Author Topic: Hydrogenation of benzylcyanide to phenetylamines  (Read 8735 times)

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  • Guest
Hydrogenation of benzylcyanide to phenetylamines
« on: July 19, 2003, 12:01:00 PM »
Hi I’m working with the hydrogenation of  some benzylcyanide to the phenetylamines (made from the red. Of the aldehyde with NaBH4 in MeOH, sub of oh with PBr3 in ether and sub of the bromine with cyanide via NaCN in DMF (ill write a synth. later)
All these reaction work good. But the hydrogenation is quite time consuming. Right now I’m hydrogenate at 6 bars with Pd/C and use 10% hydrochloric acid(aq) in ethanol. It work’s but hydrogenation of 5g takes 1-2dayes. Anyone with experience with other solvent systems??


  • Guest
Re: Hydrogenation of benzylcyanide
« Reply #1 on: July 19, 2003, 01:13:00 PM »
SWIM experience hydrogenating   mostly chloroephedrine to meth, using methanol as the solvent and Pd. 10%/C. SWIM found that many times the catalyst gets poisoned , although it will hydrogenate but slow , so it’s best to change your catalyst 2-3 times until it kicks and you see  it taking hydrogens at a good rate so you can be done in less than and hour.  At a good rate the hydrogen gets consumed so fast that at the end your bottle is very hot from the reaction

Edit :see also Patent US3458576 originally provided by polysam, then Roger2003 , and recently reviewed by Aurelius

Post 439559

(Aurelius: "US Patent 3458576  reduction of phenylnitropropene", Methods Discourse)


  • Guest
« Reply #2 on: July 20, 2003, 06:27:00 AM »
Ups, the hydrogen flas was not turned off, that's why no presuredrop was seen. Here is the writup
(To Rhodium, iff you wan't a HTML I mail you one)

From aldehyde to alcohol

50g(0,28mol) 3,4,5-trimethoxybensaldehyde was dissolved into 600mL 0°C methanol (ice bad) under stirring. Then 10g NaBH4 was added in 3 portions, the reaction was left over night.
The next day most of the methanol was removed (rotorvap, important to get a nice extraction)) and the rest diluted with water (500mL) and made acid with 37% HCl(aq). The water was extracted with 4*100mL CH2Cl2, the organic phases was combined, dried and concentrated on the rotor vapor.
Yield 47,2g(93%) 3,4,5-trimethoxybenzylakohol.
Rf (40% EtOAc in Heptane) 0,27

From alcohol to bromide

47,2g(0,24mol) 3,4,5-trimethoxybenzaldehyde was dissolved into 1L ether at 0°C (ice bad) under stirring. Then 25g(0,1mol) PBr3 was added over 30min, the ice removed and the reaction left for 60 min. After that the mixture was poured out into 300mL water, the organic phase was separated, the water extracted with 2*100mL ether, the ether phases combined, washed with 2*50mL water, dried and concentrated (rot. vap.)
Yield 55g(88%) 3,4,5-trimethoxybenzylbromice
Rf (50% EtOAc in Heptane) 0,63

From bromide to nitile

50g(0,19mol) 3,4,5-trimethoxybenzylbromide was dissolved into 600mL DMF under stirring at 0°C (ice bad), then 20g NaCN vas added and the ice bad removed. After 1 hour the mixture was poured out into 2L water, the water was extracted with 4*100mL CH2Cl2. The organic phases was combined, washed with 2*100mL water, dried and concentrated.
Yield of 3,4,5-trimethoxybenzylcyanide 36g(90%)
Rf (50% EtOAc in heptane) 0,45

From nitrile to ammine

15g(0,07mole)3,4,5-trimethoxybenzylcyanide was dissolved in 100mL ethanol, 10mL 37% hydrochloric acid and 100mg 10% Pd/C was added and the mixture was hydrogenated at 5,5bar for 12 hours, then the mixture was filtrated, most of the ethanol was evaporated off, then the mixture was dissolved into 200mL water, extracted with 50mL ether (to remove starting material ect.), made basic with NaOH, extracted with 3*40mL CH2Cl2, the organic phases was combined, dried and evaporated.
Yield 13,7g mescaline freebase.


  • Guest
Phenethylamines via Mandelonitrile Carbamates
« Reply #3 on: July 20, 2003, 07:12:00 AM »
Nice Hest! :)

I have two questions:

- What is your setup to contain 6 bar of pressure? Is there any way to do it for a kitchen chemist, without Parr Apparatus?

- For EveryknowledgableBee:
This is the hydrogenation of a mandelonitrile intermediate to the PEA, at RPT condition, is there any reason that it could not work on a normal phenylacetonitrile, or is this only applicable to O-Ethoxycarbonyl mandelonitriles? Otherwise it would bee a very convenient way to PEA from acetonitrile derivates.

