Inorganic Non-Stoichiometric Metal Salt Complexes as a Useful Method for Purifying Neutral Organic Compounds

The particular process development strategy of KiloMentor emphasizes using non-traditional reversible derivatization to enable simple isolation of as many functional group classes at scale as possible.

KiloMentor has already emphasized the importance of process intermediates that reversibly form salts such as carboxylic acids and amines, and has recommended the preparation of O-sulfates from alcohols, phenols, and some amines. Herein KiloMentor will discuss what is known about the formation of inorganic non-stoichiometric metal salt complexes with substances comprising a wide variety of neutral functional groups.

The only citation in the chemical literature, which points at the scope of this method, is the patent family of which US452988 is a member. The patent titled, Process for the Isolation of Organic Compounds and Lithium Salt Complexes useful in such Processes, lists alcohols, phenols, enols, amides, imides, carboxylic acids, primary and secondary amines having a pKa in water of at least 10^-10 and sulfoxides as suitable for the method. Using the particular salts lithium perchlorate or lithium tetrafluoroborate the same methodology is disclosed to complex aldehydes and ketones. For our present purpose separation of amides, imides, stable enols, and sulfoxides stand out in importance because few other reversible derivatives are available for isolation and purification. Although not disclosed or claimed, it would seem that sulfonamides might also work in the method.

One of the only non-patent references to this methodology is K. Barry Sharpless, Anthony O. Chung, and James B. Scott’s paper, Rapid Separation of Organic Mixtures by Formation of Metal Complexes in J. Org. Chem. 40(9) 1252-1257 (1978). Sharpless teaches the use principally of calcium or manganese chloride complexes to separate mixtures of alcohols and to separate alcohols from non-alcohols. Although the paper was much commented on at the publication time very few citations of it in subsequent particular applications have emerged. It may be that anhydrous calcium and manganese chlorides are not as generally applicable as originally proposed.  On the basis of everything that has been reported up to the present, it would seem that the preferred regents are lithium and calcium bromide.

Calcium Bromide/Chloride, Lithium Bromide as Reagents

Literature published before these aforementioned contained examples, which limited the methodology to 3-hydroxy and 3-ketosteroids. In GB 1555968, the authors used calcium bromide dehydrate exclusively and taught the as solvents methyl isobutyl ketone (MIBK) and 5-methyl-2-hexanone (methyl isoamyl ketone, MIAK). This literature appears to teach:

(1). That calcium bromide dihydrate can form a 30% by weight solution in MIBK or a 15% by weight solution in MIAK.

(2). That such solutions can be used to prepare insoluble derivatives by mixing with solutions comprising such steroids in the corresponding organic liquid

(3). That the calcium bromide is easily rsplit from the complexes by extraction with water to remove the inorganic salt and precipitate the steroid.

Both MIBK and MIAK have useful binary azeotropes with water. MIAK has an azeotrope bp 94.7 C which is 37% by volume water and which separates into clean phases on cooling. MIBK has bp 87.9 C and removes 19.6% by volume of water and separates on cooling.

It is significant that in the worked examples of GB 1555968 steroid mixtures without alcohol functionalities were precipitated so long as the solvent used to dissolve both calcium salt and steroid was the steroidal ketones was n-amyl methyl ketone.

Besides this natural product application  and a use for prostaglandin intermediates purified in US 4529811, the only other particular application is in my own isolation of finasteride  This is found in CA 2389666.

In addition to the functional groups already mentioned there is some evidence that these complexes can be used for the isolation of phosphine oxides. Chem. Soc. (A) Inorg. Phys, Theor. 1968 449-450 where an adduct LiBr.4 Ph3PO is reported in Table 1 of that article. Since phosphine oxides are good Lewis bases this seems likely to be general.

Another salt which is likely to form complexes with alcohols in nickel (II) bromide.  In the Kilomentor article discussing oxidizing reagents there is a reference to the use of nickel (II) bromide which states that alcohols form strong metal complexes and that this is the reason that primary alcohols are converted cleanly to acids rather than giving ester by-products; the alcohol substrate is bound strongly and is not freely available for making esters.

In addition there are many patents discussing complexes of phenols with inorganic salts for separation of complex mixtures of phenols, but such separations are not so interesting because dissociative extraction technology can be applied to these.