Ketones bisulfite compounds

Gastaldi synthesis. Formation of dicyanopyra-zines by cyclization of two molecules of an amino-cyanomethyl ketone, produced by treatment of an isonitrosomethyl ketone bisulfite compound with potassium cyanide, heating in hydrochloric acid, and oxidation. 

A solution of 100 g of sodium bisulfite in 200 ml of water is added, and the stirring is continued for 10 hours with exclusion of air. A thick precipitate separates after a few minutes. The bisulfite compound is collected by suction filtration, washed with ether until colorless, and then decomposed in a flask with a lukewarm solution of 125 g of sodium carbonate in 150 ml of water. The ketone layer is separated, and the aqueous layer is extracted four times with 30-ml portions of ether. The combined organic layers are dried over anhydrous magnesium sulfate, the ether is removed at atmospheric pressure, and the residual oil is fractionated under reduced pressure through a short column. The cycloheptanone, bp 64-65°/ 2 mm, is obtained in about 40% yield. 

Benzyl alcohol, 23, 14 BeNZYLAMINE, a-METHYL-, 23, 68 Benzyl carbamate, 23, 14 Benzyl chloride, 21, 99 Benzyl chloroeormate, 23, 13 Benzyl cyanide, 23, 71 Bisulfite compound, use for purification of an aldehyde, 23, 78 use for purification of a ketone, 23, 79 Blood, defibrinated, 21, 53 Booster pump, use of, for hydrogenation, 23, 69... 

The products are useful for two reasons. They are usually crystalline and so can be used to purify liquid aldehydes by recrystallization. This is of value only because this reaction, like several you have met in this chapter, is reversible. The bisulfite compounds are made by mixing the aldehyde or ketone with saturated aqueous sodium bisulfite in an ice bath, shaking, and crystallizing. After purification the bisulfite addition compound can be hydrolysed back to the aldehyde in dilute aqueous acid or base. 

The reversibility of the reaction makes bisulfite compounds useful intermediates in the synthesis of oilier adducts from aldehydes and ketones. For example, one practical method for making cyanohydrins involves bisulfite compounds. The famous practical book Vogel3 suggests reacting acetone first with sodium bisulfite and then with sodium cyanide to give a good yield (70%) of the cyanohydrin. 

The second reason that bisulfite compounds are useful is that they are soluble in water. Some small (that is, low molecular weight) aldehydes and ketones are water-soluble—acetone is an example. But most larger (more than four or so carbon atoms) aldehydes and ketones are not. This does not usually matter to most chemists as we often want to carry out reactions in organic solvents rather than water. But it can matter to medicinal chemists, who make compounds that need to be compatible with biological systems. And in one case, the solubility of bisulfite adduct in water is literally vital. 

The solution is to make a bisulfite compound from it. You may ask how this is possible since dapsone has no aldehyde or ketone—just two amino groups and a sulfone. The trick is to use the formaldehyde bisulfite compound and exchange the OH group for one of the amino groups in dapsone. 

Further purification of the product may be effected by converting the ketone into the bisulfite compound, washing this with ether, decomposing with sodium bicarbonate, and steamdistilling. 

Gastaldi (286) first described this synthesis, in which an a-hydroxyimino ketone was treated with aqueous sodium bisulfite saturated with sulfur dioxide, and the bisulfite compound treated with potassium cyanide followed by hydrolysis with hydrochloric acid. By this procedure, Gastaldi prepared 2,5-dicyano-3,6-dimethyl-pyrazine from hydroxyiminoacetone, and 2,5-dicyano-3,6-diphenylpyrazine and some 3-cyano-2,5-diphenylpyrazine from hydroxyiminoacetophenone. He proposed a reaction mechanism involving the intermediate compounds (21) and (22). Sharp and Spring (287) used the same procedure to prepare 2,5-dicyano-3,6-diethyl-pyrazine from ethyl hydroxyiminomethyl ketone. 

The obvious answer is as early as possible. The first chiral intermediate is 146 and that already has two chiral centres. The first intermediate with a useful functional group is 149 with its two alcohols. The chemists at what was then Glaxo (now GlaxoSmithKline) chose an ingenious resolution of the stable ketone 147. Because this is a strained ketone it forms a stable adduct with bisulfite and that could be resolved as a salt with our old friend 1-phenylethylamine 2. The bisulfite compound reverts to the ketone 147 on treatment with base and the resolution was complete. 

Unless the carbonyl group is sterically strongly hindered by -substituents, as in aromatic ketones, the C-O double bond of most aldehydes and ketones readily adds hydrogen sulfite in an exothermic reaction, to give bisulfite compounds (geminal hydroxy sulfonic acids) these are easily reconverted into their components by acid or alkali. 

According to Bucherer and Grolee,170 it is sometimes possible to treat the bisulfite compound of a ketone or aldehyde with aqueous potassium cyanide solution, and it is often unnecessary to isolate the bisulfite compound. This is exemplified as follows ... 

Corticosterone ll/ ,20/ -Dihydroxy-3-oxo-4-pregnen-21-al, when treated in aqueous-methanolic solution with sodium hydrogen sulfite, gives the bisulfite compound that is derived from the aldehyde form since the aldehyde is regenerated by decomposition with acid. However, sodium methoxide solution decomposes the bisulfite compound with isomerization to afford the hydroxy ketone, corticosterone, in 60% yield. 

The second reason that bisulfite compounds are useful is that they are soluble in water. Some small (that is, low molecular weight) aldehydes and ketones are water-soluble—acetone is an example. But most larger (more than four or so carbon atoms) aldehydes and ketones are not. 

Dapsone is an antileprosy drug. It is a very effective one too, especially when used in combination with two other drugs in a cocktail that can be simply drunk as an aqueous solution by patients in tropical countries without any special facilities, even in the open air. But there is a problem Dapsone is insoluble in water. The solution is to make a bisulfite compound from it. You may ask how this is possible since dapsone has no aldehyde or ketone—just two amino groups and a sulfone. The trick is to use the formaldehyde bisulfite compound and exchange the Off group for one of the amino groups in dapsone. 

Stelling (1928) found an absorption band in formaldehyde and acetone bisulfite addition compounds at 4992.0 A similar to that in sulfonic acids at 4992.2 and differing from that of metal alkyl (4996.0) and dialkyl sulfites (4997.7). He concluded from this that the sulfonic acid structure must be present. Raman spectral examinations of several aldehyde and ketone bisulfites by Caughlan and Tartar (1941) revealed the presence of a carbon-sulfur bond, possibly a carbon-hydroxyl bond, but no carbon doubly bonded to oxygen. This thus aided in discrediting both the tripartite molecule and the sulfurous acid ester structures. Sundman (1949) believes that formation of a stable monomolecular complex of boric acid and glucose bisulfite would be impossible if Schroeter s tripartite molecular structure were correct. His examinations of this complex led him to believe that its structure could be represented only by ... 

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