[orgopete]

Don't use chloroform or dichloromethane. i used a procedure to isolate an amino acid from its hydrochloride salt by treating with triethylamine and extracting the triethylamine hydrochloride out with dichloromethane. While the reaction would work, it will retain too much of the salt. Use an ether.

Isn't benzene a regulated carcinogen?

[nox]

I tosylate my indoles in DCM with 3 equiv of KOH at room temperature. Reaction works beautifully and is done in 30 minutes. Only issue is TsCl co-elutes with my product so if I have to be very precise with how much TsCl I use. Eventually I found that 1.03 equiv is enough, and with this I am able to regularly obtain ~95% yields.

[OC pro]

Here in Germany benzene is regulated but we can buy it. It is not that bad as many people may think.
Co-elution of TsCl and tosylated compound happens somehow often. I also made the experience several times.

[orgopete]

Okay, I was only referring to using DCM with triethylamine. I agree with NOX about KOH, no problem.

Re: benzene is regulated, but not that bad.
This statement suggests the regulators erred. I don't know how toxic it is or isn't. It is found fairly commonly. None the less, why wouldn't you use toluene instead? I would, if I needed to use benzene in this example.

[opsomath]

This statement suggests the regulators erred.

Yes, it does, and she is probably right. Benzene is one of the most useful solvents. It is brilliantly effective for crystallization of nonpolar materials and is considerably easier to remove than toluene. It is also stable towards free radical oxidation, a handy property in many reactions which also means that you don't have to worry as much about the purity of an old bottle.

Its regulatory and hazard treatment is disproportionately severe compared to many other common compounds such as aniline or phenol. It should be used in the hood and disposed of in a sealed waste container, but that's most solvents.

[OC pro]

Totally agree with opsomath.
Just for your info guys: according to the newest investigations chloroform is a mutagenic and cancerogenic substance. Moreover, 1,4-dioxane is now also classified as toxic. That´s why we have to store it now in special cabinets.

[fledarmus]

The real difference between benzene and toluene in biological terms is that the body can metabolize toluene and get rid of it, while benzene tends to accumulate. The methyl group on toluene gives the body a handle for oxidation and elimination. Consequently, there is no level of benzene exposure which is considered "safe" - any exposure will accumulate until enough is present to cause damage.

I think the bad reputation of benzene was caused by the very clear association between exposure and various leukemias. Benzene was widely regarded as a harmless solvent before this link was established, and was widely used as a solvent and even for hand-washing to remove oils in many industries. Consequently, a lot of people were affected. Benzene is now very difficult for me to get and use even in a research lab in drug discovery, and if we can replace it with anything else to run our reactions, we will.

[OC pro]

@fledarmus:

In fact, benzene gets almost completely metabolized. The highly reactive benzene epoxide (cytochrome P 450 oxidases) yields hydroxybenzenes (phenol, hydroquinone...) which decompose into reactive oxygen species (radicals?). These specimen cause oxidative DNA damage. radicals?). These specimen cause oxidative DNA damage. radicals?). These specimen cause oxidative DNA damage.
Moreover, its flat architecture enables it to intercalate into DNA.

And of course, one should avoid to work with this stuff.

[fledarmus]

Thanks for the corrections OC pro - rereading my post, it does appear that I overstated the case.

The distinction I intended to make was that most of the toluene that enters the body is readily oxidized by the CYP450 enzymes in the liver to form innocuous glucoronides that are rapidly excreted. The body can efficiently clear toluene from its system. This metabolic pathway is not available to benzene. Instead, any benzene that is metabolized goes through a much slower pathway involving direct oxidation of the benzene ring, leading, as OC pro pointed out, to highly reactive oxygenated species that are not excreted and are particularly adept at causing DNA damage. The body will slowly clear the benzene out, but it is removed unchanged, and the longer it is present, the more likely it is to undergo this alternative metabolic pathway and cause damage.

Toluene, due to the stabilizing effect of the methyl group, would be expected to undergo this second metabolic pathway even better than benzene, except that it is so rapidly cleared by the first metabolic pathway.

[Honclbrif]

I always thought that was a pretty rude thing that the liver did with benzene, making it even worse and all.

[helenn]

Going back to the original topic, I have done this reaction a number of times recently on scales of up to 15 g and consistently acheived >95% yield. I add TsCl to the alcohol in pyridine in ice, then stir overnight at room temperature. Add ether and filter off the pyridine Cl salt, wash the ether filtrate with HCl, water NaHCO3 and water, dry and evaporate the organic layer to give clean product.
ref: tetrahedron asymmetry, 1995, 1181