Limonene + HCl solution = Dihalide ? Dangerous?

[endlessness]

So 13th Merck Index says about limonene:

Monograph Number: 5515
Title: Limonene
CAS Registry Number: 138-86-3
CAS Name: 1-Methyl-4-(1-methylethenyl)cyclohexene
Additional Names: p-mentha-1,8-diene; cinene; cajeputene; kautschin
Molecular Formula: C10H16
Molecular Weight: 136.23.
Percent Composition: C 88.16%, H 11.84%
Literature References: Occurs in various ethereal oils, particularly in oils of lemon, orange,
caraway, dill and bergamot. Isoln of d-limonene from mandarin peel oil (Citrus reticulata Blanco,
Rutaceae): Kugler, Kováts, Helv. Chim. Acta 46, 1480 (1963). Review: J. L. Simonsen, The
Terpenes vol. I (University Press, Cambridge, 2nd ed., 1947) pp 143-165.

Derivative Type: dl-Form
Additional Names: Inactive limonene; dipentene
20.85
Properties: Liquid. Pleasant lemon-like odor. bp763 175.5-176.5°. d4
0.8402. nD 1.4744.
Practically insol in water. Miscible with alcohol. With dry HCl or HBr it forms monohalides, and
with aq HCl or HBr, the dihalide.
Boiling point: bp763 175.5-176.5°
Index of refraction: nD 1.4744
20.85
Density: d4
0.8402

I asked Benz on the chat:

00:20:55 ‹endlessness› dihalide
00:20:56 ‹endlessness› whats this?
00:21:11 ‹endlessness› is the limonene we have also forming dihalides when salting alkaloids with hcl ?
00:21:15 ‹endlessness› what is the significance of this?
00:25:00 ‹benzyme› means that water in the mix will cause reduction of the double bond, allowing two halogen species to attach as opposed to one
00:25:14 ‹benzyme› like two bromine molecules
00:25:37 ‹endlessness› is this potentially toxic? will it be in the final product?
00:25:55 ‹benzyme› good question, idk


Can any of our chem experts give some feedback here? Are people using HCl solutions to salt mescaline from HCl at any risk?

 

[Adivino]

The halogenation of the double bond with HCl(aq) proceeds via a SN1 mechanism, in which the acid first forms a carbocation which is then attacked by the Cl-. SN1 reactions are generally slow and require heat. A mildly acidic media doesn't favour the formation of the carbocation. The stability of the carbocation is also diminished because the solvent is a non-polar one (limonene).

My guess is that, although possible, the acid-base reaction is much faster than this halogen addition.

 

[Mydriasis]

I have found some information I guess...

''Hydrogen Chloride reacting with either d or l limonene in the presence of moisture gives dipentene dihydrochloride'', Then the google books snippet stops before getting to the juicey details.

Organic Synthesis: Open-chain unsaturated compounds, alicyclic compounds, aromatic compounds
Page: 1189

I also found

"On the contrary, the action of mineral acids on limonene in the cold yields, terpin hydrate and terpineol(alcohols) due to hydration"

Pharmacognosy And Pharmacobiotechnology By Ashutosh Kar
Page: 229

{my undereducated opinion}
I'd assume the first reaction is more likely as hydrochloric acid isn't particularly an oxidizing acid, and they vaguely refer to ''mineral acids''(referring to the second reaction). I wouldn't discount this from happening in HCl, but I would assume and probably wrongfully that the first reaction mentioned is the favored when dealing with HCl gas and liquid. Bearing in mind the water content won't be sufficiently high(when gassing), it shouldn't pose as a significant product. Can't say any of this is true, hopefully someone can find a nice article with evidence.
{/opinion}

*edit - nice post(one above this one), yes the acid base reaction would likely occur faster and be favored. The solubility of HCl as in d-limonene is probably very low also...hmm

 

[endlessness]

Thanks for the two posts!

So do other chemists agree that with the quick contact the HCl solution with limonene during salting, the halogenation should be negligible?

Now lets say if it wasnt negligible and it formed in big amounts, how toxic would that be? What is the exact compound being formed (or are the many halogenated compounds that can be formed?), and do we know anything about it's solubility? For example, would an acetone wash of the alkaloid salt remove it?

