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Synthesis and resolution of alpha-phenylethylamine


Synthesis

Place 125 g. of ammonium formate, 75 g. of acetophenone and a few chips of porous porcelain in a 250 ml Claisen flask with fractionating side arm, insert a cork carrying a thermometer extending nearly to the bottom of the flask, and attach a short condenser set for downward distillation to the side arm. Heat the flask with a small flame or in an air bath; the mixture first melts to two layers and distillation occurs. The mixture becomes homogeneous at 150-155C and reaction takes place with slight frothing. Continue the heating, more slowly if necessary, until the temperature rises to 185C (about 2 hours); acetophenone, water and ammonium carbonate distil. Stop the heating at 185C, separate the upper layer of acetophenone from the distillate, and return it without drying to the flask. Heat the mixture for 3 hours at 180-185C and then allow to cool; the acetophenone may be recovered from the distillate by extraction with 20 ml of benzene (1). Transfer the reaction mixture to a 250 ml. separatory funnel and shake it with 100 ml of water to remove formamide and ammonium formate. Run off the crude a-phenylethylformamide into the original Claisen flask; extract the aqueous layer with two 15 ml portions of benzene, transfer the benzene extracts to the flask, add 75 ml of concentrated hydrochloric acid and a few chips of porous porcelain. Heat the mixture cautiously until about 30 ml of benzene are collected, and boil gently for a further 40 minutes; hydrolysis proceeds rapidly to alpha-phenylethylamine hydrochloride except for a small layer of unchanged acetophenone. Allow the reaction mixture to cool, remove the acetophenone by extraction with 25 ml of benzene and then with three 15 ml portions of the solvent (1). Transfer the aqueous acid solution to a 500-ml roundbottomed flask equipped for steam distillation, cautiously add a solution of 62.6 g. of sodium hydroxide in 125 ml of water, and steam distil: heat the distillation flask so that the volume remains nearly constant. Most of the amine is contained in the first 500 ml of distillate; stop the operation when the distillate is only faintly alkaline. Discard the residue in the flask which contains inter alia a little dl-a-phenylethylamine. Extract the distillate with five 25 ml. portions of benzene, dry the extract with sodium hydroxide pellets, and distil off the benzene but use a flask having an inset side arm and a soda lime guard tube; the amine attacks cork and rubber and absorbs carbon dioxide from the air. Collect the a-phenylethylamine at 184-186C (2). The yield is 45 g.

(1) The acetophenone may be recovered by washing the benzene solution with dilute alkali, drying with anhydrous magnesium sulphate and distilling ; the fraction b.p. 198-205C is collected.

(2) The b.p. under diminished pressure has been given as 80-81C at 118 mm. To obtain a very pure sample of the amine, dissolve 1 part (by weight) of the above product with a solution of 1.04 parts of crystallised oxalic acid in 8 parts of hot water, add a little decolourising carbon, and filter. The filtered solution deposits crystals of the acid oxalate; about 5 g. of this salt remains in each 100 ml of mother liquor, but most can be recovered by evaporation and further crystallization, the amine may be liberated from the acid oxalate with sodium or potassium hydroxide, steam distillation, and purification as above. The salt provides a convenient method of obtaining a known weight of the amine in water, since it can be weighed out and decomposed with alkali hydroxide.

Resolution

(-)-a-Phenylethylamine: Add 31.25 g of D-tartaric acid (0.208 mole) to 450 ml of methanol in a one-liter Erlenmeyer flask, and heat the mixture almost to boiling. To the hot solution, add cautiously 25 g of D,L-a phenlylethylamine (26.6 ml; 0.206 mole); too rapid addition will cause the mixture to boil over. Since crystallization occurs slowly, the solution must be allowed to stand at room temperature for about 24 hours. The (-)-amine-(+)-hydrogen tartrate separates as prismatic crystals. Collect the product by suction filtration, and wash it with a little methanol. Yield: 18.l grams(65%).

A second crop (3.8 grams) may be obtained by concentrating the combined mother liquor and washings to 225 ml, and allowing crystallization to proceed at room temperature for 24 hours.

Partially dissolve the product (21.9 grams) in about 90 mI of water and add 12.5 ml of 50% sodium hydroxide solution in order to convert the amine salt to the free base. Reextract the amine with ether, and dry the extract, over anhydrous magnesium sulfate for about ten minutes. Remove most of the ether by heating the extract on the steam bath, and distill the residue (considerable foaming) to obtain (-)-a-phenylethylamine. Yield: 6.9 grams, 55%; bp: 184-186'; L(+)-a-Phenylethylamine: Allow the methanolilc solution remaining from the isolation of the (-)-amine(+)-hydrogen tartrate to evaporate to dryness (done most easily by leaving the solution in an evaporating-dish in the hood overnight), and recover the remainder of the amine by treating the residual salt with sodium hydroxide, extracting with ether, and distilling as described above.

The (+)-amine is isolated by treating a hot ethanolic solution of the recovered amine with an amount of sulfuric acid in ethanol slightly greater than that necessary to convert the excess (+)-amine to the neutral sulfate salt. The resulting cyrstals of (+)-a-phenylethylamine sulfate yield the (+)-amine.

Dissolve 12.5 g (0.103 mole) recovered amine, in 88 ml of 95% ethanol. (This solution contains 0.062 mole excess (+)-amine, and 0.041 mole racemic amine. Heat the solution to boiling and add to it a solution of concentrated sulfuric acid (3.2 g of 98% H2SO4; 0.032 mole H2SO4) in 180 ml of 95% ethanol. After allowing the mixture to cool slowly to room temperature, collect the crystalline (+)-amine sulfate by suction filtration and wash it thoroughly with ethanol. Yield: 7.8 g (74%).

Isolate the free (+)-amine as described above (treatment with sodium hydroxide, extraction, and distillation) using 40 ml of water and 5 ml of 50% sodium hydroxide for each 10 g of the sulfate salt. Yield: 4.4 g (59%); bp: 184-186C.