(Hive Bee)
09-04-02 19:44
No 352630
      Phenylnitroalkanes from benzyl chlorides / 4-OH-A
(Rated as: excellent)

Here are few interesting citations from "Synthesis of Paredrine and Related Compounds", J. Org. Chem, 12, 501 (1947). I didn't know it was possible to prepare phenylnitroalkanes this way. Paredrine is a synonym for 4-hydroxyamphetamine, for the sake of TFSE.


Paredrine, a proprietary name for p-hydroxyphenyl-2-propylamine, is a synthetically-prepared, racemic mixture of the HO-C6H4-CH2CHNH2CH3 bases, which is marketed as the hydrobromide. Solutions are used for shrinking the nasal mucosa in head-colds and hay fever, for sinus irrigation, and in ophthalmology as an adjuvant to 1% atropine or 4% homatropine. It has the advantage of producing practically no stimulation of the central nervous system and minimum of side effects.



In the first of these, p-nitrobenzyl chloride is condensed with a salt of nitroethane and the dinitro compound which results is reduced to diamine. That amino group which is atteached to the benzene ring, is then replaced by a hydroxyl group by formation and decomposition of the diazonium salt.



Synthesis Number One

    The synthesis beginning with p-nitrobenzyl chloride involves, at the outset, an aralkylation of a salt of an aci-nitro alkane. Although the aralkylation has not been studied extensively enough to permit of prediction in all cases, Weisler (5) has shown that it is correlated with the stability of the aci-form of the nitro compound, and is probably dependent on the rate at which the aci-form tautomerizes to the normal form. If the stability of the aci-form is high, the tendency is toward aralkylation on the carbon atom instead of on the oxygen. Also, the greater the reactivity of the halide selected, as evidenced by its tendency to ionize or to form free radicals, the greater is the tendency for reaction with the carbon atom.
    In the reaction between the salt of aci-nitroethane and p-nitrobenzyl chloride, aralkylation occurs both on carbon and oxygen, but fortunately aralkylation on carbon greatly predominates. (Reaction with an oxygen produces minor quantities of a nitronic ester or its decomposition products; p-nitrobenzaldehyde was therefore isolated as a by-product in step one.) Another competing reaction, which takes place to a greater extent than reaction on an oxygen atom, is the formation of 1,1-bis-(p-nitrobenzyl)nitroethane. If no excess nitroethane is used, this reaction predominates over the reaction desired, but formation of the monoaralkylated product can be favored by using an excess of nitroethane so that disubstitution is largely suppressed. This effect can be explained by considering the following reactions:

(I) p-O2N-C6H4CH2Cl + O-2N:CHCH3 --> p-O2N-C6H4CH2CH(NO2)CH3 + Cl-

(II) p-O2N-C6H4CH2CH(NO2)CH3 + ON:C-2HCH3 <==> p-O2N-C6H4CH2CH(:NO-2)CH3 + CH3CH2NO2
(I believe there is a typo and it should read O-2N:CHCH3 instead)

(III) p-O2N-C6H4CH2Cl + p-O2N-C6H4CH2CH(:NO-2)CH3 --> (p-O2N-C6H4CH2)CNO2CH3 + Cl-

    Since the formation of the aralkylated product probably occurs in accordance with equation (III), the rate of its formation depends on the concentration of the ion p-O2-C6H4CH2CH(:NO-2)CH3. An excess of nitroethane will lower the concentration of this ion by affecting equilibrium (II). The result is to decrease the yield of bis-compound and increase the yield of monoaralkylated product.