 

[Adivino]

If you are so preoccupied about the halogen addition products, and you are unable to test the solution for their presence, in my humble opinion you should use a solvent that's less reactive. Chloroform or DCM should be good alternatives.

 

[Poekus]

I stumbled upon this topic and unfortunately, because quite some teks on the board involve D-limonene, the answers in this topic are rather inconclusive and the topic died out pretty quick. I found this article about the reactiveness of D-limonene where the reactions with Hcl are described in bit more detail.

Limonene - A. F. Thomas - Y. Bessiere

Page 294

" The addition of hydrogen chloride to limonene to give its monohydrochloride (31) works well only in the absence of moisture and in a solvent, e.g. carbon disulphide,petroleum ether, or dichloromethane. Hydrogen bromide reacts similarly, and the halides are converted into a-terpineol by the action of magnesium and air, or with 2% potassium hydroxide (a stronger base yields hydrocarbons, mostly dipentene).Zinc oxide (in acetone for a-terpineol, or in acetic acid for the acetate) has also been recommended.Because the chloride that is made in this way is optically active, so is the terpineol.The di-addition products (24; X = C1) and (24; X = Br) have also been known for a long time;'"' they are best made by the action of concentrated halogen acids in methanol or acetic acid on limonene and can be converted into the terpineols by adding a base. The safest route from limonene to y-terpineol (23) is still the original one from Baeyer, consisting in brominating the dihydrobromide (24; X = Br), to obtain 1,4,8-tribromomenthane (32),loi and then reducing this with zinc in acetic acid to the acetate of (23), with overall yields of 50-60% "

This article might suggest that using a diluted aqueous HCl solution to salt has less chance to have undesired reaction as opposed to crash out the salts by gassing the d-limo with anhydrous Hcl which also is mentioned in some topics.

The di-addition products seems to form best in concentrated hydrochloric acid/methanol solutions.

In another article I read it was also stated that to have an aqueous HCl solution to react properly with d-limonene, a solvent like methanol should be mixed in.

So changes are, if a very diluted aqueous Hcl solution and no heating is used during the salting, there would be minimal or no reaction at all during the short time they are in contact in the salting process.

Now lets say if it wasnt negligible and it formed in big amounts, how toxic would that be? What is the exact compound being formed (or are the many halogenated compounds that can be formed?), and do we know anything about it's solubility? For example, would an acetone wash of the alkaloid salt remove it?

I think because the alkyl dihalides that might have formed out of the d-limo are not supposed to be water soluble the changes that they come into the product using aqueous salting are small. The main theoretical problem would be the possible reaction of the dihalides with the freebase alkaloids out of which either the alkaloids are altered and/or by-products are formed.

 

[Nathanial.Dread]

I can't give any specifics on the chemistry side of things, but Poekus' concern about reactions with the DMT is a legitimate one. How likely that is, I'm not sure, but as a rule, your body doesn't like ingesting organohalide compounds. They can interact with your biology in weird ways, either by forming reactive radical species, or interfering with other systems by mimicking (with differences) an endogenous ligand. Some halogenated compounds are highly lipid soluble and can stick around your body long after you'd rather they were gone.

Very useful for drug design, but a little concerning when you could be ingesting some kind of unknown DMT derivative, especially if it can cross the blood-brain barrier.

The list of halogenated compounds that are toxic to human health is long and nasty. There's a reason that all the labs I've worked in have had a separate waste container specifically for halogenated waste.

On the whole, I'd tread with caution. There are plenty of organic acids that might be a safer bet.

Blessings
~ND

 

[Mindlusion]

yeah, the double bond on the limoene is fairly reactive, a good nucleophile. It is definitely going to get halogenated, but in HCl or HBr, its not very favored either in the conditions of an extraction, would likely end up as small concentration in equilibrium.

The kicker is, it will have no effect on your extraction product, the DMT isn't going to be halogenated or reactive with the dihalide. The dihalide is actually less likely to react with DMT than HCl is. The dihalide can undergo elimination in the presence of a base, like NaOH. But it will simply regenerate limonene and form halogen salt, like NaCl, or in solution, harmless Cl ions, poor nucleophiles, are not going to attack the indole.

the 2-position of indole is fairly reactive, but no where near that of a terminal alkene, the resonance would make the carbocation (if it could be generated by attack on H) is extremely stable, It could not be attacked by such a weak nucleophile as Cl-. Aromatics are usually only halogenated by direct attack on the halogen molecule, Cl2 or Br2. Then again, it could always happen through an transition state intermediate, which is generated (like a bromonium ion, doesn't really happen with Cl though.) , but even less likely.

