Iminium Perchlorates & Fluoroborates: Crystalline Reversible Derivatives for Isolating and Purifying Carbonyl Compounds

An important element of the KiloMentor strategy for the synthesis and scale-up is to enable the separation of crystallizable derivatives that are readily reconverted to the pre-derivatized substance.  A major uncertainty in a theoretical paper synthesis using standard reactions lies with the workup of the intermediate steps.  The importance of intermediates, which are carboxylic acids, amine bases, phenols, or other ionizable substances has been stressed because these classes are most easily cleaned up.  For the same purpose, the reversible conversion of alcohols into O-sulfonic acids or phthalate half-ester acids was reviewed in KiloMentor blogs. Reviewing the formation of complexes of several functional groups, including alcohols, with inorganic salts such as lithium bromide, calcium bromide, and calcium chloride served the same purpose of simple purification. 

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

Aldehydes and methyl ketones do form bisulfite salts. Aldehydes can be separated by the little known and poorly tested extraction method published by Shunsaku Ohta and Masao Okamoto, Chem. Pharm. Bull. 28(6) 1917-1919(1980).

Aldehydes and ketones both form another type of ionic addition product that seems to crystallize out quickly and dependably, but which is hardly 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 iminium perchlorate salts with the formation of a mole of water as co-product.  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, particularly at scale, and made some tetrafluoroborate salts as well, 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 melting points all greater than 99°C with a median mp. of 238°C (15 compounds).

Two procedures were 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 pyrrolidine 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-isopropylidene pyrrolidinium perchlorate, m.p. 232-233 C.

Minor variations 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 accelerated, 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 was added 19.2 g. (0.200 moles) of cyclohexanone (note again 100% carbonyl 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-cyclohexylidene morpholinium perchlorate, 25.2 gm (94%) melted at 237-239° C.  Recrystallization from acetonitrile-ether raised the melting point to 239-241° C The 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 combination of pyrrolidinium perchlorate and diethyl ketone giving the iminium product in 86% yield.”

As I have indicated with my italics, the actual stoichiometry used employed a 100% molar excess of the carbonyl. Unfortunately, the paper doesn’t specify whether this is essential for good yields. There is a good chance that this stoichiometry was used to drive the reactions rapidly to a 100% conversion. Since it is also noted that the reaction rate can be catalyzed with a tertiary amine base it may be possible to eliminate the excess carbonyl when catalysis is employed. Also, since the removal of water should drive any equilibrium, that also could make the excess carbonyl unnecessary. An excess of an expensive carbonyl that we are trying to derivatize for isolation would of course completely defeat the purpose proposed. 
On the other hand, an excess of the secondary amine perchlorate would be more of a problem to remove in the recrystallization.  It would be very interesting from our perspective to know whether the same fast, high yields can be obtained using some excess of pyrrolidine tetrafluoroborate.  Although the authors state that the tetrafluoroborate is less useful I wonder whether the trifluoromethyl sulfonate or trichloroacetate might work. As I envision using the precipitation, the formation even of a crude solid mixture of the iminium salt with excess secondary amine salt will allow the filtration and washing away of non-adducts.  The mixture can then be recrystallized; the reported yields are very good. Decomposition by the addition of water and an acid catalyst should set the carbonyl free again. The inorganic salts will dissolve in water and the amines can be extracted from the organic solution with an aqueous acid.

A route C to prepare these salts would probably also work. A mixture of enamines could be prepared by treating the ketone with the nucleophilic secondary amine and a small amount of catalysis, while azeotroping away the water as it forms. Then, when the enamine formation is judged complete an equivalent of the anhydrous acid, perchloric, fluoroboric, trichloroacetic, etc. would be added. This might protonate the enamine and the non- nucleophilic anion would serve as the counter-ion. The salt should crystallize from the nonpolar solvent.