Sciencemadness Discussion Board - Homegensitate Synthesis?

Homegensitate Synthesis?

Rich_Insane - 11-5-2009 at 21:13

I am trying to synthesize a Homogensitate product and methylate it (easily, via esterification. I do not care if I have mixed isomers).

The name of the final product would be 2,5-dihydroxy-4-methylbenzoic acid

But all I need to get to is 2,5-dihydroxybenzoic acid

It shouldn't be hard. Benzoic acid is fairly easy to obtain, but how do I add those two hydroxyl groups? Can someone write a synthesis to produce, perhaps 10 g of it. Just the latter. I know how to methylate it with methanol. I might chlorinate instead too. Which would be cheaper?

What equipment would I need, and how soluble would the un-methylated product be? My guess is it would be soluble on the grounds that it is similar to benzoic acid AND its got those two hydroxyl groups that could be attracted to water via hydrogen bonding.

Thoughts on synthesis? BTW, the product I am trying to make from this polymerizes to melanin. According tot he several microbiology papers I've read, it polymerizes extra-cellularly. But will I need to add any exterior energy to activate the polymerization? It should form large MW polymers in some conditions, preferably alkaline, since that is where it will dissolve the best.

Ok, new process. I will oxidize salicyclic acid with potassium persulfate. Are there any other BETTER (more accessible) oxidizng agents? And how exactly would I do this?

[Edited on 12-5-2009 by Rich_Insane]

Arrhenius - 12-5-2009 at 00:02

Is this a paper exercise?

I doubt anyone would try to make 2,5-dihydroxy-4-methylbenzoic acid from benzoic acid. The acid moiety is a meta director, so nitration or halogenation of the benzene ring won't get you to the 2,5 isomer.

I think you're a little confused (or I am). You won't be able to put a methyl group on an aromatic ring using methanol. This 4-methyl would need to be added via a Friedel-Crafts reaction, or using palladium coupling chemistry; not a trivial task, and poorly selective for the 4 position.

benzoic acid isn't THAT water soluble (3.4g/L), and this probably would only be slightly more so.

I don't think you'll successfully get there from salicylic acid. A more reasonable starting material would be 2,5-dihydroxy toluene or 4-bromo-2,5-dihydroxytoluene, which could get you to the product in 1 or 2 steps (feasible). 10g is a lot, which means you need to shorten the synthesis (realistically).

DJF90 - 12-5-2009 at 02:00

Off the top of my head I can come up with:

> From toluene, nitrate and separate out the 2-nitrotoluene.

> Brominate the 2-nitrotoluene, leading to a mixture of 4-bromo-2-nitrotoluene (major) and 6-bromo-2-nitrotoluene (minor). You want the first isomer.

> Reduce the nitro functionality, diazotise and hydrolyse to form the 2-methyl-5-bromophenol

> Nitrate again, and the synergic directing effect of the bromine and phenol functional groups should lead to the 4-nitrophenol (2-methyl-4-nitro-5-bromophenol) as the major product.

> Reduce the nitro functionality, diazotise and hydrolyse to form the 2-methyl-5-bromohydroquinone.

>Form the grignard reagent (ether, magnesium) and then bubble through dry CO2 to form the carboxylic acid. This should be the product you are after so long as you have managed to separate out the correct isomer in the previous steps.

[Edited on 12-5-2009 by DJF90]

Nicodem - 12-5-2009 at 07:20

Quote: Originally posted by Rich_Insane

I am trying to synthesize a Homogensitate product and methylate it (easily, via esterification. I do not care if I have mixed isomers).

The name of the final product would be 2,5-dihydroxy-4-methylbenzoic acid

But all I need to get to is 2,5-dihydroxybenzoic acid

Didn't they thought you how to use references when at school? How are we suppose to know what "Homogensitate product" is supposed to be unless you provide a reference.

If your final product is 2,5-dihydroxy-4-methylbenzoic acid, then how are you going to get it from 2,5-dihydroxybenzoic acid? That thing about esterification with methanol makes no sense in this context.

Quote:

It shouldn't be hard. Benzoic acid is fairly easy to obtain, but how do I add those two hydroxyl groups? Can someone write a synthesis to produce, perhaps 10 g of it. Just the latter. I know how to methylate it with methanol. I might chlorinate instead too. Which would be cheaper?

