Experimental Principle
(R/S) α-phenylethylamine is a general chiral resolution agent, which can be synthesized by many methods. In this experiment, racemates were synthesized from ethylbenzene by α-bromination and ammonolysis, and then optically pure α-phenylethylamine was obtained by chemical resolution.
1. Bromination Principle of N-bromosuccinimide (NBS)
The compounds with a propylene-based structure can undergo the free radical substitution reaction of α-H at high temperatures. If you want to proceed under laboratory conditions, N-bromosuccinimide is often used as a bromination reagent, and the reaction needs to be carried out in an inert solvent (such as carbon tetrachloride) in the presence of a free radical initiator (such as benzoyl peroxide BPO), such as:
NBS is prepared by the reaction of succinimide and bromine, and an equimolar amount of hydrogen bromide is produced at the same time, so NBS inevitably contains a very small amount of HBr.
The generated bromine generates a bromine atom under the condition of a free initiator and then undergoes a free radical substitution reaction of α-H with a compound having a propenyl structure.
NBS actually only plays the role of supplying bromine, but because bromine is continuously produced in a small amount, the concentration of bromine in the mixture is always kept very low, which improves the selectivity of the bromination reaction at the propylene position. In this experiment, the important intermediate α-bromoethylbenzene of α-phenylethylamine was prepared by using the special properties of NBS. The action of α-bromoethylbenzene and hexamethylenetetramine generates the target product racemic α-phenylethylamine.
2. Synthesis Principle of Racemic α-Phenylethylamine
Hexamethylenetetramine, also known as urotropine, is formed by the condensation of formaldehyde and ammonia, and it is easy to decompose under acidic conditions to release ammonia and formaldehyde. α-Bromoethylbenzene reacts with hexamethylenetetramine to generate quaternary ammonium salt first and then decomposes into amine by heating in a concentrated hydrochloric acid solution of ethanol. This synthetic method is only applicable to primary haloalkanes, not to secondary and tertiary haloalkanes. Among the primary halogenated alkanes, active halogenated hydrocarbons are especially preferred, such as allyl halides, benzyl halides, α-halogenated ketones, and iodoalkanes. The method is characterized by readily available reagents, mild reaction conditions, and simple operation.
3. Principle of Chemical Resolution
When chiral compounds are synthesized under non-chiral conditions, all the racemes are obtained. In order to obtain chemically pure single isomers, chiral resolution must be carried out. There are many methods to separate racemic mixtures, such as chromatographic separation, biological resolution, chemical resolution, crystallization, and so on. Among them, the chemical separation method has the advantages of low cost, convenient operation, suitable for mass production, and is widely used. The resolution principle is that a pair of enantiomers of racemes react with an optically pure chiral resolution reagent to form diastereomers, and then make use of the differences in physical properties (such as boiling point, solubility, crystallinity, etc.) of diastereomers to achieve the purpose of separation. It is not easy to obtain pure single enantiomers in practical work, and it often takes a long time to separate and recrystallize. The resolution reagent should not only react easily with the racemate and combine with it, so as to turn a pair of enantiomers into non-enantiomers, but also be easy to remove. Resolution reagents that meet this requirement can often form salts with separated substances. The common alkaline resolution reagents are quinine, ephedrine, α-phenylethylamine, etc., and the common acid resolution agents are tartaric acid and its derivatives, camphor sulfonic acid, malic acid, and its derivatives. In this experiment, L-(+)-tartaric acid reacts with (±)-α-phenylethylamine to produce a mixture of two non-corresponding isomers. The solubility of the two salts in methanol is significantly different, and they can be separated by step-by-step crystallization. Then the two separated salts were treated with alkali to separate (±)-α-phenylethylamine and (-)-α-phenylethylamine respectively. Thus optically pure (±)-α-phenylethylamine and (-)-α-phenylethylamine were obtained.
Instruments and Reagents
- Instruments
Collector magnetic stirrer, 100 mL round bottom flask, 100 mL Erlenmeyer flask, distillation device, 50 mL three-necked flask, vacuum distillation device, thermometer, reflux condenser, constant pressure drop funnel, Buchner funnel, suction filtration flask, liquid funnel, ordinary funnel, electric heating mantle.
- Reagents
Ethylbenzene, NBS, benzoyl peroxide, hexamethylenetetramine, carbon tetrachloride, chloroform, concentrated hydrochloric acid, ethanol, 20% sodium hydroxide, diethyl ether, anhydrous magnesium sulfate, L-(+)-tartaric acid, methanol, 50% sodium hydroxide, concentrated sulfuric acid.
Experimental Procedure
1. Preparation of (±)-α-Phenylethylamine
In the 100 mL round bottom flask with reflux condensing tube and drying tube, 6 g NBS, 4 g ethylbenzene, 0.1 g benzoyl peroxide, and 20 mL carbon tetrachloride were added, refluxed under electromagnetic stirring, 30 min stopped heating, cooling, and filtration to remove succinimide, distillation out carbon tetrachloride, vacuum distillation (1.86x103 Pa/14mmHg), collecting 91~93 oC fraction, about 4.5 g of α-bromoethylbenzene was obtained.
In the 50 mL three-port flask with a reflux condensing tube and constant pressure drop funnel, about 4.3 g hexamethylenetetramine and 10 mL chloroform were put into the flask, heated and refluxed, stirred, and dripped into 4.5 g α-bromoethylbenzene chloroform solution, which took about 2 hours to cool and filter to form a white solid.
