Sciencemadness Discussion Board

benzoic acid to benzoyl chloride ; non benzotrichloride route to hippuric acid

pomegranate - 14-9-2019 at 06:05

ok, so i’m still digging around on the forums, just reading loosely related data;

also, it seems VWR doesn’t sell to individuals now; but, i haven’t went deeper into it.

BUT there doesn’t seem to be a direct mention of reaction conditions/procedure/guidelines, or success in

for acylation with glycine to hippuric acid. ( a little mention on that synth, is also appreciated )

i see routes that go from benzotrichloride; but am wondering about going from benzoic acid. benzaldehyde is watched and experimenting would add up over time; and nothing simple on benzoic acid seems to afford it ( i think i read that around, but my mind isn’t on that now; just this process from Cl2 generated and reacted with benzoic acid

(maybe “dumb” question, but can TCCA be added into a reaction mixture itself and generate Cl2 directly mixed with benzoic acid (i don’t know what the intermediates / cyanuric acid would do; but i assume there would be reactions at the amines)


i don’t know if • bleach/NaOCl can be used
• if bleach with an HCl drip
• or just bubbling dry Cl2 into benzoic acid (what solvent, and temperature )
maybe iodine is easier for the bezoyl iodide and can be recovered from H2SO4 on alkali salt; and sublimation; if that salt is crystallized out of the hippuric acid reaction mix (HCl step has me wondering if metathesis, HI would mess with the hippuric acid.

please just let me have some good info. and, at least realistic-theoretical procedural steps


[Edited on 14-9-2019 by pomegranate]

also; i don’t have good material sources, so i’m just trying to find good solutions. also excessive ring iodination ; is something that just came to mind as something i don’t know about ; help is appreciated

i don’t know if a peptide coupling using a lithium reagent could link the glycine straight to the benzoic acid; because of there being a COOH group on glycine, so maybe if it was first protected with 1,3-dioxolane first; it could happen; and then be de-protected; but that seems alot, and beyond where i already have many questions .

alright, thanks again

[Edited on 14-9-2019 by pomegranate]

mayko - 14-9-2019 at 08:58

what is your goal here? to prepare hippuric acid? in what quantity?

UC235 - 14-9-2019 at 12:55

Ingestion of benzoate salts results in excretion of hippuric acid in the urine. It is possible to prepare small amounts in this manner.

Check out Fieser in our own library,

Section of interest begins on page 113.

Also, you are going about preparing acyl halides in entirely the wrong manner. Conventional chlorinating agents can't convert benzoic acid to benzoyl chloride. They are for oxidative chlorination of materials, generally substituting a hydrogen.

What you need is a material that will preferentially remove OH and replace it with Cl. These are generally very moisture sensitive (as is the resulting acyl halide). It is not an oxidizing reaction.

Traditional reagents for this are PCl5 and SOCl2. An acid anhydride can also react with dry HCl to produce an equimolar mix of acyl chloride and free acid.

There are a number of incomplete experiments on this board for performing this reaction, one of the most promising being reaction with perchloropropylene in the presence of a lewis acid. Perchloropropylene is an allylic trichloride with similar chemical characteristics to benzotrichloride and should be able to react with a donor acid forming trichloroacryloyl chloride, HCl, and acyl chloride.

pomegranate - 14-9-2019 at 14:54

i guess i’m looking to be able to do 10s of grams, 50 grams, 100 grams; idk, i bet i’ll mess up with expectations in experiments and hope to have a good supply or be able to whip some up, every now and then. and it’s good practice, i presume; so probably starting in the 10s of grams, with a 100g as a hopeful ability in reserve. idk

but getting it from pee , seems laborious; but still interesting; and nasty; but ok, right ?:) !

but i guess perchloropropylene is not easy to come by. i wonder if 2,3,3,3-Tetrafluoropropene, HFO-1234yf could be chlorinated, (or brominated easier) to a similar compound, with 2 halogens on the 1-alkene ; but i would want to be absolutely sure the flourines weren’ leaving the hydrocarbon. i don’t think i understand it, that the two hydrogens wouldn’t be merely substituted by bromines, for example.

but; besides eventually crafting a ketene/Ac2O reactor; i was wondering about production of COCl2 from CHCl3 ; and using it direct, in slow addition of something to chloroform or visa versa (likely CHCl3 would volatilize through the gas line into the reaction , somewhat, right ? ); or running through a tube that pulls SO2 in as well , to make SOCl2. or pulling Cl2 through a heated coke over cooler activated carbon and through a venturi of SO2 i guess; all aspirated or something through a sufficient condenser setup and or cold trap; i assume the industrial details are available somewhere; but that seems a further off achievement than the ketene/Ac2O setup. it seemed that COCl2 and SO2 was the cleanest way to reach SOCl2; and COCl2 with GAA was the cleanest way to reach AcCl besides Ac2O and HCl. (and the CO2 from both could seemingly be brought back over the coke bed to max CO production if C reactive sites are in exess , i guess.)