This looks like some rambling of someone who is too seriously lacking basic chemical knowledge to safely work with dangerous reagents. I really don't know how to properly comment on this or what advice to give you (except to keep learning, of course).

Quote:

What equipment would I need, and how soluble would the un-methylated product be? My guess is it would be soluble on the grounds that it is similar to benzoic acid AND its got those two hydroxyl groups that could be attracted to water via hydrogen bonding.

What equipment you need depends on what are you up to and since nobody knows, nobody can tell you what is the minimum equipment you would need. Same goes with solubility. We can not estimate how soluble something is unless you tell us in which solvent.

Quote:

Thoughts on synthesis? BTW, the product I am trying to make from this polymerizes to melanin. According tot he several microbiology papers I've read, it polymerizes extra-cellularly. But will I need to add any exterior energy to activate the polymerization? It should form large MW polymers in some conditions, preferably alkaline, since that is where it will dissolve the best.

Again some rambling without a single reference. How is anybody to answer?

Quote:

Ok, new process. I will oxidize salicyclic acid with potassium persulfate. Are there any other BETTER (more accessible) oxidizng agents? And how exactly would I do this?

How about checking the literature? The least you can do is read the review of the Elbs reaction in Organic reactions, 35 (1988), particularly since it covers both substrates, salicylic acid and the one you would really need, 5-methylsalicylic acid.

PS: Congratulations! Now this thread is the only hit google offers when searching for "homogensitate". Somehow, I believe you were trying to coin a word derivative from "gentisic acid" or "gentisate" which would be its salt/ester. Homogentisate would be an ester or salt of 2,5-dihydroxyphenylacetic acid which however is not identical to 2,5-dihydroxy-4-methylbenzoic acid. Are you sure you know what is it that you want?

DJF90, you can not form a Grignard reagent from a bromophenol for the obvious reason. You would have to use protection groups for those two phenolic hydroxy groups.

[Edited on 12/5/2009 by Nicodem]

DJF90 - 12-5-2009 at 07:55

Oh dear... Sorry, didnt have much time to write a reply so it really was quick thinking. You're right though, you should probably include an acetylation step with Ac2O just before forming the grignard. Form the phenoxide first by reducing the pH to about 10, and then add the acetic anhydride. Hopefully you won't get substitution of Br by OH? (SnAr reaction)

[Edited on 12-5-2009 by DJF90]

Nicodem - 12-5-2009 at 09:12

No need to excuse, you are not having an exam!

Anyway, acetylation provides no protection for organomagnesium compounds. Aryl acetates are still too electrophilic to be inert toward Grignard reagents. In this particular case O-methylation would be the simplest option, while MOM or THP protecting groups would be ideal due to their simple introduction as well as removal (but they are not stable enough for electrophilic bromination).
A nice tabular review of protecting groups and their stability can be found here: http://www.organic-chemistry.org/protectivegroups/hydroxyl.s...
But if one would chose to use a Grignard reaction then you might as well start from 2,5-dimethoxytoluene, brominate it, prepare its Grignard intermediate and quench it with CO2. Then you can demethylate the so formed 2,5-dimethoxy-4-methylbenzoic acid to 2,5-dihydroxy-4-methylbenzoic acid using BBr3 or HI, depending on which works better. Luckily, there is also a simpler one step route given that 5-methylsalicylic acid is commercially available.

DJF90 - 12-5-2009 at 11:54

Again I should have realised that the use of esters to protect the phenols is no good if grignards are to be involved. And the thing is, I actually have an exam on this in a few weeks

However, your point about the phenolic hydroxy groups needing protection, this is because you will waste the grignard reagent as it forms by deprotonating them? On a side note, I seem to remember grignard reagents reacting with carboxylic acids, but now I cannot find information on this. Am I going crazy or was it only organolithiums that could in the first place?

UnintentionalChaos - 12-5-2009 at 13:16

Quote: Originally posted by DJF90

Again I should have realised that the use of esters to protect the phenols is no good if grignards are to be involved. And the thing is, I actually have an exam on this in a few weeks

A single equivalent of grignard will pop the acidic hydrogen off a carboxylic acid (RCOOH) first and turn your R'MgX into R'H and RCOO- MgX+

I don't see much on an excess of grignard, but assume it would give you a ketone (and a huge mess) after acidification.

