Halogenation of Amino Alcohols and their Separation

java · Consumer

It's known that when chlorinating amino alcohols there are many routes, the chlorinated phosphorous acids, thionyl chloride and ZnCl +HCl are a few known to SWIM.

In the chlorination of the benzyl type amino alcohol, thionyl chloride works well and the solvent of choice has mostly been chloroform. Once the chlorination has occur the separation of the chlorinated amino alcohol has been facilitated with ethyl ether and although acetone works , it reduces the yields.

In the case of primary non-benzylic amino alcohols the chlorination occurs the same way , using chloroform as the solvent and thionyl chloride. The question arises as to the separation of the chlorinated aminoalcohol. Will the separation occur as well using the said and mentioned solvents or will it be different .

A good example of benzylic amino alcohols are the popular ephedrine, pseudo ephedrine, phenylpropanolamine to name a few plus their isomers. One of the primary non -benzylic amino alcohols SWIM is familiar with is Phenylalaninol.

The reduction of the latter amino alcohol to an alkane has been a task of SWIM for quite a while now, due to the scarce supply of thionyl chloride and the chlorinated phosphorous acids, SWIM has resorted to the use of ZnCl + HCl (37%), for the chlorination of the amino alcohol with some fair results. It seems that once the amino alcohol has been introduced to the zinc chloride and HCl solution and stirred with some mild warming to assist in the process the chlorination takes place. There after the separation of the chlorinated amino alcohol takes place with some addition of NaOH and then the organic layer separated , from here in its base it can be hydrogenated with Pd 10% and reduced to the desired alkane base.

The salts conversion of the reduced phenylalaninol base to the HCl saltsis accomlished by gassing, but it has been reported that the HCl salts are very hydroscopic ( water hungry), and are hard to keep from mush. It's been suggested that the carbonated salt , done with dry ice and ethanol as the solvent, turn out some great ice chunks. There is also the phosphate salt, which is also a smokable salt with this reduced amino alcohol.

I have some questions as to the name of the chlorinated phenylalaninol and two if the method of separation from chloroform is as valid as with the chloroephedrine method.......java

java · Consumer

Here is a thread that was posted over at WD, on resources and inquiries o the same topic and some recent reply by WizardX.......java

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java
Doctor Who

I've been looking for an effective methos for chlorination of non benzylic primary amino alcohols. There has been some suggestions of using the Lucas test i.e. ZnCl +HCl which is good for tertiary>secondary>primary alcohols , in which it works fine for benzylic alcohols such as pseudo(ephedrine).

There has been some articles with the use of cyanuric compound combination ......
A Novel Laboratory Hydrochlorinating Reagent for Alcohols
Sandler
J.Org. Chem., Vol. 56, No. 11, 1070 3967

An Efficient Route to Alkyl Chlorides from Alcohols Using the Complex TCT/DMF
Lidia De Luca, Giampaolo Giacomelli,* and Andrea Porcheddu
ORGANIC LETTERS 2002 Vol. 4, No. 4 553-555

PDF
I'm sure there are many other methods for which I haven't found , so if you know of some let me know . I have ruled out the obvious, thionyl chloride and the halogenated Phosphoric acids for lack of access to them.........java

It's better to die on your feet, than live on your knees...............Emiliano Zapata (UH)

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java
Doctor Who

Here are a few things that I found....

Patents: GB418043 Process for the Chlorination of Hydrocarbons

GB570374 Chlorination of Unsaturated alcohols

US3290395 Chlorination of Unsaturated alcohols in the Substantial absence of water and in the Presence of Hydrogen
Chloride.

I will read through this, there may lie an gem within.......java

It's better to die on your feet, than live on your knees...............Emiliano Zapata (UH)
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java
Doctor Who

Posted - Dec 12 2004 : 09:42:41 AM Show Profile Edit Reply Reply with Quote Delete Reply

Here is a nice document on the chlorination of alcohols in general........java
A Systematic Study of the Preparation of Alkyl Chlorides from the Corresponding Alcohols
R.H.Clark, F.R.S.C .and H.R.L.Streight , M.A.

http://home.ripway.com/2004-11/211899/asystemicstudyofthepreparationofalkylchloridesfromthecorrespondingalcohols.djvu

It's better to die on your feet, than live on your knees...............Emiliano Zapata (UH)
Edited by - java on Dec 26 2004 11:22:20 AM
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java
Doctor Who