right now; i just wonder about the ease of reacting chloroform slowly and bringing the phosgene over into a reaction with benzoic acid; or with SOCl2 i guess, from a sulfur burner through a teflon stopcock in claisen connection which has the phosgene coming in from a 120 degree male male connector to one par , through maybe a warm water condensor (maybe staged into a cool-ish water one; dripping into the benzoic acid flask; with i guess a reflux and vacuum take off to a scrubber/bubbler or some setup into Na2CO3; to an aspirator or small low powered vacuum pump (maybe with a cold trap gefore hand, if needed; or just a tube of sodium hydroxide, and then another bubbling in base before the pump. i wouldn’t want to run anything like that unless i got info on the heat of COCl2 and SO2 reaction; so the claisen/stopcock meeting and/or the condensor wasn’t burst. i would guess that; the SO2 could be metered by the teflon hole in the stopcock; and the phosgene; from the addition funnel. and the excessive SO2 from the exposed burner, pulled out through a fume hood or vented away somehow.

what do you think? is this to naive ? is there a safe solvent to react the benzoic acid in ; and importantly; what forms COCl2 on demand safely from CHCl3 ? would it be, dripping CHCl3 into a flask with a catalyst like aluminum and AlCl3 , with a dry oxygen source pulled in ? O3 makes a different reaction right (and might travel up the pressure equalizer arm in the addition funnel to ill dangerous effect ? unless the addition funnel was non equalizing, and had a drierite tube on the top; but then; the O3 would probably not be all reacted and end up in the flask, causing problem or maybe making SO3, so that seems dangerous to start.) ?

i’m tired and going to bed, but i drew a sloppy picture,

[Edited on 15-9-2019 by pomegranate]

Pumukli - 15-9-2019 at 00:02

"what do you think? is this to naive ?"

Yes, it is.

You can't get benzoyl chloride but are mindstorming about phosgene and/or thionylchloride synthesis... And for what? To make hippuric acid???

COCl2 already killed at least one amateur chemist in the last few years. He also thought he could handle it safely, obviously couldn't. Do you think you are different and you can do it? He surely thought so too.

You seem to be attracted to the most hair-rising routes, don't you? :)

What about easier acylating agents? E.g. benzoic acid anhydride? Or even methyl-benzoate? (An ester can be ammonolyzed. Maybe refluxing Me-benzoate with glycine for a few hours would yield hippuric acid.) Or simply melting together benzoic acid and glycine would yield something. I don't know if these routes are useful or not, surely not the cleanest ways but are less likely to end in a coffin.

Pardon me, but based on your questions it seems that you have to learn a lot before you try putting together a phosgene generator or anything like that.

pomegranate - 15-9-2019 at 05:18

that is terrible; but, does anyone know what he did wrong, so no one thinks that’s the way to go ? did he make a large addition or something, or not use a mask, and breath in chronic/acute amounts over the period of the reaction ?

i hope to learn small scale industrial semi labtop chemistry ; but accessing reagents for smooth synthesis in the beginnings would be great :/

the methyl benzoate one may be interesting to try; i read that methanol and benzoic acid condense to form it “Methyl benzoate is formed by the condensation of methanol and benzoic acid, in presence of a strong acid.[1] [2]

Methyl benzoate reacts at both the ring and the ester, depending on the substrate. Electrophiles attack the ring, illustrated by acid-catalysed nitration with nitric acid to give methyl 3-nitrobenzoate. Nucleophiles attack the carbonyl center, illustrated by hydrolysis with addition of aqueous NaOH to give methanol and sodium benzoate.”

[1] Maki, Takao; Takeda, Kazuo. "Benzoic Acid and Derivatives". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH.

[2] John McMurry (2008). Organic Chemistry, 7th Edition. Thompson - Brooks/Cole. ISBN 1-4390-4972-6 Page 623

so i guess that is the fischer esterification

i was looking for info on amidification; and, found this:

“One-pot synthesis of amides by aerobic oxidative coupling of alcohols or aldehydes with amines using supported gold and base as catalysts”
DOI: 10.1039/c2cc16768a
supplementary files :

and there is this paper:

“A Heterogeneous Niobium(V) Oxide Catalyst for the Direct Amidation of Esters”

DOI: 10.1002/cctc.201500601

supporting info :

( and; this article seems to be related ; i stumbled on it from an auto google search for the other one’s doi address with the http spaced (before the address, from a pdf text copy format error); after it didn’t link to the url:

“Nb2O5·nH2O as a Heterogeneous Catalyst with Water-Tolerant Lewis Acid Sites”

supporting information :
it seems it is somewhat water tolerant) (<—edit: haha, i was frankenstiening this together from far spaced internet browser tabs; so my memory forgot the exact saying and i gave my general idea of why i was looking at it :/ which was the verbatim phrase i forgot i remembered; after looking at the description of the cool diagram and grabbing other links and reordering the paragraphs. heheha)


i was guessing that if the nucleophile was a strong organic lithium ; it would couple; and when i looked, i found this paper/article:

Indian Journal of Chemistry
Vol. 42B, October 2003, pp. 2641-2642

“A facile conversion of aromatic esters to amides by using lithium amide under mild reaction condition”
Dibakar C Deka*, Biswajit Purkayastha & Maumita Paul

“One pot conversion of aromatic esters to amides has been achieved by use of lithium amides derived ill silu by reacting /1- butyl lithium with a primary or secondary amine at 0° C in diethyl ether as the solvent.”

so; i guess it would need amino acid protection of the carboxylic acid end of glycine, before that reaction. idk ; and it would have to be cleaved by something that wasn’t a base ; or reducer, hopefully , and hopefully not too strong an acid that it messes up the hippuric acid. ha ha

[Edited on 15-9-2019 by pomegranate]

[Edited on 15-9-2019 by pomegranate]

[Edited on 15-9-2019 by pomegranate]