DJF90 - 12-5-2009 at 14:01

Well I thought that 2 eq. of grignard would add to a carboxylic acid simply just as an organolitium will, forming a ketone, but apparently not as I cant seem to find any mention of this reaction (using grignards)

Always with carboxylic acid derivatives (but not amides) and no mention of reaction with carboxylic acid. Is it just the organolithiums that participate in this reaction? Perhaps the grignard is not nucleophilic enough to attack the carboxylate (seeing as its a negativily charged molecule). Sorry for dragging the thread OT but this is really getting to me!

Rich_Insane - 12-5-2009 at 14:48

This is an actual synthesis I am about to do.

The structure was obtained from this paper: http://www.actabp.pl/pdf/3_2006/429s.pdf

The biological pathway for Pyomelanin.

Benzoic acid is the material used in several water-based lotions, so I assumed. I typed on this question just before I was to sleep. Then i edited it again. I am just at general chem, so i am not that great at org chem. The actual biological synthesis of this is like this: Tyrosine --> p-hydroxyphenylpyruvate --> (via HPPD and Cu Ascorbate) Homogentisate. Sorry I spelled it wrong. However that step from p-hydroxyphenylpyruvate is large, and I don't get how I'm going to do it. Forget the methylation. I was thinking of something else. But you can methylate the aromatic ring. Methyl benzoate is formed by that process. So my naming was off. I should have added the methyl before.

The name of the Homogentisate (how I named it) is 2,5-Dihydroxybenzoic acid, however.... I see an error. I added a hydroxyl group instead of just 1 oxygen atom on that group. That makes it acetic acid. The structure from the paper is not the same as acetic acid. So you are right Nicodem, it would be 2,5-dihydroxyphenylacetic acid, not the 2,5 - dihydroxybenzoic acid.

The paper never synthesized the product. They took it from bacteria. I will not do that, because this bacteria costs thousands of dollars to culture. I just want the Homegentisate which, according to (my theory) this paper: "Vanadium(V) Reduction by Shewanella oneidensis MR-1 Requires Menaquinone and Cytochromes from the Cytoplasmic and Outer Membranes " requires menaquinone (vitamin K) to form polymers with. My theory is that menaquinone and this homogentisate are monomers in a chain that form a melanin known as pyomelanin.

That's all I have to correct so far. All I need is an explanation and a brief outline of the synthesis (but some amounts might be needed).

[Edited on 12-5-2009 by Rich_Insane]

Nicodem - 13-5-2009 at 01:45

I currently don't have the time to read that review, but just rapidly checking it I found no organic chemistry in it. The schemes there appear to show some biochemical transformations as far as I saw.
Also, I'm still not sure what is it that you want? You are asking about the synthesis of a compound? Then, exactly which one? At times you speak of some homogentisate, but you never explain the homogentisate of what? An ester or a salt, how are we supposed to know? Then you mention 2,5-dihydroxyphenylacetic acid, but this would at most be homogentisic acid and not a homogentisate of anything. Can't you say exactly what is your desired target by using proper IUPAC nomenclature? (or post its structure)
Also, your main question is obviously on how to synthesise this certain target compound that you have yet to specify. But why don't you check the literature? What exactly is wrong with the published procedures? Unless you explain why you find the published procedures not suitable, then it is pointless for anybody to give you guesswork examples and speculations.

Rich_Insane - 13-5-2009 at 17:31

Alright, new possibility:

What about doing: AlCl3 + dimethoxybenzene (Friedel Crafts reaction) , then do the ammonium polysulfide Willgerodt rearrangement on the 2, then hydrolyze that product with HCl. Is that good?

What ratio is this going to be done in?

Structure is

[Edited on 14-5-2009 by Rich_Insane]

Nicodem - 15-5-2009 at 12:25

You are approaching a problem from the completely wrong side. When one plans a synthesis of a specific compound, the first thing to do is to do a literature search for the already published routes. Doing like you do, that is to first do the guess work rather than research work, is contraproductive. If you are not pleased with the published procedures then you can plan a synthesis of your own, but this must be supported by references or else is just some idle speculation that has no use a lab situation.
Since I'm not sure if you understand what I'm talking about let me be more specific. For example, just think about your proposal? You gave not a single reference for any of the proposed steps, yet you finish your post with specific question like "What ratio is this going to be done in?" This is a question which can in no way be answered without first comprehending the theoretical background of these chemical transformations, and this can only be done once the pertaining references are checked.
So try the other way around first...

