Reaction: Pyrrolidine + p-fluorobenzaldehyde (K2CO3 as basis, DMF as solvent and T=80ºC). (1) We have to react the pyrrolidine + K2CO3 on DMF for 30 min and after that we mix the aldehyde. Why?
I am very familiar with this reaction as I have made 4-pyrrolidinobenzaldehyde at the kilo scale in industrial plant. The process involved nucleophilic substitution of the halogen substituent in 4-flurorobenzaldehyde with pyrrolidine in hot DMSO with an acid scavenger to mop up the acid (HF) generated as the fluoro group is displaced with amine. Without the base, the reaction is hindered because of the interaction between liberated acid and the remaining pyrrolidine. DMSO was preferred over DMF because of tox and cost. Carbonate can be used, but at large scale an acid scavenger like MgO is preferred because it does not evolve CO2 gas which can be problematic. The acid scavenger does not need to be soluble (nor does a carbonate if used) as it can be screened out of the warm reaction mass upon completion of the reaction. The product is precipitated by adding the screened solution to water (or the other way round), then filtered and washed free of DMSO and inorganics. If performed correctly, yield should be well over 90% of 4-pyrrolidinobenzaldehyde.
All of the components (aldehyde, amine, acid scavenger, solvent) can be added at the start. We would add 4-fluorobenzaldehyde first along with the acid scavenger, then add DMSO, stir to dissolve the aldehyde and ensure the acid scavenger is in suspension, then with stirring add pyrrolidine washed in with a little more DMSO. There is no need to stir the acid scavenger, such as carbonate, with the amine in solvent first!
I'm not an expert organic synthesis, but my best guess is that the K2CO3 is being used to absorb the water impurities, since water will hinder the reaction between Pyrrolidine and p-fluorobenzaldehyde. That's why it takes some time. But I'm not sure if this is correct because I never knew whether pyrrolidine or DMF is really hygroscopic or not.
This does seem unusual, while getting rid of water would make sense, typically imine formation occurs faster under mild acidic conditions. Though I assume you are adding a nucleophile to this reaction? This could be the reason, if your nucleophile is water sensitive carbonate addition early in the reaction may be a way to buffer out all the water prior to its addition.
And what do you obtain by this reaction? 1,1 '- [(4-Fluorophenyl) methylene] dipyrrolidine or 4-pyrrolidin-1-yl-benzaldehyde? The reaction conditions are suitable for synthesis of the second molecule, K2CO3 is the base for binding of the resulting HF (aromatic nucleophilic substitution - addition elimination mechanism via Meissenheimer complex). For the first molecule you need acidic conditions. The answers above are irrelevant.
This article has not undergone proper editorial management probably, because it contains a number of errors and uncertainties.
1. It is not stated whether and how the solvents were dried. If a solvent was not dried, anhydrous K2CO3 created with the water present sesquihydrate (K2CO3. 1.5 H2O), which is in the solid phase in an aprotic solvent, very good base. But do not think that would be enough to deprotonate the present cyclic amine.
2. In the scheme of synthesis piperidine product 1c is misspelled unsubstituted benzaldehyde.
3. Scheme for preparation of 1a (4-methylpiperazine derivative) demonstrate using of pyrrolidine - the same as scheme for 1b.
4. Unless indicated whether the reactions were carried out in an autoclave. Table 3 applies to that from solvents? The temperatures above 110 °C at atmospheric pressure (Table 3) for the solvents 1, 3-6 (Table 2) are illusory. See B. P. of applied solvents.
5. Demonstration of obtained yields is not significant, determine the conversion directly in the reaction mixture is correct (in particular for separation from DMSO).
6. The amount of K2CO3 in the first synthesis is sub-stoichiometric and probably will not be correct - compare with other mentioned synthesis.
Because of these deficiencies may be the presented information about mixing of the amine with K2CO3 in applied solvent fully irrelevant.
At first one of my guess was the same with Mr. Yadav, but that didn't explain why it has to be 30 minute. As for aiding the formation of nucleophile is the same, it doesn't has to be 30 minute.
