3-acetyl-indole ?

[Midi]

indole + SnCl4 and acetonitrile => 3-acetyl-indole:

Post 451545

(Chimimanie: "Thanks", Tryptamine Chemistry)

To a stirring solution of indole (1.17 g, 10 mmol) in CH2Cl2 (20 mL) under argon at 0 °C was added SnCl4 (1.44 mL, 12 mmol) was added in a single portion via syringe. After the ice bath was removed, the mixture was stirred at room temperature for 30 min, and then acetonitrile (100 mmol, 5.3 mL) was added in small portions to the suspension, followed by nitromethane (15 mL). The mixture was stirred for 4 h at room temperature. After being quenched with ice and water (30 mL), the mixture was filtered to remove inorganic precipitates, and the organic material was extracted with ethyl acetate (50 mL). The organic phase was dried over Na2SO4 and concentrated at reduced pressure to give the product as a crystalline solid.

Yield: 96%, mp: 185-191°C.

This rxn was carried out exactly as described, minus inert atmosphere, and minus the final extraction of the rxn contents being dried over Na2SO4.

During the course of the rxn the contents changed a few colors.. mainly bluish grey, to greyish blue, then grey, finally a brownish shit color.

At the end of the rxn, the contents were filtered and no  visible debris was noted. This was the extracted with ethyl acetate and evaped under reduced pressure.

The flask never crystalized as expected. As the 250ml flask spun away in a 70c water bath, some darkish redish crystals were formed on areas not exposed to liqud. As the last amount of ethyl acetate left the flask time seemed to draw on and on and on. Finally it was decided that the last 1ml or so of liquid was h20 that may have carried over from the rxn's extraction. So.. fuckit, you decide to call it a night and let that last little bit evap at room temp and come back to crystals of 3-acetyl indole.

You remove the flask and see crysals forming within the liquid as the flask is cooling in your hand. You pour the contents into a 250ml beaker while it is pourable. You figure it's just h2o so let it sit in the beaker in the open air, untop of a furnace.. lightly being heated from the bottom. You come back 36h later and you have 1ml to 2ml or so of a redish/golden colored, indoly smelling liquid/oil.

SO hive dear friends, what do you think? What is the true color of acetyl indole produced this way?

The vacuum source that was used was weak, could 70c external bath temps have caused the ketone to crumble and not crystalize?

The use an inert gas was not deemed necessary due to an industrial size dehumidifier (removes moisture from air) located next to the workspace. I don't know if this could have been a factor here, or if not drying the ethyl acetate extraction is to blame. I just figured fuck the drying as the h2o couldn't possibly be that much of a pain in the ass to remove at room temp for a day. Am I wrong??

Either way, x10 scale must be attempted as we all know how addictive the smell of indole is     Maybe at this scale things will go smoother??

Thanks!

[Lilienthal]

Because SnCl4 hydrolyzes with water to SnO2 and HCl everything, i.e. all reagents, all solvents, and all glassware, has to be dried before performing the reaction. Even a new bottle of solvent might contain enough water to kill your SnCl4. The protecting gas keeps humidity out. The dehumidifier on your bench doesn't make sense. Never ever skip the drying of extraction solvents! They can dissolve a lot of water (usually around 10%!). The easiest way to dry your product mixture is to redissolve it, to dry it, and to evaporate again.

This is probably not bathtub-chemistry    and shouldn't be attempted without TLC control.

[Midi]

Thanks Lilli, I now realize the importance of using an inert atmosphere and have gotten myself some argon. This time around the reagents are being dried.

Is there a sign that the SnCl4 has turned into SnO2??? I recall seeing salts form through out this rxn.
At T-2h, after all reagents had been added, the stir bar stopped and after sitting like this for a little while, a salt-like layer was noted at the bottom of the flask. The color of the rxn at this point was a dull grey with the slightest hint of blue.

Could that be the SnO2?

[yellium]

>Is there a sign that the SnCl4 has turned into SnO2??