Rich_Insane - 15-5-2009 at 19:07

Yes I have read some papers. From those papers I know that I must use the Friedel-Crafts acylation no matter what.

However, this is all i can find on the actual synthesis. The rest are are papers on how 2,5 - dihydroxyphenylacetic acid is a precursor to pigments.

The papers I have read are:

http://tinyurl.com/homogentisicacid

and

http://www.evilshare.com/8c6eea4a-90...e-0030489aabc6

These are not the only ones, but the most informative ones so far. But I have found easier routes, that would work, and are simple. I probably won't do this at home, since I'm just beginning synthesis stuff at home (setting up my lab). I have an O-Chem professor who will review my procedure, and if all goes well, let me synthesize the acid in his really nice lab.

Nicodem - 16-5-2009 at 10:04

Quote: Originally posted by Rich_Insane

Yes I have read some papers. From those papers I know that I must use the Friedel-Crafts acylation no matter what.

I don't see why one would have to use any Friedel-Crafts acylation for this target. There are several syntheses of 2,5-dihydroxyphenylacetic acid in the literature and I saw none using any Friedel-Crafts reactions. For example, there is a one step preparation starting from the commercially available 2-hydroxyphenylacetic acid that uses the Elbs oxidation (check the above mentioned review on the Elbs reaction for the reference). Then there is a four step synthesis starting from p-methoxyphenol [1]. The simplest I saw consisted in the Micheal addition of diethyl malonate on p-benzoquinone [2]. There must be other ones described in the literature, but I'm not going to loose time on something that you should have done already in the first post - that is doing a literature search.

[1] Synthesis of homogentisic acid by carbonylation.
Prasad, Chalasani S. N.; Adapa, Srinivas R.
Indian Journal of Chemistry, Section B, 31B (1992) 626-627.

[2] An efficient synthesis of homogentisic acid.
Bloomer, James L.; Damodaran, Kalyani M.
Synthesis (1980) 111.

Quote:

The papers I have read are:

http://tinyurl.com/homogentisicacid

and

http://www.evilshare.com/8c6eea4a-90...e-0030489aabc6

The first link only leads me to "The Journal of Physiology" google book page. This ebook is however inaccessible for on screen reading. How about quoting what it says about the synthesis of this compound.
The second link does not work. Please give proper references so that those who have access to the literature can read them, not just some links.

Quote:

These are not the only ones, but the most informative ones so far. But I have found easier routes, that would work, and are simple.

Well, where are the references?

PS: Are you aware that 2,5-dihydroxyphenylacetic acid is comercially available (by A***s)?

[Edited on 16/5/2009 by Nicodem]

Rich_Insane - 17-5-2009 at 08:19

The Journal of Physiology was the one I used the most.

I can't copy the whole thing onto here, but basically what it says is:

1. Prepare a dimethyl-hydroquinone ether
2. Friedel Craft's reaction (prepares dimethylhomogentisic acid)
3. Demethylation, extract the final product with ether

The 2nd one is:

"Chemical Preparation of Homgentisic Acid"
Lynn DeForrest, et al.
The Journal of Biological Chemistry page 365

I said that I found more, but I found these to be far simpler than the others.

A search on Google Scholar yielded "Synthesis of homogentisic acid by carbonylation", but I would have to buy the article. Same with the one from Synthesis. It asks me for a subscription.

The easier routes refer to what I am suggesting.

Simga Aldrich sells 2,5-dihydroxyphenylacetic acid, but it is hellishly expensive for a small quantity. $480 for 1 gram. Synthesizing maybe three grams of it would be so much easier.

Nicodem - 17-5-2009 at 11:24

Quote: Originally posted by Rich_Insane

A search on Google Scholar yielded "Synthesis of homogentisic acid by carbonylation", but I would have to buy the article. Same with the one from Synthesis. It asks me for a subscription.

With a reply like that I can only assume you never heard of the existence of scientific libraries. These are places where you can read or photocopy the scientific papers you need. Probably every scientific library has Synthesis and a lot of them can at least provide you the paper from the Indian journal via library interexchange service (this journal is otherwise more common in libraries than you might think). So gather some courage and step into the nearest scientific library. It might be a small step for the humanity, but trust me when I say that it will be a huge step for you.

Rich_Insane - 18-5-2009 at 16:40

I have searched for quite a few. The professor with obtains his papers from the city library, but a search yielded nothing in the library. So either the papers are locked in some subterranean vault with no access, or somethings wrong. I can't find anything like a scientific library nearby.