Posted - Dec 21 2004 : 2:50:11 PM Show Profile Edit Reply Reply with

The Preparation of Alkyl Chlorides
James F.Norris and Hazel B. Taylor
JACS vol.46,no.3, 753-757,1924

http://home.ripway.com/2004-11/211899/alcohols2halides.hcl-zncl2.pdf

It's better to die on your feet, than live on your knees...............Emiliano Zapata (UH)
Country: Mexico | Posts: 265 Go to Top of Page
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java
Doctor Who

Chlorinating Phenylalaninol with thionyl chloride using chloroform as the solvent one would get chlorophenyalaninol,not sure this would be the name. Hence the separation of the product from chloroform via ether? or would acetone work.

As the parallel procedure although using paeudo(ephedrine), with the same solvent and halogenating agent, thionyl chloride, the separation of the chloropseudo(ephedrine) works fine with either of the two , save better yields using diethyl ether, but that's not available to SWIM. Any suggestions as to the...

I.name of the halogenated phenyalaninol.
2. the separation of the halogenated phenylalaninol from the chloroform save distillation

gracias, ........java

It's better to die on your feet, than live on your knees...............Emiliano Zapata (UH)

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WizardX
Wizard Master

Posted - Mar 23 2005 : 8:27:50 PM Show Profile Email Poster Visit WizardX's Homepage Reply with Quote

quote:name of the halogenated phenyalaninol

2-Amino-3-Phenylpropan-1-ol, Phenylalaninol, C6H5CH2CH(-NH2)CH2-OH

2-Amino-3-Phenylpropan-1-chloro, C6H5CH2CH(-NH2)CH2-Cl

OR

1-Chloro-3-Phenylpropan-2-amino

quote:the separation of the halogenated phenylalaninol from the chloroform save distillation

The amino will form the HCl salt, with can be precipitated with dry diethyl ether

java · Consumer

Silica Chloride (SiO2-Cl), a New Heterogeneous Reagent, for the Selective and Efficient
Conversion of Benzylic Alcohols to Their Corresponding Chlorides and Iodides
Habib Firouzabadi,* Naser Iranpoor,* Babak Karimi, and Hassan Hazarkhani
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 21, pp. 3671–3677, 2003
pdf

ABSTRACT
Structurally different benzylic alcohols were efficiently converted to
their corresponding chlorides by silica chloride (SiO2-Cl) in CHCl3 at
room temperature. Silica chloride is also able to convert benzylic
alcohols to their iodides in the presence of NaI in a mixture of
CH3CN/CHCl3 in excellent yields.

Key Words: Silica chloride; Benzylic alcohols; Benzylic chlorides;
Benzylic iodides.

Note : unfortunately this method won't work with primary non-benzylic amino alcohols, this of course would be great to convert the ephedrine to chloroephedrine or chloroiodine one step closer to honey ......edited by java

java · Consumer

Immobilization of HX: [Hmim]X as Halogenating Agent, Recyclable Catalyst and Medium for Conversion of Alcohols to Alkyl Halides
WU, Hai-Hong( ) SUN, Jing( ) YANG, Fan( ) TANG, Jie*( ) HE, Ming-Yuan( )
Chinese Journal of Chemistry, 2004, 22, 619 621
Direct Link URL: http://home.ripway.com/2005-1/247174/ConversionofAlcoholstoAlkylHalides.pdf
Alternate URL: http://host.picturewizard.com/2005-1/247174/ConversionofAlcoholstoAlkylHalides.pdf

Abstract
HX is immobilized by reaction of halogen acid with methylimidazole, and the formed ionic liquid [Hmim] was used as halogenating agent, catalyst as well as medium for conversion of alcohols to alkyl halides. Excellent yields were obtained. The halides produced could be easily separated from the reaction mixture via simple decantation, and the ionic liquid [Hmim]X could be regenerated conveniently by adding equivalent of halogen acids followed by removal of water.