Synthesis of meta-Methoxyphenethylamine via O-(Ethoxycarbonyl)-3-Methoxy-Mandelonitrile

J. Org. Chem. 47, 2638-2643 (1982)

This is the original reference for

the KrZ way to 2C-H


Attempted preparation of 2-(m-methoxyphenyl)ethylamine (4) by reduction of nitrostyrene 6 with lithium aluminum hydride1 gave a product containing a persistent impurity which could be eliminated only if nitrostyrene 6 was rigorously purified. Catalytic hydrogenation2 of 6 gave variable results as the scale was increased. However, an efficient and convenient synthesis of phenylethylamine 4, independent of scale, proceeded in high yield from m-anisaldehyde (5) by first treatment with potassium cyanide and ethyl chloroformate to form O-(ethoxycarbonyl)-3-methoxymandelonitrile (7). Hydrogenation3,4 of 7 over palladium on charcoal in ethanol at atmospheric pressure gave 4 reproducibly in 92% yield.

O-(Ethoxycarbonyl)-3-methoxymandelonitrile (7)

To a stirred solution of 13.6 g (0.1 mol) of m-anisaldehyde (5) and 11.9 g (0.11 mol, 10.8 mL) of ethyl chloroformate in 20 mL of THF, cooled in an ice-water bath, was added in one portion 7.2 g (0.11 mol) of KCN dissolved in 25 mL of water. The reaction mixture was stirred for 4 h at 5°C and then slowly warmed to room temperature overnight. Water (100 mL) was added, the aqueous solution was extracted with 3x40 mL of ether, the combined extracts were dried and evaporated, and the residue was distilled to afford 21.4 g (0.92 mol, 92%) of the cyanohydrin carbamate 7: bp 110-115°C/0.3mmHg [lit. bp 132°C/0.4 mmHg].

2-(m-Methoxyphenyl)ethylamine (4)

A solution of 23.5 g (0.1 mol) of 7 in 300 mL of absolute ethanol was added dropwise (0.5 drop/s) to a mechanically stirred solution of 300 mL of absolute ethanol containing 1.5 g of 10% Pd/C catalyst and 12.9g (0.13 mol, 7 mL) of concentrated sulfuric acid as hydrogen was bubbled through the solution. After the addition, stirring and bubbling were continued for 8 h, the reaction mixture was filtered, the filtrate was evaporated, water (100 mL) was added, and the cooled aqueous solution was made alkaline with 4 M sodium hydroxide. The solution was extracted with 4x50 mL of ether, the combined extracts were dried and evaporated, and the residue was distilled to afford 13.9 g (0.09 mol, 92%) of phenylethylamine 4: bp 93-95°C/0.1mmHg [lit. bp 122-123°C/1.0mmHg].


[1] J. Chem. Soc. C, 2632 (1971)
[2] Synth. Commun. 1, 47 (1971) and references cited therein.

Post 472313 (missing)

(Rhodium: "Catalytic Hydrogenation of Nitrostyrenes", Serious Chemistry)

[3] J. Am. Chem. Soc. 55, 2593 (1933)

Post 471993 (missing)

(Rhodium: "Catalytic Reduction of Mandelonitriles", Serious Chemistry)

[4] Justus Liebig's Ann. Chem. 564, 49 (1949)

Post 485823

(Rhodium: "Kindler: Phenylacetonitriles to Phenethylamines", Serious Chemistry)


  • Guest
« Reply #4 on: July 20, 2003, 08:38:00 AM »
It was done in a Parr apparatus.


  • Guest
I have had similar problems.
« Reply #5 on: July 22, 2003, 11:23:00 AM »
I have had similar problems. You get the aldehyde as a byproduct by hydrolysis of the imine.


  • Guest
« Reply #6 on: July 26, 2003, 09:30:00 AM »
Now the hydrogenation is also done witj RaNi. Works as greath as Pd/C

5g 3,4,5-trimethoxybenzonitril was disolved into 100mL ethanol, 20mL 25% ammonia in wather and 1g RaNi was added, the reaction was the hydrogenated at 6 bar for 12 houres, filtrated, evaporated, disolved into 2M HCl(aq), ekstracted with DCM, made basic with NaOH(s), ekstracted with 2*50mL DCM. The organic phases was combined, dryeat and evaporated. Yeald 83%.


  • Guest
« Reply #7 on: July 26, 2003, 10:47:00 AM »
That's good  ;) .

Hest, if you have the time and enough catalyst/nitrile, could you try the hydrogenation at atmospheric pressure, with a bigger amount of Pd/C, like one gram for 15g nitrile?

To see if bees without Parr apparatus  :(  have some hope in that reduction...


  • Guest
Kindler: Phenylacetonitriles to Phenethylamines
« Reply #8 on: February 01, 2004, 04:52:00 AM »
This is reference #5 from

Post 471993 (missing)

(Rhodium: "Catalytic Reduction of Mandelonitriles", Serious Chemistry)

Studien über den Mechanismus chemischer Reaktionen. II.
Ûber den Mechanismus der Synthese von sekundären und tertiären Aminen durch Reduktion
Karl Kindler

Ann. Chem. 485, 113-126 (1931)

____ ___ __ _

This is reference #4 from

Post 448639

(Chimimanie: "Phenethylamines via Mandelonitrile Carbamates", Serious Chemistry)

Studien über den Mechanismus chemischer Reaktionen. XI.
Ûber die Lenkung der Katalytischen Hydrierung bei Estern des Mandelonitrils
Karl Kindler und Karl Schrader

Ann. Chem. 564, 49-54 (1949)