Sciencemadness Discussion Board

Friedel-Crafts acylation of aliphatic imines derivatives of amino acids

yanzi - 16-1-2016 at 05:49

This is a unwanted potential side reaction while methylenating carbidopa (or methyldopa) in dichloromethane (with 1% tetrabutylammonium bromide catalyst + 0.1-0.2 molar sodium iodide catalyst). Is there a good chance of side reactions (polymerizations) happening if imines formed from the reaction of the amino group with DCM isn't reduced right away? In methyldopa, the methylimine formation is wanted (anticipating reduction with NaBH4), with carbidopa, it is not.

yanzi - 18-1-2016 at 18:09

Sorry -- can you move this back -- this is not a schoolwork question. I have a bachelors' degree in biochemistry.

UC235 - 18-1-2016 at 18:20

It's not that it's a schoolwork question. It's that you've provided no relevant references for the procedure.

yanzi - 18-1-2016 at 21:40

I didn't realize I needed references to discuss a well-known procedure. I'm running a standard methylenation of catechol procedure but using methyldopa (L-DOPA methylated at the alpha carbon) instead of catechol or demethylated vanillin? I am using the reference "PTC Methylenation of Catechol (Using TBAB) under https://www.erowid.org/archive/rhodium/chemistry/methylenati...

I'm modifying it with addition of sodium iodide (should have bought tetrabutylammonium iodide) based on the paper that showed that adding sodium iodide to a PTC reaction (using TBAB or TBAI) increases reaction rates and yields http://onlinelibrary.wiley.com/doi/10.1002/jccs.199100038/ab... -- they mainly discussed the alkylation of benzyl chlorides into benzyl esters using a combination of TBAI and sodium iodide. I already know the methylenation reaction is mechanistically sound -- it is well-studied, I have read a variety of papers on it, etc. what I am asking is the issue of side reactions when the amino group reacts in basic conditions with activated dichloromethane to form imines.

My big question is: are aliphatic (non-resonance-stabilized) imines vulnerable to attack from phenols and activated aryl groups? Or does it require the formation of an imine chloride to do so? My undergraduate education says that formation of acyl halides is an absolute requirement for Friedel-Crafts acylation, but I note for example, formaldehyde reacts with phenols to form polymers. Do imines share the same vulnerability?

I have read two papers which suggest that primary amines react with DCM, but one paper said that primary amines react very slowly while the reactivity of secondary amines and tertiary amines is more noticeable due to their increased nucleophilicity. However, if I am activating the halide groups with iodide ions, especially phase-transfer-catalyzed iodide ions in the organic phase, then there should occasionally be [Cl-CH2-I] intermediates which are more reactive, which then will readily react with primary amines to form imines.

Imines are strong electrophiles, so in this case, I am just wondering about the *general vulnerability* of imine-derivatives of tyrosine-like or DOPA-like amino acids to a sort of intramolecular Friedel-Crafts acylation (formation of a 5-membered ring). Firstly, what is the vulnerability of deprotonated L-DOPA or methyldopa to cyclization, if the hypothetical imine forms before the diols are protected, and what is the vulnerability following successful methylenation? (I believe methylenation should be faster than imine formation, due to the reduced nucleophilicity of primary amines.)

Also, does this sound like a question that belongs in "beginnings"?

[Edited on 19-1-2016 by yanzi]

yanzi - 18-1-2016 at 21:51

Also, if this acylation would be slow, then having sodium borohydride present in the PTC mixture should reduce any imines that form? (Methylation of amines through imine intermediates is the target objective.)

Also, along this same line of Friedel-Crafts acylation of non-acyl-halide acyl groups , if methylenated catechols would react slowly enough with formaldehyde at pH 5, then surely this would allow methylation through formaldehyde + NaBH4 before noticeable polymerization takes place?

Scr0t - 23-1-2016 at 16:24
Quote:

However, if I am activating the halide groups with iodide ions, especially phase-transfer-catalyzed iodide ions in the organic phase, then there should occasionally be [Cl-CH2-I] intermediates which are more reactive, which then will readily react with primary amines to form imines.

Describe to me what you think an imine is and how is an imine formed here?

And what's this about Friedel-Crafts acylations!? what's that got to do with this? You sound like you're talking gibberish.
Provide some references so we can tell what the hell you're talking about.

Stick to biochemistry and leave the drugs alone.

[Edited on 24-1-2016 by Scr0t]

zed - 29-1-2016 at 15:58

Sounds like you would like to Methylene-ate the hydroxyls to form the Amino acid analog X-stacy. The vulnerability of the amino group to attack is not something I know of.

It is a complex situation involving a Zwitterion. Dunno.

