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Reaction Mechanism Of Diclofenac

chemistry diclofenac reaction mechanism

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#1 HeavensDrill

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Posted 27 May 2018 - 04:01 PM

Hi there,

 

I found a route of synthesis for diclofenac and I am trying to make a reaction mechanism of this route. I have almost finished it but have a little trouble with the first and second step of sythesis route. 

 

You can see in the attach file that the first reaction combines the 2-chlorobenzoic acid with the 2,6-dichloroaniline using copper, as a catalyst, in a basic environment forming 2-((2,6-dichlorophenyl)amino)benzoic acid. This reaction seem pretty familiar to me but I have forgotten the name for this type of reaction. If you would know the name I will have a starting point to finish the mechanism for this step.

 

Also in the attach file you can see that the second reaction removes the carboxylic acid from the molecuul by only using heat. The cooled melt is dissolved using benzene and the benzene solution is extracted using sodium carbonate and Water. The Solution is dried with sodium sulfate. I have not made much progress with this step and I would like to know what the reaction mechanism looks like.

 

you can find the link to the article where i found the route of synthesis for diclofenac here: https://patentimages.../US3558690.pdf 

 

 

Attached Thumbnails

  • reaction mechanism step 1-3.jpg


#2 exchemist

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Posted 28 May 2018 - 03:47 AM

Hi there,

 

I found a route of synthesis for diclofenac and I am trying to make a reaction mechanism of this route. I have almost finished it but have a little trouble with the first and second step of sythesis route. 

 

You can see in the attach file that the first reaction combines the 2-chlorobenzoic acid with the 2,6-dichloroaniline using copper, as a catalyst, in a basic environment forming 2-((2,6-dichlorophenyl)amino)benzoic acid. This reaction seem pretty familiar to me but I have forgotten the name for this type of reaction. If you would know the name I will have a starting point to finish the mechanism for this step.

 

Also in the attach file you can see that the second reaction removes the carboxylic acid from the molecuul by only using heat. The cooled melt is dissolved using benzene and the benzene solution is extracted using sodium carbonate and Water. The Solution is dried with sodium sulfate. I have not made much progress with this step and I would like to know what the reaction mechanism looks like.

 

you can find the link to the article where i found the route of synthesis for diclofenac here: https://patentimages.../US3558690.pdf 

I can't find a mechanism for straight thermal decarboxylation of aromatic acids, I'm afraid. I'd be interested to know what it is myself, being very rusty on this kind of thing.  



#3 exchemist

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Posted 28 May 2018 - 07:54 AM

Hi there,

 

I found a route of synthesis for diclofenac and I am trying to make a reaction mechanism of this route. I have almost finished it but have a little trouble with the first and second step of sythesis route. 

 

You can see in the attach file that the first reaction combines the 2-chlorobenzoic acid with the 2,6-dichloroaniline using copper, as a catalyst, in a basic environment forming 2-((2,6-dichlorophenyl)amino)benzoic acid. This reaction seem pretty familiar to me but I have forgotten the name for this type of reaction. If you would know the name I will have a starting point to finish the mechanism for this step.

 

Also in the attach file you can see that the second reaction removes the carboxylic acid from the molecuul by only using heat. The cooled melt is dissolved using benzene and the benzene solution is extracted using sodium carbonate and Water. The Solution is dried with sodium sulfate. I have not made much progress with this step and I would like to know what the reaction mechanism looks like.

 

you can find the link to the article where i found the route of synthesis for diclofenac here: https://patentimages.../US3558690.pdf 

I've done a bit more digging and this suggests a mechanism: http://pubs.rsc.org/...31#!divAbstract

 

The zwitterionic option could apply, I should have thought, with the proton migrating to the amine group.



#4 HeavensDrill

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Posted 31 May 2018 - 09:50 AM

srry for the late reply.

 

And thank you for this useful information. However I am still stuck on how the proton migration to the amine group can occur. I think that it will begin with the proton on the amine group. if you look at the file that is attached you can see the hydrogen bond between the carbonyl and the hydrogen of the amine group. if the double bond attacks that hydorgen i think we will end up with something like in the picture of "step 2 reaction mechanism klad". But im still looking for the right mechanism and im not sure if this is the right approach.  

Attached Thumbnails

  • step 2 begin product reaction mechansim.png
  • step 2 reaction mechansim klad.png

Edited by HeavensDrill, 31 May 2018 - 09:50 AM.


#5 exchemist

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Posted 31 May 2018 - 12:00 PM

srry for the late reply.

