Solubilities alkaloidal salts

It is a general observation that aging leaves lose at least a proportion of their alkaloids while attached to the plant. This could be due to a slow evacuation of soluble alkaloid salts into the stem. It could also be due to breakdown in situ, either with or without subsequent transport, of the degradation products. Detached belladonna leaves do break down their alkaloids after a more or less prolonged period of detachment, and similar destruction of nicotine has been observed by Mothes in old tobacco leaves, though Vickery et al. failed to observe it in leaves which were, perhaps, younger (99). 

Ewing et al. (2) noted that C. bowiei, a small shrub in New South Wales and southern Queensland and a tree growing to about 10 m (30 feet) in northern Queensland, afforded alkaloids which were different but structurally closely related. Methods of isolation were essentially the same, and the alkaloids were obtained as sparingly soluble iodide salts after addition of potassium iodide. (—)-Cryptaustoline iodide (C20H24NO4I) was obtained from extracts of the bark of larger northern trees, and (-)-cryptowoline iodide (C,gH2oN04l) was found to be present in the smaller southern shrubs. 

Most alkaloids exist in nature not in their free-base form but rather as the salt of naturally occurring acids known as tannins, a group of phenol-based organic acids that have complex structures. The alkaloid salts of these acids are usually much more soluble in hot water than in cold water. The caffeine in coffee and tea exists in the form of the tannin salt, which is why coffee and tea are more effectively brewed in hot water. As Figure 12.19 relates, tannins are also responsible for the stains caused by these beverages. 

Alkaloid salts are not very soluble in the organic solvent diethyl ether. What might happen to the free-base form of caffeine dissolved in diethyl ether if gaseous hydrogen chloride, HC1, were bubbled into the solution ... 

This chapter documents enhancements of the efficiency of SFE extraction of alkaloids from plant matrices using basified modifiers. Hence (1) The pure compound solubility of some free bases in pure supercritical C02 has been measured by investigating the effects of temperature, pressure or density of C02 (2) The solubilities of the alkaloidal salts were compared with those of their free bases in order to evaluate the difference of their solubilities influenced by a changing from free bases to salts (3) Polar solvents such as methanol and water, as initial modifiers, were used for the enhancement of the solubilities (4) The solubilities of the salts by non-basified modifiers such as neat methanol or water were compared with those of methanol or water basified with diethylamine (5) The effect of modifiers employed on the desorption of the compounds from a matrix were measured and compared with each other (5) On the basis of the results of pure compound extractability, SFE was performed on alkaloids from the plant... 

Although there were some differences on the effects of temperature and pressure according to each particular compound, the free bases of hyoscyamine (1), scopolamine (2), and pseudoephedrine (6) were all found to be highly soluble in supercritical CO,. However, the hydrochloride salts of these compounds were scarcely extracted by pure CO, under any conditions employed. These results were consistent with preliminary evidence indicating that these alkaloids are not extracted from plant materials by pure CO,. This means that the alkaloids in living cells in the plant are not in the form of their free bases but rather as water-soluble salts in the cell vacuole [40]. Therefore, it was necessary to develop a procedure to enhance the solubilities of alkaloidal salts in CO,. 

Modifying Effect of Methanol and Water on the Solubility of Alkaloidal Salts... 

To improve supercritical C02 solubilities of target alkaloidal salts, an appropriate modifier to raise the polarity of C02 had to be used. As previously mentioned, the most common modifier used in SFE is methanol because of its high solvation parameters, which can greatly increase the resultant polarity of C02. Water has been chosen as another modifier because some alkaloidal salts are freely soluble in water as well as methanol. Moreover, the addition of water into C02 has been reported to improve the extraction yield of some alkaloids [29]. Methanol or water as a modifier was added into the extractor at the concentration levels of 1, 5 and 10% (v/v), respectively. The effect of methanol and water on the solubilities of hyoscyamine (1) and scopolamine (2) is shown in Figure 5. Analogous information on ephedrine derivatives such as methylephedrine (3), norephedrine (4), ephedrine (5), and pseudopehedrine is illustrated in Figure 6. 

While increasing the concentration of water did not show any significant influence, the addition of a greater proportion of methanol yielded great enhancements in the resultant solubilities of the alkaloids, except for methylephedrine (3). These observations may be due to the fact that water is not so miscible as methanol in CO, (Figure 7). Therefore, water was less effective than methanol in terms of the enhancement of the SFE efficiency. Even though the addition of methanol in CO, resulted in slight improvements in solubilities, they were still poor, hence another modifier to enhance the solubilities of the alkaloidal salts was required. 

Generally, alkaloidal salts are insoluble in nonpolar solvents but their free bases are quite soluble in the solvents. Therefore, the basified modifier should be introduced into the SFE to solubilize alkaloids in CO,. For the evaluation of the effects of basified modifiers, diethylamine was added to methanol or water at a 10% (v/v) concentration level. Then, the basified modifiers were continuously incorporated into the extraction cell at concentrations of 1, 5, and 10 % (v/v). The effects of methanol basified with diethylamine as a modifier on the solubilities of hyoscyamine (1) and scopolamine (2) are shown in Figure 8. The addition of diethylamine (10% v/v) into methanol dramatically enhanced the solubilities of the alkaloidal hydrochloride salts compared with those of pure methanol alone. This may be due to the fact that methanol basified with diethylamine changed the salts to the free bases. 