If you see your SnCl4 turn into white powdery or clunkly stuff, more or less right after you add it to your solution, you know that you're effectively drying your solution with SnCl4. Not a very cheap way to dry solvents.

[Midi]

Ok, so basically LOTS of drying of ALL reagents..

Run #2
When the SnCl4 was added the solution went from clear, to blue.. light blue, but very distinctive blue.. 30 minutes passes and acetonitrile and nitromethan are added, then argon balloon is placed back over flask.. as time goes on the solution goes from blue, to grey, then to a dark greyish dirty color. When the stirbar is stopped, 2 layers seem to form.. a bark clearish layer on top, and a cloudy almost emulshiony lookin layer on bottom.. do these details sound familiar?

Is acetonitrile usually anhydrous when purchased? Not sure what grade we are workin with here.. regardless, all reagents will be dried 3x over magnesium sulfate next run..

Good thing that x10 was put on hold  

Lili, a mp will be done on all products.

[yellium]

MgSO4 might not be enough. There's a whole section in Vogel dedicated to drying and purification of solvents. Check out

http://www.chm.bris.ac.uk/safety/solvd.htm

[Rhodium]

I dry most of my solvents (except alcohols) by covering the bottom of the bottles (both the larger 2.5 L storage bottles and the 1L lab bench bottles) with ~1 cm of 4A molecular sieves, and I haven't had a failed reaction this far due to wet solvents. Twice a year I replace the sieves and regenerate them by heating them in the oven for a few hours, and I only re-use them with the same solvent (to eliminate the risk of cross-contamination).

To pre-dry organics after extracting an aqueous solution with them, it always work great to wash with 1/4 the volume of concentrated sodium chloride (brine) before drying with MgSO₄ or similar - the water content goes directly from ~10% to ~1% by such a wash.

[Midi]

I found that info very informative and have printed and laminated the following:

Solvent             Drying Agent 

Tetrahydrofuran     Sodium wire/benzophenone 
Ethanol             Magnesium 
Acetonitrile        Calcium hydride 
Acetone             Calcium chloride 
Dichloromethane     Calcium hydride 
Ethyl acetate       Calcium hydride 
40/60 Petrol ether  Calcium hydride or Sodium 
Toluene             Sodium 
Diethyl ether       Sodium wire/benzophenone 
Methanol            Magnesium 
Hexane              Calcium hydride or Sodium  
Pentane             Calcium hydride or Sodium wire 
Heptane             Calcium hydride or Sodium wire 
Benzene             Calcium hydride or Sodium wire 
Xylene              Sodium 

Nitromethane        ?

I was under the incorrect assumption that a drying agent such as magnesium could be used for all solvents.. that would explain alot..

I found a source for Anhydrous Calcium Hydride at $400 per 500g,   is this correct? It sure is expensive, do you use just a tiny bit? Is it reuseable?

Maybe a distillation of the solvents DCM & acetonitrile would produce equal results in drying these solvents.

[Midi]

To pre-dry organics after extracting an aqueous solution with them, it always work great to wash with 1/4 the volume of concentrated sodium chloride (brine) before drying with MgSO4 or similar - the water content goes directly from ~10% to ~1% by such a wash.

Excellent! So when the ethyl acetate extract is isolated, this should then be washed with a saturated solution of NaCl, then dried over Magnesium, then evaped.

Im officially a bit smarter than I was an hour ago!  

[Rhodium]

I found a source for Anhydrous Calcium Hydride at $400 per 500g, is this correct?

Yup.

It sure is expensive, do you use just a tiny bit? Is it reuseable?

You need one mole of calcium hydride for every two moles of water you want to remove, which is 1.16g CaH₂ per gram water, and it is not reusable as Calcium Hydride reacts with water to give hydrogen gas - CaH₂ + 2 H₂O -> Ca(OH)₂ + 2 H₂

I was under the incorrect assumption that a drying agent such as magnesium could be used for all solvents...