 

And thank you for this useful information. However I am still stuck on how the proton migration to the amine group can occur. I think that it will begin with the proton on the amine group. if you look at the file that is attached you can see the hydrogen bond between the carbonyl and the hydrogen of the amine group. if the double bond attacks that hydorgen i think we will end up with something like in the picture of "step 2 reaction mechanism klad". But im still looking for the right mechanism and im not sure if this is the right approach.  

Hmm. I will need to think about this, as I agree it is not obvious. 



#6 HeavensDrill

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Posted 01 June 2018 - 03:45 AM

also I still do know the name to the first reaction that combines the 2-chlorobenzoic acid with the 2,6-dichloroaniline using copper, as a catalyst, in a basic environment to form 2-((2,6-dichlorophenyl)amino)benzoic acid. The reaction type seems familiar to me but i can't recall the name for this type of reaction.



#7 exchemist

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Posted 02 June 2018 - 06:14 AM

also I still do know the name to the first reaction that combines the 2-chlorobenzoic acid with the 2,6-dichloroaniline using copper, as a catalyst, in a basic environment to form 2-((2,6-dichlorophenyl)amino)benzoic acid. The reaction type seems familiar to me but i can't recall the name for this type of reaction.

Having dug out my old ROC Norman organic synthesis book :), this first reaction seems to be an aromatic nucleophilic substitution.

 

These proceed via formation of a carbanion, which benefits from being delocalised in the aromatic pi system. This is helped by electron-withdrawing groups, which are ortho/para directing, carboxylate being just such a group. However one needs an anionic leaving group to complete the reaction. The presence of Cl in the ortho position is just such a leaving group.  So it looks fairly classic, from that point of view.

 

However I don't know why KOH and Cu catalyse it. I have a sneaky feeling that as amines are good ligands for Cu, there may be some fancy mechanism involving some sort of Cu-NHR complex, but I am just speculating ex ano.

 

I'll have to come back to the second step, as it's now time to prepare lunch.....


Edited by exchemist, 02 June 2018 - 06:14 AM.


#8 exchemist

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Posted 02 June 2018 - 01:02 PM

srry for the late reply.

 

And thank you for this useful information. However I am still stuck on how the proton migration to the amine group can occur. I think that it will begin with the proton on the amine group. if you look at the file that is attached you can see the hydrogen bond between the carbonyl and the hydrogen of the amine group. if the double bond attacks that hydorgen i think we will end up with something like in the picture of "step 2 reaction mechanism klad". But im still looking for the right mechanism and im not sure if this is the right approach.  

OK, again consulting Norman, I think this step is an electrophilic substitution.

 

The amine group can lend a lone pair to take part in the pi system of the ring with COOH attached to it, leading to a partial-ve charge at ortho and para positions relative to the amine group. H+ can therefore add to the position ortho to the amine group, and the -COOH is at one of those ortho positions.  

 

So H+ adds to the carbon to which COOH is attached, and then if this deprotonates to form the carboxylate anion, this becomes a leaving group. (The O-  can push the electrons in the C-C sigma bond back onto the aromatic ring, breaking the bond, restoring a neutral aromatic structure and releasing neutral CO2.)  

 

So we have, rather elegantly, first a nucleophilic substitution, due to the electron-withdrawing property of the -COOH group, followed by an electrophilic substitution driven by the electron-donating property of the -NHR amine group. 

 

Does that make sense? Sorry I can't draw diagrams.


Edited by exchemist, 02 June 2018 - 01:05 PM.


#9 HeavensDrill

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Posted 05 June 2018 - 06:03 AM

The information you gave me really makes sense. Not only have you helped me solving the biggest part these reaction steps but i have learned more than i would have on my own. 

 

The first reaction between 2-chlorobenzoic acid and 2,6-dichloroaniline using copper powder, as a catalyst, in a basic environment to form 2-((2,6-dichlorophenyl)amino)benzoic acid is known as a ullmann condensation. But i find the procedure a bid odd. i know a base and a copper catalyst is needed in this type of reaction.  But in the first step the o-chlorobenzoic acid is exposed to the basic environment and will therefore deprotonate creating a carboxylate which is a inductive electron donating group at the ortho and para position. But this is not favourable for the reaction. The base is needed to deprotonate the primary amine and this will allow the copper to bind it but I’m still looking for the mechanism that will explain the catalytic cycle of copper as multiple mechanisms are proposed. 

 

the second step makes perfect sense now. But first i thought that the amine could not lend his lone pair because he is sp3 hybridized. But i think this is where the high temperature comes in play to allow for a pyramidal inversion and for the lone pair to take part in the pi-system. 