In spite of the difficulty in definitely characterizing alkaloids by definition, they do have a surprising number of physical and chemical properties in common. For the most part, the alkaloids are insoluble or sparingly so in water but form salts (by metathesis or addition) that are usually freely soluble. The free alkaloids are usually soluble in ether or chloroform, or other immiscible solvents, in which, however, the alkaloidal salts are insoluble. This permits the isolation and purification of the alkaloids as well as their quantitative estimation. Most of the alkaloids are crystalline solids, although a few are either amorphous (coniine, nicotine, sparteine) or liquid. It is interesting to note that the liquid alkaloids have no oxygen in their molecules. Alkaloidal salts are invariably crystalline, and their crystal form and habit are often useful in their rapid microscopical identification (Sollmann, 1944). 

The hydrogen succinates are prepared by procedures closely similar to those followed for the phthalates, except that succinic anhydride is used.10 The crude ester is best taken up at once in ether or benzene, and the solution is washed with water to remove succinic acid. The hydrogen succinates are more soluble in the usual solvents than the corresponding phthalates and often do not crystallize readily. Their alkaloid salts also... 

Thalistyline, a monoquaternary salt from the quaternary fraction of the chloroform-soluble alkaloids of Thalictrum longistylum and T. podocarpum, has strong hypotensive action at 1.0 mg kg-1 in normotensive dogs and rabbits. It has the structure (46), and both the related bis-tertiary base and bis-quaternary salt have been isolated in small quantities from the same plants.61 The structure of (46) was determined by its fission with sodium in liquid ammonia to form the bases (47) and (48), and by its oxidation to the isoquinolone (49) and the acid (50) when it reacted with potassium permanganate.61... 

Following cultivation of the plant material, the leaves from which the cocaine will be prepared are harvested and dried in the sun. From these, coca paste and, subsequently, cocaine is produced. In general, coca paste is prepared by one of two methods. The first involves wetting the leaves and macerating them with dilute sulfuric acid, thus forming the water-soluble sulfate salts of the alkaloids. The mixture is then extracted with kerosene. After phase separation, the aqueous layer is basified with ammonia, lime or sodium carbonate, and the alkaloids precipitated. They are then recovered by filtration. 

It is important to use sulfuric acid at this point to ensure efficient extraction. The sulfate salt of the alkaloid is more soluble in water and less soluble in organic solvents than the hydrochloride salt. In the ADH of other alkenes the preferred system is sulfuric acid/diethyl ether. However stilbene diol Is only sparingly soluble in diethyl ether, which necessitates the use of ethyl acetate. Chlorinated hydrocarbon solvents should be avoided since both alkaloid salts have appreciable solubility in them. When diethyl ether is used as the organic phase, not all of the reaction mixture dissolves in it, but the material that remains undissolved is derived solely from 4-methylmorpholine. 

Since lupin seeds are used in some areas in cattle feeding, it is of practical as well as theoretical interest to determine the stage at which the seeds will be rich in the alkaloidal material responsible for toxicity. It has also been important to devise methods for the removal of alkaloids from the seeds so that the detoxified or debittered material can still be used as feed (111). Extraction procedures which accent the recovery of non-alkaloidal material have less interest to the alkaloid chemist than those which provide for the isolation of the pure organic bases. Given below are typical examples of the extraction procedures employed for the isolation of the lupin alkaloids lupinine, cytisine, Z-sparteine, d-lupanine, and anagyrine. The methods selected are representative of those utilized for the isolation of the less abundant or well-known lupin alkaloids as well. These methods are also representative of the different quantities of materials which are handled. One of the methods was selected (for anagyrine) to indicate some of the complexities of separation when there are a number of alkaloids present in a plant, rather than only one main alkaloidal constituent. The techniques of fractional distillation of the bases, fractional crystallization of alkaloid salts, such as perchlorates and picrates, and extractions dependent upon differential solubility have been employed for the isolation of pure individual alkaloids from a mixture. 

Table 7. Melting and boiling points, and crystalline appearance. Table 8. Solubilities of salts of the alkaloids.

Alkaloids are usually basic and combine with acids to form alkaloid salts, a property often exploited to extract them from their source. Other alkaloids occur naturally as salts of organic acids. Common salts include hydrochlorides, salicylates, sulphates, nitrates, acetates, and tartrates such as morphine acetate, cocaine hydrochloride, and strychnine nitrate. Water, alcohol, and ether solutions of alkaloids and their salts are often used to administer or carry the alkaloid, particularly for medicinal purposes. Nicotine preparations can include a variety of liquid and solid mixtures of nicotine (soluble in alcohol, chloroform, ether, and water), nicotine salts, and many other nicotine compounds (e.g., nicotine sulphate and nicotine tartrate). 

Most alkaloids are solnble in organic solvents such as chloroform, ether and alcohol, bnt are practically water insoluble. Water-soluble alkaloids include ephedrine and colchicine. Alkaloidal salts are generally solnble in water and alcohol. 

Sample preparation methods without any loss of the target compounds are important, especially when a quantitative assessment of all alkaloids in a given plant sample is required. Eor many alkaloids, the sample preparation procedure is based on the difference in the solubility of the alkaloids salt in comparison with the free bases. An acidic aqueous extraction must be basified to transfer alkaloids into the free base for extracting into organic solvents nonmiscible with water. Excessive use of alkali, however, is detrimental for the ester alkaloids. 

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