The Catechol ring itself might be quite vulnerable to attack not by methylene Chloride/Iodide, but rather by Elemental Iodine. The addition of Iodine to such ring systems is well known. The Hydroxyl group is very activating.

Consider the preparation of 3,4,5-Trimethoxy benzaldehyde, via vanillin.

yanzi - 7-2-2016 at 10:22

Quote: Originally posted by Scr0t  

Quote:

However, if I am activating the halide groups with iodide ions, especially phase-transfer-catalyzed iodide ions in the organic phase, then there should occasionally be [Cl-CH2-I] intermediates which are more reactive, which then will readily react with primary amines to form imines.

Describe to me what you think an imine is and how is an imine formed here?

And what's this about Friedel-Crafts acylations!? what's that got to do with this? You sound like you're talking gibberish.
Provide some references so we can tell what the hell you're talking about.

Stick to biochemistry and leave the drugs alone.

[Edited on 24-1-2016 by Scr0t]


lolz I majored in and tutor organic chemistry. I know what I'm talking about.

Formaldehyde is electrophilic enough to react with activated aromatic rings (like phenols, and probably by extension anilines and catechols) in acidic conditions. Thus, the preparation of imines by reacting primary amines with formaldehyde (where the amine is attached to an electron rich aryl substituent) might also result in the aromatic ring attacking the formaldehyde.

Hence, Bakelite and phenolic plastics formed by the condensation of phenols and formaldehyde (pretty well known). What I am asking is how this side reaction might be suppressed or avoided.

Now what I am asking is -- will electron rich aryl rings (those containing phenolic or catecholic groups) react with primary imines as well? Thus, even if you react amines with dichloromethane with a tetrabutylammonium iodide + sodium iodide catalyst (http://onlinelibrary.wiley.com/doi/10.1002/jccs.199100038/ab...) so as to avoid using formaldehyde, will the imine group react with the catecholic group as well?

[Edited on 7-2-2016 by yanzi]

yanzi - 7-2-2016 at 10:34

Quote: Originally posted by zed  
Sounds like you would like to Methylene-ate the hydroxyls to form the Amino acid analog X-stacy. The vulnerability of the amino group to attack is not something I know of.

It is a complex situation involving a Zwitterion. Dunno.

The Catechol ring itself might be quite vulnerable to attack not by methylene Chloride/Iodide, but rather by Elemental Iodine. The addition of Iodine to such ring systems is well known. The Hydroxyl group is very activating.

Consider the preparation of 3,4,5-Trimethoxy benzaldehyde, via vanillin.



Sigh methylenation of catechol groups by dichloromethane and alkyl dihalide is well-studied. There are numerous papers on this topic which you can find on Google. Generally, yields are good if a phase transfer catalyst is used -- I have tetrabutylammonium bromide plus some sodium iodide.

I am not worried about the yield of the methylenation reaction.

The basis of the question is what happens when primary amines that have catechol substituents (protected by a methylene group) react with dichloromethane.

Now, generally, from various papers I have read, uncatalyzed reactions of DCM with primary amines are poor but not with secondary and tertiary amines. However, this would appear to change with the addition of sodium iodide, which can be brought into the DCM phase through TBAB or TBAI.

zed - 7-2-2016 at 15:36

Ummm. Do an experiment. Carbodopa looks like it MIGHT be easily cyclized, into an Indole.

The reaction of Methyl Dopa, could easily have unexpected consequences. IF an imine were to form, under your reaction conditions, the Methyl Dopa might rapidly decarboxylate. Usually, an imino-acid decarboxylation requires heat, but USUALLY may not apply in this case. There aren't enough bonds, to go around.

Depends on what products you are looking to produce. Got a lot of reactive groups present.

Perhaps protecting groups, will be required.

Tyrosine is cheap. Play.









[Edited on 7-2-2016 by zed]

yanzi - 7-2-2016 at 20:18

Decarboxylation is an eventual desired reaction (this is why I have cyclohexanol and 2-cyclohexenone). I guess the issue would be acid-base extraction workup. I could extract at 2 different pH's.

Right now I'm torn between decarboxylating first or methylenating first. Methylenating first would help with dissolving a neutral zwitterionic methyldopa in cyclohexanol for the decarboxylating step. But decarboxylating first might avoid side reactions or complications of workup after methylenation.

zed - 9-2-2016 at 17:39

To be remembered. Whatever you start with, decarboxylation might result in racemizing your product. An imine is the intermediate in decarboxylations of this type. And, the more stable imine isn't methylene.

Nicodem - 10-2-2016 at 09:20

Quote:
lolz I majored in and tutor organic chemistry. I know what I'm talking about.

Was that supposed to be a joke?