Even if it COULD get substituted, it would happen in your stomach too.


Just because your solvent smells like oranges, doens't make it 'safe' or 'foodgrade'. I would suggest toluene if you don't want any side reactions

Then again, there is always a small, immeasurable quantity of side reactions, toluene can undergo EAS. In that case, benzene is less reactive than toluene, maybe use benzene.

See where I am going with this?

--

Also,
they are best made by the action of concentrated halogen acids in methanol or acetic acid on limonene and can be converted into the terpineols by adding a base.

do any limonene extractors use concentrated acids in methanol or glacial acetic acid? I don't think so, not to mention that all limonene extractors use a base at some point the procedure, converting any immeasurable amount of dihalides back to limonene.


Check out the reactivity of alkenes here: Alkene Reactivity Look at the molecular structure of limonene, it has two interesting alkenes.
Theres a lot more possible reactions than just dihalides. Limonene is possibly quite a versatile reagent, not a solvent. I would recommend picking a more inert solvent, like toluene or benzene

 

[Poekus]

Thank you both for the replies.

I just realized this monohalide / dihalide forming can be ruled out by an extra step based on some cleanup advise I got here on the forum a few years back:

- Salt the d-limonene with acetic acid.
- Add equal amount of 10% HCl to the salting after separation from the d-limo. (HCl is a stronger acid than acetic so the salt is converted)
- Proceed with usual HCl cleanup.

In this way the solvent never comes in contact with the HCl so the undesired possible (di)halide reaction can't occur.

As long as we don't know for sure what the effect of these halides/dihalides is in an extraction procedure involving d-limonene and halogens, this extra step would be a good thing to do.

 

[moyshekapoyre]

Interesting topic, but if limonene is toxic when mixed with HCl even in small amounts, then we are all goners if we eat oranges since as someone mentioned here, we have lots of HCl in our stomach. Every time i peel an orange i get limonene (orange oil) on my hands and the orange that i eat. Also many people take limonene capsules for acid reflux among other indications.

 

[DrSeltsam]

Interesting topic. I would deem this as no problem for me(!) for two reasons:

1.) The reaction is slow. Salting with strongly diluted HCl usually takes 10 minutes per pull without heat. In this time SN1 reactions do not occur. When you gas with HCl this is an issue.

2.) The addition products are not well water soluble and will stay in the organic solvent. When separation is good, they are not ending up in your product. Even if they do, they are likely to be removed with the acetone/IPA washes.

Does this sound plausible do you?

 

[Elrik]

That was my first impulse as well.

But for a more disturbing thought: phenoxides react with alkyl halides, what if you reused the solvent?
A hydroxy-alkaloid, hordenine for instance, would be deprotonated when lye is added. If alkyl halide contaminated solvent were then added it could potentially form a never before seen ether that would accompany the target alkaloid into the product.

I've seen people gas limonene with HCl and add anhydrous acetone-HCl to it, I'm glad people are questioning its safety.

 

[downwardsfromzero]

Phenoxides would mostly effect elimination from the tertiary alkyl halide centres, thus regenerating the alkene.

I've seen people gas limonene with HCl and add anhydrous acetone-HCl to it

The safety or otherwise of these actions depend entirely on what the intended outcome of the process was.

 

[DrSeltsam]

Elrik, I am not sure if this is so much of an issue. It will depend how you do the extraction.

E.g. with Ron69's tek the deprotonated hordenine shouldn't go into the organic phase as it is way too polar or it would react with something from the plant matter bevor you extract it.

However, a while ago I did ron69's tek and salted with diluted HCl (pH ~3-4). endlessness was so kind to run LC-MS on the results (many thanks for this!). Currently I am not able to open the spectra due to problems with OpenChrom but once I manage I can have a look if I find traces of reacted limonen in it.

Then we will not at least if it is a problem if you salt with diluted HCl for 10-20 minutes per pull