Sciencemadness Discussion Board - Synthesis of Triclosan [Expert Help Needed!]

Synthesis of Triclosan [Expert Help Needed!]

PorcelainPrincess - 14-4-2015 at 21:22

So for my lab project I'm trying to synthesize triclosan (a common anti-microbial compound in soaps and deodorants). I have drawn out the steps and made the precursor reagents: 2,4-dichloro-1-nitrobenzene and 1,4-dichloro-2-nitrobenzene but now I'm stuck because I'm not sure how to go about combining the two (steo #3 in the picture).

Maybe forming 2,4-dichloroaniline would be a helpful intermediate? How? Then what?

Any advice or links to related material would be great! I only have one 5 hour lab left to do as much as I can.

Chemosynthesis - 14-4-2015 at 21:49

This probably belongs more in Beginnings as you should have references for this section.

Are you are required to use those reagents (how did you reach the conclusion to use them without a plausible retrosynthesis? I don't mean this as an insult, but unless this was the assigned project, that is pretty half-assed)?

I have a simple solution, but I am kind of debating on whether to just hand it out for an assignment. You really should be graded on your effort, not ours, so if you could provide a bit more of your reasoning for getting the two combined, I would consider telling you a straightforward way to do it. Then again, if you aren't sure how to reduce a nitro group, I am not sure you will be able to succeed, as I am not sure if you are required to have relatively pure product....

PorcelainPrincess - 14-4-2015 at 23:17

I used Scifinder to aid in finding the procedure (reference: Hua, Yuxia, Xiaoyun Jiao, Lixin Yu, Sicheng Zhu, and Zhichen Zou. "Study on the Bactericides of Polychlorophenoxylphenols." SciFinder. American Chemical Society, 2003. Web. 22 Feb. 2015.)

I'm not required to use those reagents but I selected them because they were not especially expensive and require a couple steps to reach the product I desire which were requirements of the project. We will mainly be graded on our NMR analysis which I have no problem doing however I spent a lot of time looking through literature to piece together the procedures which is what we were told to do.

I know that to reduce the nitro group I'd probably can use a metal catalyst like iron (powder? or filings?) and a source of hydrogen (H2 gas). My issue is how do I know how much to use, what solvent to do the reaction in, under what conditions? Also hoping it won't affect the Cl atoms and produce HCl in the process.

Chemosynthesis - 14-4-2015 at 23:42

Probably best to put a DOI with that reference for ease of perusal.

The way you write your post " I only have one 5 hour lab left to do as much as I can" sounds like you slacked off severely and are pretty screwed. Is your lab tomorrow? It doesn't sound like you yet empirically appreciate the stability of aromaticity. If you have SciFinder, you shouldn't need any more assistance (already more than I or probably most of the people on this forum received in school), as nitro reduction is very standard and is the industry method of making chloroanilines. From there, three more second semester introductory undergraduate organic chemistry reactions may yield your product for resolution. Honestly, if you're graded on NMR, I think you're pretty screwed at this point. If yield weren't a concern, maybe you could save chromatographic resolution for the end... but I am dubious.

Chemosynthesis - 25-4-2015 at 20:12

Seeing as how it has been ten days with nary a word, I think it is safe to post what I was thinking without risking the OP's academic integrity. I doubt they will return anyway.
I would have looked at reducing 2,4-dichloro-1-nitrobenzene to 2,4-dichloroaniline, which is a relatively common procedure that can be found in pharmaceuticals and old dye manufacturing intermediates. It's the standard industry method for production of chloroanilines. I would probably not use hydrogen for this, as a hint.
Examples:
Synthetic Communications, 37, 2007, 2777-2786 (modification of the classic Bechamp reduction)
Green Chem., 2013,15, 1006-1015

I would then consider diazotizing this, converting the diazonium salt into the 2,4-dichlorophenol, and using the phenoxide salt in a Williamson ether synthesis of the substituted diphenylether product.
Examples:
1). J. Chem. Soc., 1959, 3116., and 2). J. Org. Chem., 1977, 42 (12), pp 2053–2058

The last portion may be the most troublesome from a workup perspective, as the proximate nitro group's sterics may reduce the yield of the desired product, and you will likely need to chromatographically resolve your product, which I think would take more than a 5 hour lab session on top of synthesis.

Here is a reference for the last procedure:
DERIVATIVES OF PHENYLETHER, II.
Alfred N. Cook
J. Am. Chem. Soc., 1901, 23 (11), pp 806–813
DOI: 10.1021/ja02037a005

Congratulations. If everything went well, you have product 3, intermediate in the synthesis of trichlosan. I doubt you got this in one five hour lab, but if you did, continue.

