Sciencemadness Discussion Board

Dumb question about the Knoevenagel reaction

Smoker Root - 12-10-2019 at 23:36

Hi. I have come acrros with this name in an article tgat talks about how drug chemist synthesise amphetamine. They react benzaldehyde with nitroethane(n-butylamine as catalyst) to yield P2NP and the resuce it to P2P using Fe, HCl to later make meth or use it directly to make amphetamine. Of course I am not interestes on doing this(cause drugs are bad for you) but I always think is good to know

The knoevenagel reaction is presented in all of the synthesis? Or just on the conversion of P2NP to P2P? Or in the synthesis of P2NP?

Thank you

unionised - 13-10-2019 at 01:29

I'm fairly sure that's a Henry reaction

Corrosive Joeseph - 13-10-2019 at 02:36

"The name of the described reaction is the Knoevenagel condensation. The Henry reaction is the name of the nitro-aldol reaction,
a reaction that gives different products, the beta-nitroalcohols, and is not catalyzed by primary amines (tertiary amines or
inorganic bases are generally used).
The Rhodium archive is full of this misnaming errors apparently originating from misconceptions created at The Hive forum.
Similarly, the rearrangement of styrene oxides or 1-arylglycols to aldehydes/ketones was obstinately named as the pinacol
rearrangement (to which it admittedly somehow resembles until one considers that overall no C-C bond is being broken or created)."

"You can call a condensation of a ketone/aldehyde with an aldehyde to give an enone as a Knoevenagel reaction whenever the reaction
goes trough the enolate addition on the iminium ion (meaning that it is catalyzed by amines, piperidine being the one most commonly used).

For example, benzaldehyde and some methyl alkyl ketones will condense under Knoevenagel reaction conditions with secondary amine catalysis
to give the corresponding enone. It is however not proper to call a base catalyzed condensation of these same reactants as a Knoevenagel
reaction even when it gives the same enone as the product, because this reaction is based on an aldol reaction followed by E1cB.

In the case of nitroalkane's condensations with benzaldehydes, the reaction is clearly a Knoevenagel under amine catalysis, but there is also
an aldol-like version of this same transformation (using NaOH or KOH followed by acidification).
This version can not be called a Knoevenagel, because it is mechanistically and methodologically different (nucleophilic addition of nitronate
on the carbonyl, which is essentially a Henry reaction, followed by acid catalyzed elimination)."

"Because ammonium acetate does not work for the Henry reaction. It catalyses the Knoevenagel condensation instead. Bases like tertiary amines,
KF, K3PO4, hydroxides or carbonates are generally used for the Henry reaction, depending on the substrates."

"No. The use of triethylamine or other tertiary amines as catalysts only gives the Henry reaction product (beta-nitroalcohol). You need ammonium
acetate or a primary alkylamine or its acetate to obtain the Knoevenagel condensation product (beta-nitrostyrene). Supposedly secondary amines,
which are otherwise generally used in the classic Knoevenagel condensation on other acidic methylene compounds, also work on nitromethane in some
Otherwise, if you have no suitable primary amine, you can always use the classical two step beta-nitrostyrenes synthesis employing NaOH and HCl.
There are a couple of high yielding examples for 3,4,5-trimethoxybenzaldehyde in the older literature. Check them out. If I remember correctly,
the yields are as high or higher than the amine catalysed Knoevenagel condensation."