Keywords halogenation, ionic liquid, alcohol, alkyl halide

loki · guinea pig

i liked the look of that silica chloride one... wouldn't that pretty much just be silica gel treated with HCl?

for my 2c on the subject, there is a scheme using kaolinite, sulphuric acid and potassium iodide that was primarily tested using microwave heating but probably works with a longer time (5min vs 1 hour at a guess) with conventional heating.

this is my probably wrong guess about the reaction mechanism:

Al2.Si2O5.(OH)4 + (H2SO4)5 + KI --> K.Si2O5 (aq) + Al2.(H2SO4)3 (aq) + (H2O)4 + HI (aq)

the numbers in this are all balanced but i'm not sure it's the correct mechanism exactly.

as far as i can tell, it would appear that the way this reaction works is, first of all, the sulphuric acid tears up the KI with too much acid, so beware of this, but basically, potassium silicate and aluminium sulphate, if i am not mistaken, are both very hygroscopic salts, and as the iodide reacts with the alcohols, liberating one water molecule each time, the water is absorbed into the hydration waters of the salts.

hmm which just reminds me of something, sodium aluminium silicate is used in table salt as a free flowing agent, implying that it absorbs a lot of water... so perhaps what happens in this reaction is one forms potassium aluminium silicate iodide sulphate (2 moles sulphate to 1 mole kaolin) and in this complexed configuration, the iodide is free to react as concentrated HI acid, and the water this reaction is produced is absorbed into the complex

This reaction obviously won't work unless you get the sulphuric acid:potassium iodide ratios correct, and the amounts of water right - or maybe that's where i went wrong, not using another solvent, for example, methanol. Nice thing about iodides is that they can do those condensations with alcohols all by themselves, so long as you either keep the HI concentrated with a recyclant, or as occurs in this scheme, keep pulling the water away from the reaction.

now, all we need is a more OTC substitute for hypophosphorous for removing the halide. I suppose to some degree any reduction system works, but one which is as accessible as KI, kaolin and sulphuric acid would be preferable. I've speculated on using ascorbic acid with iodides for this, using the theory that since ascorbic acid is well known for liking to attach hydrogens to iodides, maybe it can do it to iodides which are only half iodide.

i wonder what ascorbic acid would do if added to that kaolin/sulphuric/KI mixture... ascorbic acid does not react with the HI acid itself, but only with iodine ions lacking a hydrogen... and is sulphuric acid the only option for that scheme? surely phosphoric acid would work as well, and nitric, as for halo acids, not sure if that would interfere with the reaction. Also, does this imply that if one had aluminium silicate crystal material, sans hydroxide, that this would perform the same function, pulling water out of the reaction and holding the halo-acid for the reaction... when i look at it, it is remarkably like an ion-exchange and dehydration mechanism that does the magic here.

i know that it is somewhat of a pain in the ass, but iodine is a much easier and safer halogen to work with than any of the others, and reacts faster, combining and cleaving from other chemicals with much less persuasion than other halides... it slices, it dices...

java · Consumer

Here are two different methods to reduce primary alcohols with references, although not tried, it seems this may be a good method to finish off the phenylalaninol to the alkane amine desired.........java

fcknut · Mon Aug 22, 2005 2:49 am

dunno if iodides are also of interest to you - but tosylation (using Me3.HCl and triethylamine - Tanabe (tenabe?) et al 1999 forget the journal though) and subsequent pseudo-finkelstein (NaI/acetone) is a nice route which uses recrystallisation of the tosyalte and iodide for purifcation.

sorry if this is off topic and off no interest....

java · Consumer

This article has an interesting section in route to the premise goal, regarding primary aliphatic alcohols, where they get chlorinated easily , hence since primary alcohols are much harder to chlorinate, both secondary benzylic type alcohol and tertiary alcohols will also chlorinate..........it's worth a try since its so OTC.......java
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The Condensation of Aliphatic Alcohols with Aromatic Hydrocarbons. I. The Preparation of Mesitylene and sym-Triethylbenzene
James F. Norris and John N. Ingraham
journal of the American Chemical Society (1938),Vol. 60, No. 6:,pp 1421 - 1423;

DOI: 10.1021/ja01273a04

http://rapidshare.de/files/4435062/The_Condensation.pdf.html

Excerp
.....alcohols react with aluminum chloride and form compounds having the formula
ROAlC12, which decompose when heated and produce RCl + AlOCI.

Note: thanks to Sandmayer for acquiring the citations

stratosphere · Mon Sep 05, 2005 4:35 pm

another intersting thing one might be able to do with benzylic halides is react them with theourea to get the benzylic thiol. why would one want to do this?
well my understanding is that thiols easily reduce with raney nickel.

so while the extra step and resultant reduction of yield from going from halo-->thiol might be a pain, it could well be more then compensated for by easier and precious metal free hydrogenation conditions.