Finally, repeat the above reactions in two additional steps analogous to the previous diazotization and phenol synthesis to trichlosan. With just reduction, diazotization, phenolation and etheration, you can reach the target product in a total synthesis. At least that's the hypothesis.

CuReUS - 26-4-2015 at 05:43

here is another method
you could couple 4-chloro-2-nitrophenol with meta dichlorobenzene(1,3 dichlorobenzene) using the Ullmann condensation
http://en.wikipedia.org/wiki/Ullmann_condensation
ortho nitro phenol could be made using claycop http://www.arkat-usa.org/get-file/19343/ and then chlorinated using TCCA
and you are anyways buying meta dichloro benzene.Then the nitro can be converted to OH using nef reaction

but I have an even crazier idea.

suppose you coupled ortho nitro phenol with chlorobenzene using ullmann,and then chlorinated the whole diphenylether together

for the benzene ring with the nitro group,the chlorine would go meta to the nitro(para to the OH),and for the chlorobenzene part,it will go meta to the chloro(or ortho to the ether)
BUUUUUUT,no chlorine will go in the space between the two rings due to steric hindrance .so basically you are blocking two places on both the rings using each other

and chlorinating the diphenyl ether wont be a big problem as the reaction will go crazy(we all know how uncontrolled chlorination of phenol is,just read the TCPO synthesis threads)
then to put the cherry on the cake,do nef reaction to convert the nitro to OH

Chemosynthesis - 26-4-2015 at 06:53

Quote: Originally posted by CuReUS

here is another method
you could couple 4-chloro-2-nitrophenol with meta dichlorobenzene(1,3 dichlorobenzene) using the Ullmann condensation
http://en.wikipedia.org/wiki/Ullmann_condensation
ortho nitro phenol could be made using claycop http://www.arkat-usa.org/get-file/19343/ and then chlorinated using TCCA
and you are anyways buying meta dichloro benzene.Then the nitro can be converted to OH using nef reaction

but I have an even crazier idea.

suppose you coupled ortho nitro phenol with chlorobenzene using ullmann,and then chlorinated the whole diphenylether together

Crazy is about right. I could maybe see swapping the Williamson with Ullman conditions. You tend to save time and selectivity seems good (if it were a problem, which I probably exaggerated), but you have to worry about solvent selection, which can be restrictive in an undergraduate environment. Once you start hinging your aromatic conversions on a nitroalkane reaction (the Nef), you are completely off the rails. There's the additional detriment that even if this were possible, your proposals don't utilize the required reagents.

CuReUS - 27-4-2015 at 01:15

Quote:

Once you start hinging your aromatic conversions on a nitroalkane reaction (the Nef), you are completely off the rails.

sorry to say ,dear chemo ,but you are slipping

https://www.thevespiary.org/rhodium/Rhodium/pdf/nef.reaction...
go to pg 12 of the PDF,or pg 1028 of the actual article

i feel sad for her ,you could have helped her chemo,instead you shattered her (pun intended)

edit:

Quote:

Seeing as how it has been ten days with nary a word, I think it is safe to post what I was thinking without risking the OP's academic integrity. I doubt they will return anyway.

Porcelien last visited SM yesterday

[Edited on 27-4-2015 by CuReUS]

Chemosynthesis - 27-4-2015 at 06:51

Quote: Originally posted by CuReUS

sorry to say ,dear chemo ,but you are slipping

https://www.thevespiary.org/rhodium/Rhodium/pdf/nef.reaction...
go to pg 12 of the PDF,or pg 1028 of the actual article

You're proposing the OP work with Meisenheimer complexes? Really, CuReUS? These citations are using highly unusual nitroalkane reactions, still, given the intermediate. Look into the primary literature. It will only help you in synthesis.

The special cases in DOI: 10.1021/jo980173v, DOI: 10.1021/jo9915628, and DOI:10.1016/S0040-4020(03)01021-4 were devised from cryogenic inert atmospheric carbanion reactions, and are only thought to proceed by going through a cyclohexadienone intermediate, which is going to be awfully tricky with the options the OP has to use (i.e. currently impossible). Note what is para to the nitro group in your proposals and then in the literature, too. Blocked. How then do you propose to convert the nitroarene to a suitably reactive adduct? You'll also note solvents and oxidizers (sometimes specific) that are even less likely to be amenable to an undergraduate lab.

