Sciencemadness Discussion Board

Replacement for Chloroform?

DraconicAcid - 17-5-2022 at 17:00

So I've been making a couple of acac-type complexes (sucha s this one here: https://www.proquest.com/docview/1477466231 ) lately, and a number of them are supposedly best recrystallized from chloroform. I'm trying to avoid halogenated solvents- any suggestions on replacements?

The stuff is not soluble in methanol, isopropanol, or acetone, and is only slightly soluble in boiling isoamyl acetate.

clearly_not_atara - 17-5-2022 at 17:10

https://www.zora.uzh.ch/id/eprint/179065/
"Chlorobenzene caused a statistically significantly increased incidence of neoplastic nodules in the liver of male F344 rats in a carcinogenicity study at the highest dose of 120 mg/kg body weight and day. As chlorobenzene is genotoxic only at high doses given intraperitoneally, and female rats and mice did not show any tumours in this study, it remains regarded neither as a carcinogen nor as a germ cell mutagen."

I don't know if it's as safe as DMF, but chlorobenzene looks an awful lot less toxic than chloroform as far as I can tell. No idea if it will substitute.

DraconicAcid - 17-5-2022 at 20:33

Chlorobenzene might work, but alas, I don't have it.

I found this: https://www.iiste.org/Journals/index.php/CMR/article/downloa...
Apparently, it's soluble in chloroform and nitrobenzene, slightly soluble in acetone and DMSO. I don't have nitrobenzene, and I don't think I'll try making it.

SplendidAcylation - 20-5-2022 at 03:17

Any particular reason for avoiding chloroform?
My daily glass of chloroform doesn't seem to have done me much harm.

But seriously, nitrobenzene is very toxic, and I can't imagine chlorobenzene being any better than chloroform, safety-wise.

If your concern regarding chloroform is phosgene, perhaps you can wash it with alkali, I believe that removes the phosgene.

clearly_not_atara - 20-5-2022 at 07:03

Quote:
I can't imagine chlorobenzene being any better than chloroform, safety-wise.

Your imagination is not an acceptable substitute for experiment. Chlorobenzene is absolutely much safer than chloroform, and this has been scientifically demonstrated.

SWIM - 20-5-2022 at 09:06

I suspect the benzene ring is a safer place in general to hang halogens than an alkyl chain.

Halides are electron hungry, and on a benzene ring they can ameliorate some of that by withdrawing from the ring (Like in ring activation theory)

On an alkane they can't withdraw much charge so they probably have a different character.

Consider the fact that you can buy paradichlorobenzene to leave in an open package in your bedroom closet and that meets with government approval, but selling DCM for such an application would probably be a big no-no.

However I still keep my big jug of chlorobenzene outside because safety with chemicals can sometimes be a matter of not having found what's wrong with it yet.

And yes, I realize there are other reasons for higher and lower toxicity in halogenated hydrocarbons, but I'm just suggesting something that might draw a general distinction between the aromatic and alkane types in cases where these other factors are not operative.

Bmoore55 - 20-5-2022 at 10:12

Do you think the solubility characteristic you are looking for is coming from the aromatic structure of your solvent or is more an issue of polarity? Just trying to reason my way to a possible alternative for you here.

DraconicAcid - 20-5-2022 at 15:19

Ccyclohexanone works somewhat, but I don't have a lot of that. Oh, well, I won't have to worry about it for a while.

Bmoore55, probably polarity. Chloroform obviously isn't aromatic.

SplendidAcylation - 21-5-2022 at 02:14

Quote: Originally posted by clearly_not_atara  
Quote:
I can't imagine chlorobenzene being any better than chloroform, safety-wise.

Your imagination is not an acceptable substitute for experiment. Chlorobenzene is absolutely much safer than chloroform, and this has been scientifically demonstrated.


Of course! I would never suggest my imagination is better than experimental evidence :P
Your original post only referred to the toxicity of chlorobenzene, with the comment "chlorobenzene looks an awful lot less toxic than chloroform as far as I can tell" which lead me to believe that you were guessing rather than basing your conclusion wholly on experimental evidence.