#10 exchemist

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Posted 05 June 2018 - 09:22 AM

The information you gave me really makes sense. Not only have you helped me solving the biggest part these reaction steps but i have learned more than i would have on my own. 

 

The first reaction between 2-chlorobenzoic acid and 2,6-dichloroaniline using copper powder, as a catalyst, in a basic environment to form 2-((2,6-dichlorophenyl)amino)benzoic acid is known as a ullmann condensation. But i find the procedure a bid odd. i know a base and a copper catalyst is needed in this type of reaction.  But in the first step the o-chlorobenzoic acid is exposed to the basic environment and will therefore deprotonate creating a carboxylate which is a inductive electron donating group at the ortho and para position. But this is not favourable for the reaction. The base is needed to deprotonate the primary amine and this will allow the copper to bind it but I’m still looking for the mechanism that will explain the catalytic cycle of copper as multiple mechanisms are proposed. 

 

the second step makes perfect sense now. But first i thought that the amine could not lend his lone pair because he is sp3 hybridized. But i think this is where the high temperature comes in play to allow for a pyramidal inversion and for the lone pair to take part in the pi-system. 

Good, I'm glad to have been of some help. I have not done this sort of thing for about 40years, since I was an undergraduate!

 

I'll leave you to research the Cu catalysis mechanism, but I'll be interested if you find it. Would you mind posting it here if you do? 

 

According to Norman, the Ullmann reaction goes via a radical mechanism, but it is done with sand and Cu powder  at 200C!  I'm not sure we are talking about the same thing.



#11 exchemist

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Posted 07 June 2018 - 08:12 AM

The information you gave me really makes sense. Not only have you helped me solving the biggest part these reaction steps but i have learned more than i would have on my own. 

 

The first reaction between 2-chlorobenzoic acid and 2,6-dichloroaniline using copper powder, as a catalyst, in a basic environment to form 2-((2,6-dichlorophenyl)amino)benzoic acid is known as a ullmann condensation. But i find the procedure a bid odd. i know a base and a copper catalyst is needed in this type of reaction.  But in the first step the o-chlorobenzoic acid is exposed to the basic environment and will therefore deprotonate creating a carboxylate which is a inductive electron donating group at the ortho and para position. But this is not favourable for the reaction. The base is needed to deprotonate the primary amine and this will allow the copper to bind it but I’m still looking for the mechanism that will explain the catalytic cycle of copper as multiple mechanisms are proposed. 

 

the second step makes perfect sense now. But first i thought that the amine could not lend his lone pair because he is sp3 hybridized. But i think this is where the high temperature comes in play to allow for a pyramidal inversion and for the lone pair to take part in the pi-system. 

I was just thinking about your perceptive comment on the hybridisation of the amine group. It turns out that aniline, for example, is almost planar, precisely because the molecular orbital formed by bringing the lone pair into the  π system is of lower energy than the sp3 arrangement in which it does not participate. I did not know this before. It is mentioned here:  https://en.wikipedia.org/wiki/Aniline. So you don't need to heat it: sp2 is already energetically more favourable than sp3, apparently. 

 

The same effect is responsible for the much lower basicity of aromatic amines than their aliphatic counterparts - the lone pair is less available to form a sigma bond to H+.  So there we are! :)


Edited by exchemist, 07 June 2018 - 08:22 AM.


#12 HeavensDrill

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Posted 19 June 2018 - 10:44 AM

I was just thinking about your perceptive comment on the hybridisation of the amine group. It turns out that aniline, for example, is almost planar, precisely because the molecular orbital formed by bringing the lone pair into the  π system is of lower energy than the sp3 arrangement in which it does not participate. I did not know this before. It is mentioned here:  https://en.wikipedia.org/wiki/Aniline. So you don't need to heat it: sp2 is already energetically more favourable than sp3, apparently. 

 

The same effect is responsible for the much lower basicity of aromatic amines than their aliphatic counterparts - the lone pair is less available to form a sigma bond to H+.  So there we are! :)

it appears so. But heat is still used is this reaction, and if it is not to help the lone pair of the amine to take part in the pi-system than it must be to help the carboxylate be a better leaving group.

