kilomentor

An important element of the Kilomentor strategy for synthesis and scale up is to enable the separation of crystallisable derivatives that are readily reversible. The uncertainty in a paper synthesis centres upon the simplicity of the work up of the intermediate steps. The importance of intermediates, which are carboxylic acids, amine bases, phenols or other ionizable substances has been stressed. The reversible conversion of alcohols into O-sulfonic acids or phthalate half-ester acids was reviewed in Kilomentor blogs. The formation of complexes of several functional groups, including alcohols, with inorganic salts such as lithium bromide, calcium bromide and calcium chloride was also reviewed.

Carbonyl compounds also form commonly reversible derivatives (oximes and phenyl hydazones for example), which are usually solids, but these derivatives do not have the overwhelming propensity to form that makes them consistently crash out of solution quantitatively and their reversible hydrolysis is something to be worked out rather than a slam dunk.

Aldehydes and ketones do form one type of ionic addition product that seems to crystallize out quickly and dependably but it is sparsely treated in the literature. In 1963, Nelson J. Leonard and Joseph V. Paukstelis reported that treatment of an aldehyde or ketone with the perchlorate salt of a secondary amine led rapidly to the crystallization of tertiary imminium perchlorate salts and the formation of a mole of water. This water could either be left behind at the stage of salt filtration or could be removed azeotropically before the filtration. These authors recognized the reluctance that many would feel to using perchlorate salts and made some tetrafluoroborates but these they found functioned “less efficiently,” Both were “far superior” to other simple anions like chloride, bromide, sulfate or nitrate [J. Org. Chem. 28, 3021 (1963)]. These salts had mps all greater than 99 C with a median mp of 238 C (15 compounds).

Two procedures where provided in the paper and these are repeated here.

A. “To 17.2 g. (0.100 moles ) of pyrrolidine perchlorate in an Erlenmeyer flask was added 11.6 g (0.200 moles) of anhydrous acetone. The pyrollidine perchlorate dissolved immediately and, on swirling. crystals separated with the evolution of heat. After a few minutes the crystals were washed with ether and recrystallized from 2-propanol yielding 20.3 g. (96%) of N-isopropylidenepyrrolidinium perchloriate, m.p. 232-233 C.

Minor variations (note: the acetone was used in 100% excess!) in procedure A included heating the combination of secondary amine salt and carbonyl compound when necessary and using ethanol as solvent to dissolve the secondary amine salt before adding the carbonyl compound. The reaction could be speeded, where necessary, by addition of a few drops of the secondary amine or of a tertiary amine such as triethylamine or pyridine”.

B. “To 18.8 g. (0.100 moles) of morpholine perchlorate were added 19.2 g. (0.200moles) of cyclohexanone (note again 100% excess) and 2 to 3 drops of morpholine. When no reaction was observed, 200 ml of benzene was added and the heterogeneous mixture was heated overnight under reflux, with stirring, while removing water continuously by means of a Dean-Stark trap. The separated solid was collected by filtration, washed with ethanol and ether and dried in vacuo. The product, N-cyclohexylidenemorpholinium perchlorate, 25.2 gm (94%) melted at 237-239 C. Recrystallization from acetonitrile-ether raised the melting point to 239-241 C Ihe use of a Soxhlet extractor containing molecular sieves and a solvent such as chloroform for azeotroping constituted a modification of procedure B, which was successful, for example in combination of pyrrolidonine perchlorate and diethylketone giving the imminium product in 86% yield”.

As I have indicated with my italics, the actual stoichiometry that is essential is not clear from the paper. Although the equation only requires a 1:1 ratio of secondary amine- perchlorate to carbonyl, the general procedures of the examples use two equivalents of carbonyl. Although the authors fail to comment on this, there is a good chance that this stoichiometry was used to drive the reactions rapidly to a 100% conversion. Clearly an excess of the carbonyl is going to be much easier to remove in the crystallization than an excess of the secondary amine perchlorate. It would be very interesting from our perspective to know whether the same fast, high yields can be obtained using some excess of say pyrrolidine tetrafloroborate. As I envision using the precipitation, the formation even of a crude solid mixture of the imminium salt with excess secondary amine salt will allow the filtration and washing away of non-carbonyls. The mixture can then be decomposed by the addition of a tertiary base to set the carbonyls free again. The inorganic salts will dissolve in water and the secondary amine can be extracted from the organic solution with an aqueous acid.

These experiments have not been tried. I commend someone to attempt making the tetrafluoroborate salts with one to one equivalents of a secondary amine and carbonyl but using an excess of amine salt if necessary. This would be useful and well within the technical skill of a beginning undergraduate chemist. (For reasons of insurance do not use perchloric acid!). It would also seem that mixtures of carbonyls might be separable using this method and a proper insufficiency of amine salt as well as mixtures of carbonyl and non-carbonyls.

If someone undertakes this, I would be really interested.