Magnesium as a drying agent only works on alcohols, and never when something is dissolved in the alcohol.

So when the ethyl acetate extract is isolated, this should then be washed with a saturated solution of NaCl, then dried over Magnesium, then evaped.

Yes, except that you use magnesium sulfate and not magnesium, and that you filter off the drying agent before evaporating.

Maybe a distillation of the solvents DCM & acetonitrile would produce equal results in drying these solvents.

Definitely not.

It seems like you need to read the articles under the heading/sub-heading Equipment & Lab Technique > Solvents on the page

https://www.thevespiary.org/rhodium/Rhodium/chemistry/

- for example these two:

https://www.thevespiary.org/rhodium/Rhodium/chemistry/equipment/dryingchemicals.html

https://www.thevespiary.org/rhodium/Rhodium/chemistry/equipment/solvent.purification.html

[Midi]

Rhodium, I found both of those links to be very informing, but i am still confused as to why distilling a solvent such as DCM with a bp of 40.8 is not a good way of seperating from h2o with a bp of 100c.

I appoligize for this is getting off track from my original post in this thread.. I suppose either way it is necessary to have the right tools when performing synthesis this moisture sensitive.

I will obtain some Calcium Hydride and if it does what im thinking it will, I should be able to get an idea of how much moisture is in my solvents by the amount of fizzing it produces when added.

I think I just found out why my yield on the LAH reduction of 2,5 dmns sucked ass. The THF was dried with magnesium sulfate prior to the reduction. According to what I have learned tonight, that didn't do much if anything in removal of h2o, and most likely a good portion of the LAH was ruined, returning 1g of product from 15g of uncrystalized 2,5..

It's all starting to make sense.. in a slightly depressing, overwhelming, yet enlightening kinda way. (sigh..)

[yellium]

The solution to that problem is quite simple: add more LAH. Expensive, but it doesn't hurt you, as you'll need an excess LAH anyway.

[Rhodium]

i am still confused as to why distilling a solvent such as DCM with a bp of 40.8 is not a good way of seperating from h2o with a bp of 100c.

It will likely get rid of most of the water if there is no DCM/H₂O azeotrope (I don't know if there is one), but some water vapor will always be carried over (say 0.1%) and some will be absorbed from the atmosphere. I assumed that we are talking about anhydrous (as in <0.01% water) and not "pretty dry" (as in ~0.1% water). 0.1% may sound like a very small number, but that means that there is still around 1 ml water per liter solvent.

[Midi]

some water vapor will always be carried over (say 0.1%) and some will be absorbed from the atmosphere.

I understand what you are saying now. Regardless of the temp, some h2o will evap over, ultimately making it impossible to obtain absolute anhydrous conditions by distillation.

Maybe it might be wise to perfom a distillation before using an expensive drying agent as calcium hydride. Then only 1 gram would be needed to remove that 1ml of h2o, per litre of solvent..

I spoke with a chemical engineer at Dow earlier today and he explained that many times a solvent, such as methylene chloride, sits for some time before making it to it's final destination, and along the way water will find it's way into the solvent. He also claimed he used to dry 100's of gallons of the stuff using Dryrite, which was a cheap and safer alternative to other agents. (according to him)

This makes me wonder.. Is Dryrite a good alternative to CaH₂??

Does magnesium sulfate do anything in removal of H₂o from DCM?

What about Nitromethane? This can not be seperated by distillation as the bp's are practically identical to that of H₂o, and I know for a fact that the stuff im using is not 100% anhydrous, but likely 99% pure.

What if too much CaH₂ is added, do you just filter out what the water didn't eat up?

[Lilienthal]

Rhod: From what I read for regenerating molsieves you have to heat them overnight at 160°C or so under vacuum.

CaH is somewhat dangerous as a dangerous a a drying agent because it developes H2 gas (flammable, overpressure). It's kept as a sediment in the bottle.

Molsieves would be a good drying agent for nitromethane.