kilomentor | 24 January, 2007 17:58
I have proposed that a synthetic chemist can assess the relative merits of two or more routes of synthesis by looking at the proposed intermediates in the schemes and rating the likelihood that they can be separated cleanly and in good yield. Schemes that have a higher proportion of these preferred intermediates on balance are more promising. One intermediate that I propose that you can depend upon being readily isolated and efficiently purifiable is salts of organic acids and bases. Below I would like to may a variety of points which all apply to using salts of carboxylic acids as dependable intermediates.
It is the cornerstone of my thinking pertaining to organic synthesis strategy and process development that intermediates that readily accept a proton (such as amines) and species that readily surrender a proton (such as carboxylic acids) are preferred intermediates because:
The extractability into aqueous is well understood. Bur even if extraction cannot achieve the purification needed there is the second recourse to purification through a reversible salt derivative.
Carboxylic acid salts with organic cations are important intermediates because they allow an unlimited variation of the properties of the salts, meaning that statistically some crystallizable and recrystallizable substance in almost certainly possible. In spite of the power of this simple understanding, to my knowledge, there has never been a systematic attempt to compile the most consistently successful methods for making salts and the most preferred salts for high yield isolations.
Stoichiometric crystalline organic salts of carboxylic acids are made for two main reasons:
Although an infinite variety of cations can in principle be used to crystallize or purify a preparatively important quantity of a carboxylic acid of interest, for practical purposes the cation must be inexpensive since the cation will normally be discarded after it has served its purpose.
For this reason I will first consider just alkali and alkaline earth metal salts. With regard to all the methodologies, wherever possible the common ion effect should be used to increase the insolubility of precipitates. That is if one is trying to crystallize a sodium salt from water it is advantageous if the water is saturated with sodium chloride to increase the total concentration of sodium ions. Although the common ion effect is well known to inorganic and analytical chemists, synthetic organic chemists tend to forget it when it can really improve recoveries.
Metal salts of carboxylic acids can be precipitated in organic solvents by metathetical exchange reaction. To do this it is necessary to have available a soluble salt made from an inexpensive acid and the metal cation of interest. For lithium, sodium, potassium, magnesium, and calcium, an appropriate reagent is the corresponding salt with 2-ethylhexanoic acid. For example a solution of potassium 2-ethylhexanoate in acetone can be added to a solution of pennicillanic acid in methyl isobutyl ketone causing precipitation of the potassium salt of pennicillanic acid.
Another tactic is to dissolve the carboxylic acid in an aqueous solution of ammonia and then add an inorganic salt containing the desired cation. This also works for magnesium and calcium which otherwise give precipitates of hydroxides in basic solution.
It is also useful to apply the rule of thumb that most potassium salts of carboxylic acids are soluble in hot ethanol.
Another useful property that should be born in mind is that an ammonium salt if it can be isolated, upon evaporation to dryness and/or drying under vacuum hydrolyzes and the ammonia can be removed leaving the free acid.
When the carboxylic acid salts needs to be recrystallized in order to achieve a practical purity for a process but the recovery is not as high as one needs, the material to be recrystallized should be recrystallized in portions recycling the solvent. Because the solvent is saturated with the desired carboxylic acid metal salt, the recover in the batches after the first will be substantially higher while the overall purity of the compound may be unaffected.
Something can be said at this point about the subsequent step of reacidifying the salt to recover the free carboxylic acid. It is often recommended in the literature that an organic acid be liberated from its salt by adding a mineral acid solution. In practice the addition of the salt solution to the acid in excess is sometimes preferable because in the case of salt formed in the presence of an excess of carbonate or bicarbonate, the carbon dioxide liberated causes less foaming problems if the medium is overall acidic. In some cases when the metal salt is in excess when the mineral acid is added, a very insoluble precipitate composed of equal molar amounts of the acid and the salt may be formed. These can be avoided by the addition of the salt to an excess of acid. It should be noted that for process development it is still usually preferable to add the mineral acid to the salt solution because this avoids the use of an additional vessel. Of course in the lab this is not a consideration.
When it comes to reforming the free acid from a salt used for isolation, it should be remembered that cation ion exchange resins in the protonated form can very conveniently be used be used to remove cations in exchange for protons.
Insoluble complex salts of carboxylic acid and metal carboxylate are dissolved by heating with aqueous-alcoholic potassium hydroxide.
The rule of thumb for forming stable salts is that the pKa value of the acid and the base must differ by at least 3 units.
It is always tedious to determine what salt forming agent can be used in what solvent to provide a crystalline material from a given carboxylic acid. It is not commonly known but it seems that a very rapid method is available by analogue with the
Dutch method of finding successful resolving agents for a given enantiomeric mixture. In this method a test solvent is chosen; then y mmoles of the carboxylic acid are dissolved in the solvent; then x different amines y/x mmoles of each are added all together to the carboxylic acid. The mixture is warmed to achieve solution if possible and then allowed to cool. Any solid that separates is filtered dried and analyzed to determine which amines are involved. Sometimes there will be several amines sometimes only one. It is these amines that become the preferred candidates for forming the quantitative salts. Thus all candidate amines are tested together and it is only solvent that must be varied in each test of multiple amines.
It would seem possible to perform the same combinatorial test on the ammonium salt of the acid in the presence of all the alkaline and alkaline earth metal ions.
The chemical literature already teaches carboxylic acid salts that have a high probability of being sparingly soluble and readily recrystallizable.
Substituted benzyl pseudothiuronium salts were disclosed in a series of papers. The reagents used were S-Benzyl thiuronium chloride [JACS 58 1004 (1936); John J. Donleavy];p-Chlorobenzyl pseudothiuronium chloride [Bartlett T. Dewey and Robert B. sperry; JACS 61 3251 (1939)]; p-Bromobenzyl pseudothiuronium bromide [Barlett T. Dewey and Henry G. Shasky, JACS 63 3526 (1941)];S-1-naphthylmethylthiuronium chloride, William A. Bonner, JACS 70 3508 (1948)]. These salts are incredibly easy and inexpensive to prepare. The appropriate benzylic halide is refluxed with thiourea in alcohol to produce the insoluble salt. It is important that the metallic salt of the acid is not in basic solution because base decomposes the pseudothiuronium salts producing at the same time bad sulfur based smells. Although it is not specifically stated it seems clear that the acid can be readily recovered by adding a sulfonic acid to the salt which immediately will precipitate the pseudothiuronium sulfonate and liberate the carboxylic acid in free form. This exchange reaction should probably be done in a mixture of non-polar solvent such as hexane and water (or water acidified with hydrochloric acid to prevent hydrolysis of the salts).
Fatty acid derivatives of piperazine have been reported to crystallize well and all these derivatives are hydrolysed by refluxing in hydrochloric acid. In preparing the salts 0.05 moles of piperazine hexahydrate is added to 0.1 moles of the acid. Upon stirring the entire solution solidifies. These derivatives are soluble in water, alcohol, hot acetone, hot monoethylether of ethylene glycol, and hot dioxane. They are insoluble in ether and hexane. [C.B. Pollard, David E. Adelson and J.P. Bain, JACS 1759 (1934)]. The salt with piperazine has also been recommended for crystallizing monoalcohol phthalates.Other salts that are reported to yield highly crystalline salts are dicyclohexylamine, cyclohexylamine, isopropylamine, diethylamine, 2-amino-2-methyl-1,3-propanediol, 2-amino-2-methylpropanol.