Org Prep Daily

July 4, 2008


Filed under: procedures — milkshake @ 8:32 pm

2-Bromo-4-iodo-5-cyanopyridine 25.320g (81.97mmol) solid in a 2L round flask with a large egg-shaped stirbar was flushed with Ar and anhydrous toluene 1L was added via canula. The mixture was stirred and gently heated until complete dissolution, then cooled to 0C. With vigorous stirring on ice bath, diisobutylaluminum hydride solution 1M in hexane, 83mL was added by syringe, dropwise over a 20 min period. The mixture was stirred at 0C for additional 90 min, then cooled down to -78C. Ice-cooled mixture of 2M aqueous sulfuric acid 170mL and THF 350mL was gradually added into the reaction mix with vigorous stirring, the cooling bath was then removed and the mixture was let stirring in open flask (gas evolution) at ambient temperature overnight (15 hours). The next day water 400mL was added and the mixture was stirred for additional 30 min and separated. The organic phase was washed with water 500mL and saturated bicarbonate 500mL. The aqueous phases were re-extracted with ethyl acetate 500mL. The combined organic extracts were dried with MgSO4 and concentrated on rotovap down to aprox 300mL total volume from a 30C bath and cooled to RT. The precipitated product (13.398g, 98% pure, a cream-colored fluffy fibrous crystals) was collected by filtration, washed with toluene (4x20mL) and hexane and dried on highvac. The filtrates were evaporated to dryness. The residue was re-crystallized from acetonitrile 80mL (dissolved at reflux, 2h at RT, then at 0C overnight) filtered, rinsed with chilled acetonitrile and dried, to provide the second crop of product 7.814g (95% pure) as a tan crystalline solid. The combined yield was 21.212g (83% th).

1H(d6-DMSO, 400MHz): 9.950(s, 1H), 8.573(s, 1H), 8.434(s, 1H); 13C(d6-DMSO, 100MHz): 193.46, 151.48, 146.35, 138.54, 130.74, 112.97

The nitrile preparation was described here on July 1, 2008


  1. 83 mL dropwise “by syringe”? You must have Popeye forearms. Any reason you avoided an addition funnel?

    Comment by squirmy — July 5, 2008 @ 3:09 am

  2. 83mL is what – four syringes? You too could push 21mL in 5 min dropwise, times four, if you had eaten your spinach. (It doesn’t have to be perfectly dropwise when you got a giant stirring egg spinning full speed and you aim into the Maelström vortex). BTW, the cheap plasticky 20mL medicinal syringes do a remarkably good job with air-sensitive reagents and they are quite easy to push (and don’t have to be dried like the glass airtight ones).

    Comment by milkshake — July 5, 2008 @ 3:19 am

  3. I’m all for the plastic syringes. especially with a solvent like hexane. With more polar solvents, they sometimes act up over several injections, especially over a long period.

    You’re right that 21 mL dropwise over 5 minutes isn’t too bad. I was thinking of slower additions, where (imo) even one injection of 20 mL is too tedious and difficult to maintain a steady rate of addition.

    Comment by squirmy — July 5, 2008 @ 4:04 am

  4. For slower additions a syringe pump could be quite handy.

    By the bye, what is your take on using e-note books, and which ones are good? What is the scientific stigma (I have inhibitions since they replace the traditional notebooks which I love the feeling of hand writing, drawing etc?) Do you recommend it for the training the younger generation in the lab?

    Comment by Me too — July 5, 2008 @ 2:14 pm

  5. I don’t like to use electronic notebook records, I guess one can have such e-notebook AND printed out and pasted pages into a regular notebook also.

    The problem is – notebook entries are precious and when something happens and you cannot access the electronic notebook files, at least you got the printouts.

    Comment by milkshake — July 5, 2008 @ 10:48 pm

  6. for large scale dropwise additions of air sensitive compounds i’ve used either an addition funnel or set up a siphon via cannula between two flasks under the same pressure of nitrogen (easy w/a schlenk line). if you have the right kind of graduated cylinder, it’s pretty easy to stick a septum over the top and use this as your “addition flask.” the rate of addition of the second method can be controlled by a)id of cannula and/or b) height differential of the flasks. either method has worked well in my experience.

    Comment by LibArtsProf — July 24, 2008 @ 1:08 pm

  7. In this case the addition is done at higher temperature and the reaction mix is more diluted than usual (this sort of cyanopyridine substrates get easily reduced with DIBAL at -40 C, at 0.2M substrate concentration) – because the starting material has a solubility problem. When doing the nitrile reductions at 0C, it is quite important to avoid DIBAL reagent excess and stirr fast and pre-cool below 0C before quench. Fortunately, the tiny amount of resulting over-reduced products (benzylic amines) goes into aqueous phase during the workup. So if you add too much too fast, the yield suffers by few % but the product purity remains pretty good. The other important detail is to give it a good overnight stirr with sulfuric acid – the aluminum crap from DIBAL takes time to dissolve completely. (If it does not, one can filter the biphasic mix before the extraction).

    Comment by milkshake — July 24, 2008 @ 4:37 pm

  8. Why do we have to wait untill the reaction was ‘warmed’ to room temperature before add water? what happen if we add the water straight away?

    Comment by james — June 23, 2010 @ 7:01 am

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