Arrhenius - 18-5-2009 at 17:14

You need to go to a public university. Go to the science library there, and tell the librarian what you're looking for. They won't care whether or not you're a student, and I'm sure they'd be glad to help you navigate the published literature. You'll also find plenty of useful print sources there. Feiser & Feiser used to be a widely used, and catalogues a variety of organic reagents and reactions. The Encyclopedia of Reagents for Organic synthesis (EROS) will probably also be there. They also probably have a print copy of Organic Syntheses (Orgysn.org), but this is also free online, and I highly recommend you read it as it's quite reliable.

Ask a librarian

Nicodem - 19-5-2009 at 00:29

A proffesor who can not get you a scientific paper from such an ubiquitous journal like Synthesis or point you toward the nearest science library? Just crazy!

Here you have it. This must be the simplest synthesis of this compound ever published. You will also need the reference No. 5 cited in this paper to obtain the non-lactonic form of homogentisic acid. But that one you will have to find yourself or else you will never learn how to use the scientific literature.

An efficient synthesis of homogentisic acid.
Bloomer, James L.; Damodaran, Kalyani M.
Synthesis (1980) 111.

Attachment: An efficient synthesis of homogentisic acid.pdf (92kB)
This file has been downloaded 688 times

Rich_Insane - 19-5-2009 at 14:29

No, that's not what I meant. Since I'm not a student at the University, I do not have a student account. What he does is order the papers from the library, which takes about a week. There are no scientific libraries nearby. I believe that the school itself has an archive of journals, but only students and staff have access to it.

I'll see what I can do, but the university I would be looking it is just really strange with access matters. I'll try to see what I can do.

The source No. 5 is online already; I'll be reading it. To me the synthesis itself is far easier, but the reaction is a little more complex (there are more steps). However, it seems pretty good. That is the one I read before (it was the Rapidshare link). It is a bit more complex, but I think it's possible. But since I only want to get rid of the lactone, it shouldn't be hard.

[Edited on 19-5-2009 by Rich_Insane]

[Edited on 19-5-2009 by Rich_Insane]

Rich_Insane - 3-6-2009 at 15:09

Sorry for the revive (It's been long enough that I am not able to edit my previous post anymore). I have done proper reading and laid out a reaction derived from the paper (J Biological Chemistry, 365, 1949). I have yet to do that for the other one you supplied.

Basically here's what I have

[img]http://s621.photobucket.com/albums/tt298/aperson444/?action=view&current=homogentisatesynthesis.gif[/img]

So I know that the first step is the Friedel Crafts reaction, but I do not know what the step converting the ketone to the carboxylic acid is. In the paper, it states that it requires elemental sulfur, which tempted me to believe it was the Willergodt reaction, but that would form a lot of amide and very little acid. The reagents used are a bit different too. What would this step be called?
(refer to the paper:

"Chemical Preparation of Homgentisic Acid"
Lynn DeForrest, et al.
The Journal of Biological Chemistry page 3650)

And thanks for all your help, I've learned a lot!

[Edited on 3-6-2009 by Rich_Insane]

Paddywhacker - 3-6-2009 at 17:13

Remind me again how you are getting from Ar.CO.CH3 to Ar.CH2.COOH?, please.

Rich_Insane - 3-6-2009 at 19:58

It's in the paper. What they do is they take the ketone formed by the FC Acylation (2,5 - dimethoxyacetophenone), then they add elemental sulfur and morpholine, and reflux it with EtOH and NaOH.

I'm not sure what you would call this reaction; That is what I need help on.

not_important - 3-6-2009 at 20:41

It is known as the Willgerodt-Kindler reaction, a modification of the Willgerodt rearrangement. Willgerodt-Kindler forms a thioamide, which must be hydrolysed to the free acid.

[Edited on 4-6-2009 by not_important]

Rich_Insane - 3-6-2009 at 21:31

Thank you!

So this would be the mechanism:

FC Acylation forms 2,5 Dimethoxyacetophenone --> Willgerodt-Kindler reaction and hydrolysis forms 2,5 dimethoxyphenylacetic acid's lactone which is opened up by the Na2SO4 and NaOH method to form the acid?

The other method looks much simpler (Supplied by Nicodem, many thanks to him!), however I just wanted to know that reaction and have an arsenal of methods to talk with the (gulp) O Chem guys to see if I can do this.