Install a reflux condenser on a 100 mL round bottom flask, put the product from the previous step in the flask, add 8 mL of concentrated hydrochloric acid, heat to dissolve the solid, add 25 mL of ethanol, heat, stir and reflux for 3~4 h, a white solid appears, cool and filter. The filtrate was distilled to 110 oC to stop. Cool, neutralize the residue with 20% sodium hydroxide solution until it is alkaline, at this time, oily matter precipitates out, extract twice with 30 mL ether, dry with anhydrous magnesium sulfate, evaporate ether, and distill under reduced pressure (3.19x103 Pa/24mmHg), collecting the 86~87 oC fraction, the product quality is about 1.8 g.
2. Resolution of (±)-α-Phenylethylamine
(1) Separation of S-(-)-α-Phenylethylamine
In a 100 mL round bottom flask, add 3.2 g of L-(+)-tartaric acid and 50 mL of methanol, heat to reflux to completely dissolve the tartaric acid, cool slightly, and slowly add 2.6 mL (± )-α-phenethylamine. After the addition, reflux slightly to make the solution clear and transparent, let it stand at room temperature for more than 24 hours, and prism-shaped crystals will precipitate. If needle-shaped crystals precipitate at the same time, re-heat in a water bath and shake continuously to dissolve all the needle-shaped crystals, and retain a few prismatic crystals. Seed crystals, stopper the bottle tightly, slowly cool and crystallize, after the crystallization is complete, transfer the clear mother liquor into another Erlenmeyer flask through a common funnel, wash the crystals twice with a small amount of cold methanol, suction filter, and dry to obtain L-(+)-Tartrate-S-(-)-α-Phenylethylamine salt, melting point 179~182 oC (decomposition), specific rotation [α]D=+13 oC (H2O, 5%). The filtrate was kept to separate the (+)-α-phenethylamine salt.
In a 100 mL round bottom flask, add 3.2 g of L-(+)-tartaric acid and 50 mL of methanol. Heat to reflux to completely dissolve the tartaric acid, cool slightly, and slowly add 2.6 mL (±)-α-phenethylamine. After the addition, reflux slightly to make the solution clear and transparent, and let it stand at room temperature for more than 24 hours, and prism-shaped crystals will precipitate. If needle-shaped crystals precipitate at the same time, re-heat in a water bath and shake continuously to dissolve all the needle-shaped crystals, and retain a few prismatic crystals. For seed crystals, stopper the bottle tightly, slowly cool, and crystallize, after the crystallization is complete, transfer the clear mother liquor into another Erlenmeyer flask through a common funnel, wash the crystals twice with a small amount of cold methanol, suction filter, and dry to obtain L-(+)-Tartrate-S-(-)-α-Phenylethylamine salt, melting point 179~182 oC (decomposition), specific rotation [α]D=+13 oC (H2O, 5%). The filtrate was kept to separate the (+)-α-phenethylamine salt.
Dissolve the above crystal product in 10 mL of water, and add 1.5 mL of 50% sodium hydroxide solution to make it strongly alkaline. Diethyl ether was extracted 3 times, 10 mL each time. The extracts were combined, dried over anhydrous magnesium sulfate, distilled off diethyl ether to obtain (-)-α-phenylethylamine. Weigh and measure the specific rotation. The specific rotation of pure (-)-α-phenylethylamine is -40.3o, and the specific rotation in ethyl acetate solution is -30o.
(2) Separation of R-(+)-α-phenethylamine
The mother liquor was evaporated to dryness, the solid was dissolved in 15 mL of water, basified with 50% sodium hydroxide solution, extracted with ether, dried over anhydrous magnesium sulfate, and distilled to remove ether to obtain crude (+)-α-phenylethylamine. Add 12 mL of ethanol to the crude product and heat to dissolve. Then add 1 mL of concentrated sulfuric acid and 20 mL of ethanol. After standing for a period of time, white flaky crystals slowly precipitated. Combine the obtained crystals, dissolve them in hot water, add acetone dropwise under boiling until cloudy, let stand, slowly cool down and precipitate white needle-shaped crystals, filter, add 20 mL water and 2 mL 50% sodium hydroxide solution to the crystals to dissolve, extract with ether 3 times, each time 10 mL, the combined extracts were dried with anhydrous magnesium sulfate. After distilling ether, collect the fraction at 81~81.5 oC (2.39x103 Pa/18mmHg) by vacuum distillation to obtain R-(+)-α-phenylethylamine, weigh it, measure the specific rotation, and calculate the optical purity of the product.
Precautions
1. BPO needs to be purified before use and can be purified by using the principle that the solubility of BPO in different solvents varies greatly.
2. In the resolution experiment, adding α-phenylethylamine to the hot solution can easily obtain better salt crystals, but when adding amine, it is easy to foam and the solution will be washed out, so extra care should be taken.
3. Pay attention to avoid open fire, use the vacuum connection pipe, and the tail gas from the branch pipe is discharged from the laboratory.
4. Due to the small amount of products, vacuum distillation is more difficult, several separated products can be combined together and then vacuum distillation.
Data Processing
1. Calculate the yield and total yield of each step.
2. The enantiomeric composition of chiral samples can be described by enantiomeric excess ("enantiomeric" or "e.e%"). It represents the excess of one enantiomer to another. It is usually expressed as a percentage. The optical purity of R-(+)-α-phenylethylamine can be calculated by the following formula:
e.e% = [α]determination / [α]absolute x100%