In my opinion I think it is imperative to know what is the reaction between pyrrolidine and 4-fluorobenzaldehyde as it will give hint to the preparation or path of reaction it will take. The link I attached above is exactly the same reaction we discuss here, and it is as Mr. Pazdera said, the reaction mechanism is aromatic nucleophilic subtitution. From the mechanism we can deduce whatever factor necessary to increase the effectiveness/yield then link the factor with the step of preparation & reaction.
In here it is clearly stated that in aromatic nucleophilic substitution using aprotic polar solvent is having higher rate constant than in protic polar solvent: http://pubs.acs.org/doi/abs/10.1021/ja01462a023?journalCode=jacsat
Now, the last step of puzzle is, the fact that K2CO3 aside from its basic property it also act as water binder and later form hydrated K2CO3. Then, DMF and pyrrolidine turns out to be hygroscopic
The preparation 2-pyrrolidinyl benzaldehyde in the supplementary material: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324311/bin/NIHMS361504-supplement-1_si_001.pdf
Interestingly they mix them all at the same time. I assume they have better preparation to reduce the effect of hygroscopic properties of both pyrrolidine and DMSO.
Well, I guess it is a common sense to use as few chemical as possible in chemical reaction, don't you think? If there are two requirement and can be satisfied by just one chemical, why using two?
The first one is the main problem, the question of why the 3 component has to be mixed first for 30 minutes prior to the addition of 4-fluorobenzaldehyde.
The second one is the real reason why K2CO3 is there.
For the first one, it is still unclear, and we still discuss it up til now. My answer would be because it act to bind the water prior to the main reaction.
For the second one, it is already clear that K2CO3 act as base (everybody here agree to that), I've never stated otherwise. Unless, in the context of the mixing for 30 minutes (which is part of the first problem).
That's why I stated 2 requirement, because there are 2 requirement that need to be fulfilled, the absence of protic solvent (which I included in first problem), and the basic condition (part of the second problem).
Anyway, I find that this discussion is no longer relevant, because from the last paper above (which is of a much higher quality than the previous one) shows that the premixing of the 3 component for 30 minutes is unnecessary.
Last but not least, my apology if any of my word makes you feel uncomfortable or any thing like that. I didn't mean to. My whole intention in this discussion is to share my thought and help this (scientific) community to become a good and nice network where we can ask and share knowledge, and help each other.
Reaction of Pyrrolidine and p-fluorobenzaldehyde we have to react pyrrolidine with K2CO3 to form to anion which is more reactive towards aldehyde than pyrrolidine itself..K2CO3 is not soluble in DMF & does not play any role with DMF during the reaction.
I am very familiar with this reaction as I have made 4-pyrrolidinobenzaldehyde at the kilo scale in industrial plant. The process involved nucleophilic substitution of the halogen substituent in 4-flurorobenzaldehyde with pyrrolidine in hot DMSO with an acid scavenger to mop up the acid (HF) generated as the fluoro group is displaced with amine. Without the base, the reaction is hindered because of the interaction between liberated acid and the remaining pyrrolidine. DMSO was preferred over DMF because of tox and cost. Carbonate can be used, but at large scale an acid scavenger like MgO is preferred because it does not evolve CO2 gas which can be problematic. The acid scavenger does not need to be soluble (nor does a carbonate if used) as it can be screened out of the warm reaction mass upon completion of the reaction. The product is precipitated by adding the screened solution to water (or the other way round), then filtered and washed free of DMSO and inorganics. If performed correctly, yield should be well over 90% of 4-pyrrolidinobenzaldehyde.
All of the components (aldehyde, amine, acid scavenger, solvent) can be added at the start. We would add 4-fluorobenzaldehyde first along with the acid scavenger, then add DMSO, stir to dissolve the aldehyde and ensure the acid scavenger is in suspension, then with stirring add pyrrolidine washed in with a little more DMSO. There is no need to stir the acid scavenger, such as carbonate, with the amine in solvent first!