According to this report, "There is inadequate evidence in humans for the carcinogenicity of chloroform."

Also, according to Wikipedia: "The hepatotoxicity and nephrotoxicity of chloroform is thought to be due largely to phosgene."


I don't know how to compare the toxicity of two compounds, except by comparing LD50s which isn't really indicative of long-term toxicity, so maybe I don't know what I'm talking about, nonetheless this topic is interesting to me, as I've always had the impression that chloroform is more-or-less harmless, and to be treated with no more or less care than, for instance, methanol, or diethyl ether, any evidence to the contrary is interesting to me.


@SWIM those are interesting explanations!
Indeed, haloarenes tend to be less reactive than the corresponding haloalkanes; Perhaps my approach to "imagining" the toxicity was rather less logical, I was simply comparing the toxicity of the two non-halogenated equivalents; Methane and benzene.
I should know better, though, that just one substituent can dramatically change the toxicity of a compound (compare chloroform with carbon tetrachloride for instance)

To play devil's advocate, there are some chloroalkyl compounds that are considered safe enough for general use, such as chlorobutanol, sucralose, etc.

OP, how about using a fluoroalkane?
These are more polar so maybe your compound would be soluble therein, and fluoroalkanes certainly aren't worryingly toxic.

unionised - 21-5-2022 at 08:01

Quote: Originally posted by SWIM  
I

Consider the fact that you can buy paradichlorobenzene to leave in an open package in your bedroom closet and that meets with government approval,


I considered it.

"The United States Department of Health and Human Services (DHHS) and the International Agency for Research on Cancer (IARC) have determined that p-DCB may reasonably be anticipated to be a carcinogen. This has been indicated by animal studies, although a full-scale human study has not been done."

From wiki.
Now, it may be that somehow the second chlorine on the ring makes it a carcinogen.
But the zero chlorine, benzene, version is a carcinogen, and the dichloro version is a suspected carcinogen.
I'd certainly not bet on chlorobenzene not being carcinogenic.

Amos - 22-5-2022 at 06:02

This is a science forum. Other users don't want to look through your petty squabbles trying to find a small percentage of useful content.

I don't see why draconic acid can't just try a few different solvents and see which ones work. You can fully recover the compound in question by evaporating your solvent. Ethyl acetate, butyl acetate, THF, and acetonitrile strike me as potential candidates, since they're all either around as polar as chloroform(except acetonitrile which is far more polar but in my experience good at dissolving metal complexes).

DraconicAcid - 22-5-2022 at 13:48

Amos, I have been doing that, with the meagre selection of solvents I have available. Cyclohexanone seems to be the best I've tried, followed by isoamyl acetate.

I posted this because I thought it might lead to a good discussion. I apologize for the results.

Texium - 23-5-2022 at 08:02

[moderation]Flaming posts were split off and Detritused. Please do not resume, or temporary bans will be considered.[/moderation]

THF would likely be a great option. Acetonitrile, I'd be concerned about using for recrystallizing a metal complex because nitriles are strong ligands and could disrupt your complex. You may end up with some unwanted acetonitrile ligands attached to your metal.

[Edited on 5-23-2022 by Texium]

DocX - 23-5-2022 at 10:11

How about DCM? It's my understanding that as a solvent, those two are almost interchangeable. Or is that wrong?

clearly_not_atara - 23-5-2022 at 10:26

SplendidAcylation: Risks associated with chloroform include the potential to produce phosgene on storage, exothermic reactions with certain metals, and phosgene production on contact with certain oxidants. In the past, other people got mad at me for underrating this. Must be a generational thing ;)

Anyway, chlorobenzene doesn't do that stuff. It might react with sodium, but the heat released per gram would be much smaller. It's a little more flammable than chloroform, but the flash point is higher than room temperature and the volatility is low, and the products are way less toxic.

Granted, you can mitigate the risks associated with chloroform by being extra careful. But people just don't want to deal with that. It's a symptom of too much theory that someone thinks "avoidable risk" = "no risk".
Quote:
Now, it may be that somehow the second chlorine on the ring makes it a carcinogen.
But the zero chlorine, benzene, version is a carcinogen, and the dichloro version is a suspected carcinogen.
I'd certainly not bet on chlorobenzene not being carcinogenic.