Synthesis Number One

    Preparation of 1-p-nitrobenzylnitroethane.  Sodium nitroethane (24.45g., 0.25 mole) was prepared in the reaction flask by dissolving sodium (5.75 g., 0.25 mole) in a small amount of ethanol, then adding nitroethane (131.2 g., 1.75 moles). p-Nitrobenzyl chloride (42.9 g., 0.25 mole) and 500 ml. of absolute ethanol were added and the mixture was refluxed eleven hours on a steam-bath, during which the solution turned red and a precipitate formed. After filtering, the filtrate was evaporated on a hot plate. The residue was dissolved in benzene and the solution was extracted with sodium bisulfite solution to remove p-nitrobenzaldehyde. (Free p-nitrobenzaldehyde was isolated from this extract, recrystallized and identified.) After removing the benzene, the residue was distilled (b.p. 145-160 at 0.5 to 0.6 mm.) from a Claisen flask; yield 28 g., 83%. The viscous oil was dissolved in alcohol and crystallized, m.p. 51.

(Hive Bee)
09-04-02 21:51
No 352657
      mmmm  Bookmark   

Two remarks/questions:

1. isn't it easier to perform O-demethylation of anethole, esdragon or anisaldehyde instead of swapping -NO2 for -OH?
2. 4-OH-amphetamine is a very potent drug. Be careful if you want to bioassay it.

WOMAN.ZIP: Great Shareware, but be careful of viruses...
(Hive Bee)
09-04-02 22:22
No 352666
      Well  Bookmark   

Actually, I wasn't suggesting a synthetic method for 4-hydroxyamphetamine. The point was the reaction between a benzyl chloride and a salt of nitroethane. The "Synthesis Number Two" in the article is condensation of anisaldehyde (4-methoxybenzaldehyde) with nitroethane and then reducing the p-MeO-P2NP to p-MeO-P2P. The oxime derivative of p-MeO-P2P is then reduced to PMA, which is demethylated to 4-hydroxyamphetamine with HCl under pressure. I couldn't bother typing the whole article as there was nothing else interesting.

One of the reasons to cite the first paragraph posted was that people could UTFSE and learn that it has been touted to lack central nervous effects even in the original article describing its synthesis. It is too polar to cross the blood-brain barrier. Where did you get your information?
(Chief Bee)
09-04-02 23:23
No 352687
      4-OH-A  Bookmark   

4-Hydroxyamphetamine is a very potent adrenergic/hypertensive, even if the central effects aren't as pronounced as with regular amphetamine.

The reaction used for the synthesis of the phenylnitropropane is to the best of my knowledge specific to benzyl halides with an electron-withdrawing group in the para position, but my only proof of this is that I have found the reaction being performed in five or so articles with p-nitrobenzyl chloride, once with para-chlorobenzyl chloride (bad yield) and NO other examples than that.
(Hive Bee)
09-04-02 23:38
No 352695
      I think Rhodium is right about the para-  Bookmark   

substitution thing, also the use of a Sodium salt of a nitro alkane looks to be dangerous?
They are unstable.
09-04-02 23:48
No 352700
      Dry  Bookmark   

also the use of a Sodium salt of a nitro alkane looks to be dangerous?They are unstable.

Only when dry are they dangerous, from Note 4 in Post 292292 (lugh: "Halides to Carbonyls", Chemistry Discourse):

(4) A small sample of dry potassium 2-propanenitronate, which had been stored in a stoppered flask several weeks, exploded violently immediately after opening the flask preliminary to weighing a portion. Consequently the use of dry salts is considered extremely hazardous. Solutions of sodium or potassium 2-propanenitronate are safe to handle. 

(Master Whacker)
09-14-02 18:25
No 356286
      Ring substituents greatly influence this rxn.  Bookmark   

I have seen several references where a nitronate salt was added to a substituted benzyl chloride and it turns out that the rxn. proceeds in extremely poor yield if the aramomatic ring does not have a p-Nitro group present.
(Hive Bee)
09-15-02 11:15
No 356504
      reaction  Bookmark   

Are we talking about Hass-Bender? 
(Hive Bee)
09-15-02 13:04
No 356521
      Well...  Bookmark   

It seems that the Hass-Bender synthesis of aromatic aldehydes is closely related to the side reaction they mention. Interesting.

(Hive Bee)
09-16-02 07:11
No 356863
      curious  Bookmark   

aurelius was just curious as aurelius try to pay a whole lot of attention to the posts, just caught enough to spark some interest