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I have an aqueous solution of N,N-dimethylphenylalaninemethylesterhydrochloride and I need to crystallise it as a salt. I'm afraid of increasing the temperature or the concentration of acid due to the possibility of ester hydrolysis.

What crystallisation method would be the most efficient in this situation?

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  • $\begingroup$ How dilute is the solution? $\endgroup$
    – Waylander
    Mar 31 '18 at 13:45
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This molecule is an ammonium anion with an ester side chain as a chloride salt.

The first option you have is to undertake the vacuum evaporation of the solvent at room temperature. This would should prevent any heat degradation. I do understand your point about increasing the acid because in effect you have a buffer solution.

Your second alternative is to partition into a warm amine-ophilic non-aqueous/organic layer and crystallize from there. The method is briefly described in Phase-Transfer Catalysis - Fundamentals, Applications, and Industrial Perspectives[1].

An excerpt from the book:

b. Simple Transfer Across the Interface A second mechanism for anion transfer is simple anion interchange across the interface, as represented in the following diagram:

Organic and Aqueous layer

This mechanism does not require catalyst to actually leave the organic phase, to the extent that the interfacial area is still considered a part of the organic phase, but it does require the quaternary salt to have a dominant presence at the interface. Large water-insoluble quaternary salts, such as tetrahexyl- or trioctyl-methylammonium salts, which are predominantly (>99%) partitioned into the organic phase, function as catalysts mostly by anion transfer across the interface. However, if the quaternary cation is extremely large, the cation will not be frequently in the interfacial region, and then the reaction rate will become transfer-limited. On the other hand, quaternary salts that are good surfactants, such as $\ce{C16H33NMe3+Cl-}$, are dominantly positioned at or in the interfacial layer. These accessible quaternary salts provide for higher rates of anion transfer across the interface.

This research paper[2] goes into further details about the process.

References:

[1]: C. M. Starks; M. Halper. Basic Concepts in Phase-Transfer Catalysis. Phase-Transfer Catalysis - Fundamentals, Applications, and Industrial Perspectives, First Edition; Springer Netherlands: Dordrecht, 1994; pp 8.
https://doi.org/10.1007/978-94-011-0687-0

[2]: Hull, R.L. and Biles, J.A. (1964), Physical chemical study of the distribution of some amine salts between immiscible solvents. II. Complexation in the organic phase. J. Pharm. Sci., 53: 869-872.
https://doi.org/10.1002/jps.2600530804

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If you have no solid to test solubility, my first attempt would be to use an anti-solvent (which you'll need to determine empirically). The anti-solvent for your hydrochloride salt should be miscible with water, so for ease, I would suggest starting with simple alcohols; methanol, ethanol, 2-propanol. See which gives you some solid precipitating out of solution, check purity and then work from there on concentrations or temperature if required.

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