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[...]

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.

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SYNTHESIS NUMBER ONE

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.

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DISCUSSION

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.

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EXPERIMENTAL

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°.

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

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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.