Quote:

i feel sad for her ,you could have helped her chemo,instead you shattered her (pun intended)

She should have helped herself. She had SciFinder access and yet couldn't find a good literary example of how to proceed?

Quote:

Porcelien last visited SM yesterday

After I posted, yes. I doubt it made much difference as most school semesters seem about wrapped up in terms of labs, and she has yet to post anything. Probably another member who wanted help with their assignments (cheat in this case) and not to learn or contribute (or cite their work properly), but hopefully I can be wrong here too.

CuReUS - 27-4-2015 at 09:36

Quote:

[qoute]which is going to be awfully tricky with the options the OP has to use (i.e. currently impossible)

she clearly said that she wasn't compelled to use only those reagents.she chose them because thought she could come up with a suitable reaction

Quote:

I'm not required to use those reagents but I selected them because they were not especially expensive and require a couple steps to reach the product I desire which were requirements of the project

and I don't understand what's so special about that reaction i posted.the first part of the cited reaction is not needed in this synthesis(the coupling of phenacetonitrile para to nitro,only the conversion of nitro to OH is needed).and in the reaction scheme I proposed,the carbon para to the nitro has an H that it can lose to re-aromatise the ring once the cyclohexadienone forms .and DMDO is very easy to make from acetone and peroxide,so I don't see a difficulty at all.I just want to avoid a messy and long Fe/HCl reduction.

I had another idea.Instead of coupling ortho nitro phenols with aryl halides like in the ullmann reaction,can salicylaldehydes be coupled with aryl halides.In other words,is a CHO group electronegative enough to substitute for nitro ?

then salicylaldehyde could be first made,then chlorinated to get 5-chlorosalicylaldehyde ,then that could be coupled with meta dichlorobenzene and finally dakin reaction could be done to convert the CHO to OH.

Chemosynthesis - 27-4-2015 at 11:19

Quote: Originally posted by CuReUS

she clearly said that she wasn't compelled to use only those reagents.she chose them because thought she could come up with a suitable reaction

That was explanation to why she chose them... but earlier she said she already prepared them, and presumably is stuck using them.

Quote:

Please see the original literature to understand what is special. You can't just ignore parts of the scheme (you haven't posted one) because it is not the nitroarene that is undergoing substitution (at the nitro)... it's the adduct. This is explicitly stated in the title of J. Org. Chem. 1998, 63, p4390-4391. You need two substitutions and receive a substituted phenol product. You can't just ignore part of a reaction scheme because it is inconvenient. The Meisenheimer complex formation was not done for the authors' fun.
Ex. Tetrahedron 59 (2003) pp6261–6266
"To avoid formation of products mixtures we
studied the reaction of 5b with p-chloronitrobenzene 4e.
The sH adduct produced when 5b and 4e were treated with
TASF was efficiently oxidized with DMD giving ethyl
(5-chloro-2-hydroxyphenyl)acetate"
That is the closest applicable substrate I could find. Notice a problem? There are other chlorinated Meisenheimer complexes used in J. Org. Chem. 2000, 65, 1099-1101, but not para substituted ones. In fact, the last citation I just gave says "Thus, the
DMD oxidation of the óH adducts of nitroarenes 2 to the
corresponding phenols is a unique process of preparative
value in aromatic substitution chemistry."
Emphasis mine.
See why I said this was special now?
Additonally, one could be more pedantic and argue it's not really a Nef reaction per se as "Although the normal Nef reaction is
a hydrolysis, the present case (Table 1) is an oxidation
process because DMD is essential" per J. Org. Chem. 1998, 63, p4390-4391, or at least be excused in questioning it without specification.
All of these citations correspond to the ones in the review you skimmed on Erowid, and the DOI's which I posted above.

For DMD... it's easy to suggest if you've never had to make it, which is low yielding and still requires cooling. These are unnecessary complications, and a professor may very well not wish to throw away reagents on that.

As for Bechamp, one could likely try formic acid, tin, or a number of additional modifications rather than Fe/HCl if that is deemed too burdensome.

CuReUS - 28-4-2015 at 03:22

in that case,the reduction of the nitro has to be done,it can't be avoided.maybe instead of metal/acid reduction,sodium sulphite could be used ?
infact there is a silver lining to the whole thing because later I remembered that ether +peroxide =boom

but can salicylaldehyde be coupled to chlorobenzene like nitrophenol ?

[Edited on 28-4-2015 by CuReUS]