All the glassware from the making of the Grignard reagent remains exactly the same with the Grignard reagent still resting in the reaction flask. The only change is that the ice bath tray is re
moved. Into the separatory funnel is placed 60g of anhydrous al-lylbromide (Br-CH2-CH=CH2, see chemicals section for how to make) and this is then slowly dripped into the Grignard solution. Another vigorous reaction will start and the addition is regulated so that things do not get out of control. After addition the solution is refluxed for 3 hours, cooled and then hydrolyzed by pouring the reaction mix into 300ml_ ice cold saturated ammonium chloride solution in a PP container.
What the chemist will see is two layers: a solvent layer (THF or Et20) and a water layer with a lot of suspended solids. The chemist can remove and discard the aqueous layer now or, preferably, the chemist can vacuum filter the entire two-layered solution to get rid of all the solids, then remove the water layer. Of course it is always a good idea to extract that water layer once with fresh solvent before it is discarded. The solvent/safrole layer is washed with a little dilute HCI and then with some fresh dH20. The solvent layer is then dried through Na2S04 and vacuum distilled. The first thing to distill over is, of course, the solvent. The next thing to come over will be a few ml_s of a low boiling oil which is going to be 1,3-benzodioxole and will be saved for reuse. At a much higher temperature comes all the safrole. The chemist will have no trouble knowing that the procedure worked because all of that high-boiling oil is going to smell just like licorice (yield=87%).
Can you believe that? A chemist just recreated a wondrously complex substance that, before now, was only a gift from God to man via plants. Man took this gift away from her fellow man but now, through the unbelievable power of chemistry, man can reclaim her right to self determination. Albeit illegally of course.
And it would certainly be illegal if Merlin had actually done the procedure she next describes. Aside of the unsatisfactory pronoun use, Merlin's accounting is astonishing:
"The Grignard Reaction
Since completing my synthesis of safrole using the methods described here, I have learnt that I am the first person in the world to do so. There may be areas in my procedures that can be improved. What I am doing here is giving you my best shot as well as a fairly detailed account of my experiences.
The Grignard reaction is well documented in many areas of chemistry literature and it would be wise to read as much as possible before attempting this reaction. The apparatus required includes: - 1000ml three neck flask, 1000ml sep funnel, a condenser and a drying tube. This apparatus needs to be set on a magnetic stir plate. For reasons which I would prefer not to go into, the presence of any water during the reaction will severely screw up yields, so everything needs to be dried including the ingredients. The best way to dry the glassware is to cook it in your oven for half an hour at 15CPC (30CfF). The solvent (THF or ether) and the bromobenzodioxole need to be dried over sodium sulphate, and the magnesium should be cooked in the oven along with the glassware. Atmospheric moisture must be kept out of the reaction by using the drying tube.
A dry reflux set-up is used with a three neck flask allowing a thermometer and sep funnel to be attached to the reaction flask. The thermometer is placed well below the surface of the flask contents. If the temperature rises above 55°C ice will need to be used to cool things down a bit. So the three neck flask will be sitting in an ice bath on the stir plate before we begin. If ether is used instead of THF the ether will boil well before 50°C is reached giving a better indication of how hot things are getting.
Place 12g of magnesium into the flask along with 200ml of THF and stir. Place 100g of bromobenzodioxole along with 200ml of
THF into the sep funnel. It is recommended that an iodine crystal is placed in the reaction flask and before the condenser is attached, nitrogen should be blown into the receiving flask to remove any air. As I didn't have any nitrogen available I skipped this step but I did place one small crystal of iodine into the reaction flask. When the iodine is added the solvent will begin to turn brown. Although this looks like the iodine is just dissolving it would appear from what I have read that this is also caused by the reaction.
The contents of the sep funnel are now added with care to the reaction flask. Begin by dripping small amounts of the bromobenzo-dioxole into the reaction flask and keep a close eye on the thermometer, remembering that the temperature should not be allowed to go above 55°C. If the temperature does begin to climb too fast, stop the addition and wait until it reduces to at least 4CfC. Addition of the bromobenzodioxole should take about 30 mins. Although the reaction was described as being vigorous, in my experience there wasn't much to see except a rapid rise in temperature. Once all the bromobenzodioxole has been added the solution should be dark brown in colour. The solution should now be left to stir for a further 60 mins., after which it will become a dark greeny-brown with only tiny particles of magnesium that will be swirling around as the solution stirs. What's left in the flask is the Grignard reagent. Anyone getting to this stage should feel happy in the knowledge that very few (only me up until now) have seen this bromobenzodioxole - Grignard reagent.
Safrole from the Grignard reagent Keeping the apparatus from the above reaction, pour 60g of allylbromide into the sep funnel. As with the ingredients of the last procedure the allylbromide must be dried over sodium sulphate. This stuff is really nasty, use a mask at least or a fume cupboard if you can get access to one or fill the sep funnel outdoors. The fumes are invisible and pretty lethal -please be warned.
The allylbromide is slowly added to the Grignard reagent. It should be added as carefully, if not even more so than the bromobenzodioxole, because when it hits the Grignard reagent things really start to get going. There is no need to keep the reaction under any particular temperature, but if it gets too hot in there your solvent boils, a sure sign telling you to slow things down. This reaction was much more vigorous than the first, which was fun as I realised it must be working.
After all the allylbromide has been added, the solution is heated and allowed to reflux for three hours, and subsequently left to cool for thirty minutes.
Prepare a 300ml saturated ammonium chloride solution in a 2000ml PP container by adding 225g of ammonium chloride to 180ml of water. Carefully pour the contents of your reaction flask into the ammonium chloride solution. Two layers will form which contain a big load of suspended solids - which are removed by vacuum filtration. These two layers are then poured into a (clean) sep funnel and allowed to settle. The water layer is discarded, leaving the organic layer which is washed once with 50ml of 5M HCL and then once with 50ml of water. Any remaining water must then be removed by drying over sodium sulphate. Now all we need to do is distil, and we have safrole.
Using a standard vacuum distillation the solvent is distilled off. This shouldn't take too long. The first thing to come over after the solvent was the safrole, which with my vacuum (2mm) started at around 90°C. The safrole will be a clear liquid, slightly viscous and will smell of liquorice. With the above measurements one can expect a yield of around 85g. No further cleaning up is necessary, and the safrole can be used as is for any further reactions."
You can see now why Strike is so proud of this chemist's hypothetical work. It is the most professionally written and applied experimentáis of this entire book. It is made all the more remarkable when Strike tells you that these three contributions were the first
chemical experiments Merlin had ever done. Here is this rookie applying some of the most advanced, and often difficult, organic syntheses processes around!
Is this a testament to Strike's masterful book writing abilities? Maybe. Or is it a testament to the fact that anyone can do these methods? Maybe. Strike likes to think that it is a testament to the intelligence and and persistence of one very good looking chemist (no, Strike is not gay!).
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