 

But now about The first reaction between 2-chlorobenzoic acid and 2,6-dichloroaniline using copper powder, as a catalyst, in a basic environment to form 2-((2,6-dichlorophenyl)amino)benzoic acid. what i have found is that this reaction is called a ullmann condensation reaction or goldberg reaction. I don’t know why Norman states the reaction goes via a radical mechanism or that sand is used. The ullmann condensation does indeed use copper power and quite the amount of heat. the reaction is for making C-N, C-C and C-O bonds and gives relative low yields. There are mutable mechanism proposed for this reaction with can be categorized in four groups. Oxidative addition of ArX on copper(I) resulting in an intermediate Cu(III) species. (2) Aryl radical intermediates, either via single electron transfer (SET) or via halide atom transfer (AT). (3) s-bond metathesis through a four-centre intermediate. (4) p-complexation of copper(I) on ArX. The article that states this is from 2010 (https://www.rug.nl/r...ansSperotto.pdf) , but more recent reports still state that the mechanism is under debate.

 

This is what i have for now.



#13 exchemist

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Posted 19 June 2018 - 02:03 PM

it appears so. But heat is still used is this reaction, and if it is not to help the lone pair of the amine to take part in the pi-system than it must be to help the carboxylate be a better leaving group.

 

But now about The first reaction between 2-chlorobenzoic acid and 2,6-dichloroaniline using copper powder, as a catalyst, in a basic environment to form 2-((2,6-dichlorophenyl)amino)benzoic acid. what i have found is that this reaction is called a ullmann condensation reaction or goldberg reaction. I don’t know why Norman states the reaction goes via a radical mechanism or that sand is used. The ullmann condensation does indeed use copper power and quite the amount of heat. the reaction is for making C-N, C-C and C-O bonds and gives relative low yields. There are mutable mechanism proposed for this reaction with can be categorized in four groups. Oxidative addition of ArX on copper(I) resulting in an intermediate Cu(III) species. (2) Aryl radical intermediates, either via single electron transfer (SET) or via halide atom transfer (AT). (3) s-bond metathesis through a four-centre intermediate. (4) p-complexation of copper(I) on ArX. The article that states this is from 2010 (https://www.rug.nl/r...ansSperotto.pdf) , but more recent reports still state that the mechanism is under debate.

 

This is what i have for now.

Well the effect of temperature is presumably just to speed it up, according to the good old Arrhenius equation: k =A exp(-Ea/RT) , isn't it?

 

But the paper you have found is very interesting. It will take me some time to digest it. Give me a few days.

 

By the way this is one of the best quality chemistry discussions I have had for months. Tell me, are you in industry or studying, and if you are studying, at what level?  (I am a retired oil industry manager, so for me all this is knowledge I have to dig up fro the depths of my memory at university. But it is fun. :)


Edited by exchemist, 19 June 2018 - 02:03 PM.


#14 exchemist

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Posted 20 June 2018 - 04:48 AM

it appears so. But heat is still used is this reaction, and if it is not to help the lone pair of the amine to take part in the pi-system than it must be to help the carboxylate be a better leaving group.

 

But now about The first reaction between 2-chlorobenzoic acid and 2,6-dichloroaniline using copper powder, as a catalyst, in a basic environment to form 2-((2,6-dichlorophenyl)amino)benzoic acid. what i have found is that this reaction is called a ullmann condensation reaction or goldberg reaction. I don’t know why Norman states the reaction goes via a radical mechanism or that sand is used. The ullmann condensation does indeed use copper power and quite the amount of heat. the reaction is for making C-N, C-C and C-O bonds and gives relative low yields. There are mutable mechanism proposed for this reaction with can be categorized in four groups. Oxidative addition of ArX on copper(I) resulting in an intermediate Cu(III) species. (2) Aryl radical intermediates, either via single electron transfer (SET) or via halide atom transfer (AT). (3) s-bond metathesis through a four-centre intermediate. (4) p-complexation of copper(I) on ArX. The article that states this is from 2010 (https://www.rug.nl/r...ansSperotto.pdf) , but more recent reports still state that the mechanism is under debate.

 

This is what i have for now.

OK I have read through it now - or most of it. It's a very well-written review of all the theories. One has to say that we obviously still don't really know how the Ullmann condensation proceeds! And in fact it may go via different mechanisms in different cases.

 

One thing, at least, I have learned from this discussion is the difference between the Ullmann reaction and the Ullmann condensation.  The reaction I found in Norman's synthesis book was the Ullmann reaction, not the condensation. I did say at the time I wondered if this was the same thing, and evidently it is not. The sand was used to moderate the reaction, apparently, so it did not run away, I suppose. The Ullman Condensation is not a reaction he mentions at all, for some reason - at least I can't find it in the index. 

 

It is plain from this paper that a lot of work has gone on over the last few decades, not least in using ligands to enable the Ullmann Condensation to take place under milder conditions. About the only consensus seems to be that it is the Cu+1 oxidation state that is thought to be the active participant. 


Edited by exchemist, 20 June 2018 - 04:57 AM.




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