I posted a link to a study where they injected rats with chorobenzene, and they (mostly, except at the highest dose tested) didn't get cancer. That's a little better than "betting", isn't it?

Paradichlorobenzene is not genotoxic but inhibits apoptosis:
https://www.researchgate.net/profile/Ding-Xue-2/publication/...

Benzene is genotoxic by metabolism to oxepin. In other words, completely different mechanisms.

SplendidAcylation - 25-5-2022 at 02:33

@DocX I doubt OP would be interested in DCM since it too is a halogenated solvent, although it is a good bit safer than chloroform (I believe, due to its inability to form phosgene).

DCM and chloroform are similar solvents, but they definitely aren't the same; Chloroform is a very good solvent for hexamine, I once tried substituting it with DCM for the Delepine reaction, but I found that it took a ridiculous amount of DCM, maybe 5x as much, to dissolve the same quantity of hexamine, so indeed, sometimes the two solvents can be quite different.

@clearly_not_atara Haha, that's funny :P
I have been meaning to try making an isonitrile via the carbylamine reaction using chloroform, perhaps that's another potential hazard, as isonitriles are supposed to smell horrific.
Well, I will certainly be more cautious with chloroform in the future, one can never be too careful with potential carcinogens!

Texium - 25-5-2022 at 06:46

Quote: Originally posted by SplendidAcylation  
@DocX I doubt OP would be interested in DCM since it too is a halogenated solvent, although it is a good bit safer than chloroform (I believe, due to its inability to form phosgene).
I’d argue that DCM is far worse. While it is marginally less toxic than chloroform, it is also much more volatile, making it easier to inhale when working with it. It is also toxic through skin contact and rapidly penetrates nitrile gloves.

Antiswat - 27-5-2022 at 07:21

ethyl formate- well rather comparable to ether in solubility- its 8g/100mL water
boiling point 54*C, easily made from H2SO4 and sodium formate- or formic acid. it also smells nice

as for DCM ive seen it claimed as one of the least toxic chlorinated solvents

methyl formate as 30*C BP, maybe extracting this from water with hexane can work, then hoping whatever youre trying to pull isnt soluble in hexane you could easily remove the methyl formate distilling it at 30*C
methyl formate supposedly smells very much like rum, i cant smell it. ethyl formate does to me however. the problem is methyl formate is quite soluble in water

Amos - 4-6-2022 at 12:10

I'm going to go ahead and type up an overreaction here that I can access later. I'm tired of this subject constantly making its way into fact-based conversations.

To anyone who wishes to avoid using chloroform because they have heard the word phosgene thrown around: You're overreacting. No lab-sized bottle of chloroform will ever accumulate enough phosgene in it to suddenly burst out of solution and pose a threat to you in a well-ventilated room.

A) The oxidation of chloroform to phosgene in storage bottles under the influence of light and oxygen is written about primarily because phosgene is a reactive molecule and thus a worrisome impurity in research, where it can react with minute quantities of compounds under study like DNA and other biological products. This phenomenon is not written about because of accidental poisonings in the lab when using it as a reagent or solvent, of which I am aware of zero.

B) It is very easy to store chloroform in an amber glass bottle out of direct sunlight with a small amount of ethanol added to it.

C) Phosgene readily reacts with and is effectively neutralized by water, which, aside from being in most homemade chloroform anyway, can also be introduced during expansion and contraction of the air in the headspace of a bottle, the same way oxygen is.

D) Chloroform itself being a liver toxin and potential carcinogen should overwhelmingly trump any worries of phosgene being the main player. No matter what imaginary scenario you're picturing, there is far more chloroform present in a given situation than a contaminating amount of phosgene. Since you should already be using your head to avoid heavy exposures to chloroform like using clean and ventilated spaces, you're also limiting exposure to phosgene.

E) There is never any scientific evidence cited along with the fearmongering that small, non-lethal exposures to phosgene will accumulate in the body or cause other permanent and lasting harm.

[Edited on 6-4-2022 by Amos]