaloid. We may further prove this by treating it with zinc and sulphuric or hydrochloric acid, when dihydroquinine, CH,N,O,, is produced (13). Or, using sodium and alcohol, especially amyl alcohol and heat, tetrahydroquinine, CH2N,O,, results (64, 66, 68). Very many other addition compounds have been prepared (30, 50), as for instance, the monomethiodide (47), ethiodide and ethchloride (9), the dialkyliodides (31, 42, 48, 53), ethiodide hydriodide, C, H,NO2·HI · C ̧H ̧I (60), quinine chioral CHNO, ·CC1CHO (34), quinine monoand dichlorhydoacetates C2HNO2 · CH2CICOOH · 2 1⁄2 H2O (36), quinine nitrobenzaldehyde, CHN2O2 · CH(NO)CHO (35), etc. Jobst and Hesse have also prepared addition compounds of quinine salts with phenol, as an example of which that of the hydrochloride with phenol may be mentioned, 2 (C2H, NO,HC1) · CH ̧O · 2 H2O(18). And Jobst has prepared an addition compound of quinine alkaloid and phenol (17). Monoand dibenzyl addition products are likewise known (37).

24 2

20 24 2 2

20 24

20 24 2 2

The action of quinine when fused with caustic alkalies affords a further insight into its composition. Betaiutidine, lower aliphatic acids, such as acetic, butyric, and propionic, quinolidine, and para methoxylepidine are formed (20, 41).

From this it seems evident that the alkaloid contains a methoxygroup (29, 41), and that its position is the same as that in quinolidine and paramethoxylepidine. We can easily further prove the presence of a methoxy group by heating the alkaloid at 140 150° C. with concentrated hydrochloric or hydriodic acid (29, 63). Methyl chloride or iodide, as the case may be, will be formed. The reaction with potassium hydroxide also indicates the presence of a pyridine ring and a quinoline formation, the latter doubtless with a methoxy group in the para position; either one or both may be present.

Probably the best proof of the internal structure of the quinine molecule is furnished by the products of its oxidation by various methods. The action of potassium permanganate in alkaline and in acid solution, both hot and cold, of chromic acid, and of nitric acid has been extensively studied, principally by Kerner, Skraup, and Ramsay and Dobbie.

Potassium permanganate gradually added to a solution of quinine in sulphuric acid, keeping the temperature below 10° C., causes the splitting off of a molecule of formic acid, and the production of a new body called quitenine, C,,HN,O,+4H2O (15, 24, 26, 57). Since the oxidation occurs with so much ease, it is probable that it occurs at the point of unsaturation. That is, at an ethylene linking, where, as has been found, addition of halogens and other compounds so easily occurs. If the presence of a condition such as this —CH = CH, is assumed, we may expect it to form addition compounds, and, upon treatment with permanganate, we may expect it to become COOH and HCOOH. The reaction, in fact, occurs in the way indicated, formic acid and a carboxyl being produced. Quitenine is thus an acid (61). We may further assume that the - CH = CH, is present in the form of a side chain, since it is so readily detached.

If the oxidation is allowed to proceed more vigorously, for example by hot permanganate or by nitric acid, the resulting products are more numerous (10, 12). One of the most important is cinchomeronic acid (21, 25).