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We’re going back to the lab! So far we’ve learned some important lab techniques that organic chemists might use day to day, like chromatography and proton NMR, but there are even more to learn. In this episode of Crash Course Organic Chemistry, we’ll introduce some new lab techniques such as distillation and recrystallization and apply them to everything we’ve been learning about EAS reactions. And we’ll do some synthesis problems!

Episode Sources:
Gilbert, J. C., & Martin, S. F. (2015). Experimental organic chemistry: a miniscale & microscale approach. Cengage Learning.

Series Sources:
Brown, W. H., Iverson, B. L., Ansyln, E. V., Foote, C., Organic Chemistry; 8th ed.; Cengage Learning, Boston, 2018.
Bruice, P. Y., Organic Chemistry, 7th ed.; Pearson Education, Inc., United States, 2014.
Clayden, J., Greeves, N., Warren., S., Organic Chemistry, 2nd ed.; Oxford University Press, New York, 2012.
Jones Jr., M.; Fleming, S. A., Organic Chemistry, 5th ed.; W. W. Norton & Company, New York, 2014.
Klein., D., Organic Chemistry; 1st ed.; John Wiley & Sons, United States, 2012.
Louden M., Organic Chemistry; 5th ed.; Roberts and Company Publishers, Colorado, 2009.
McMurry, J., Organic Chemistry, 9th ed.; Cengage Learning, Boston, 2016.
Smith, J. G., Organic chemistry; 6th ed.; McGraw-Hill Education, New York, 2020.
Wade., L. G., Organic Chemistry; 8th ed.; Pearson Education, Inc., United States, 2013.

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Hi! I’m Deboki Chakravarti and welcome to Crash Course Organic Chemistry!

 In this series, we've been sprinkling in synthesis episodes to introduce   lab techniques that an organic chemist might use in a typical day – it can get pretty busy!

 A lot of research and planning goes into running new reactions, so first they perform structure-based computer searches of chemical reactions to find what's been done before. They could be making new chemicals, so they’ll spend lots of time reading procedures and consulting safety data sheets of compounds similar to what they want to make. Once our chemist finds procedures, they’ll want to try different reaction conditions to see which works best. So, they set up tiny reactions to preview using thin layer chromatography – remember, that's TLC for short! And if TLC looks promising, they may take a proton NMR of the unpurified reaction mixture to check for characteristic product peaks. Next, the chemist will scale up the best reaction to make a larger amount of product. When the reaction is done, they’ll work it up, which is lab lingo for performing an extraction to remove some side products based on solubility.

Now it’s purification time! Organic chemistry involves a LOT of flash chromatography – sometimes running several columns in one day. Remember, this type of purification lets us separate compounds based on polarity. But we can also use other chemical properties to purify organic compounds. So, let’s learn about some different lab techniques and practice some synthesis problems along the way!

 [Theme Music]

 In the past three episodes, we learned five major electrophilic aromatic substitution reactions: halogenation, nitration, sulfonation, Friedel-Crafts alkylation, and Friedel-Crafts acylation. We also learned that the Friedel-Crafts reactions have three main limitations. First of all, both of them don’t work so well on rings with powerful electron-withdrawing groups, like nitrobenzene. Second, the Friedel-Crafts alkylation reaction can lead to over-alkylated products. And third, those alkylation products can rearrange if a more stable carbocation intermediate can form.

In Episode 39, we learned how to work around both overalkylation and rearrangement using a Friedel-Crafts acylation reaction. By introducing the deactivating acyl group, we avoid the overalkylation issue. And by reducing the carbonyl completely off the molecule, we can form an alkylated product without rearrangement. In that episode, we also saw that benzylic carbons have special reactivity, allowing them to be halogenated or oxidized to carboxylic acids.

And in Episode 38, we learned that EAS reactions are influenced by groups already on the ring, which direct the incoming group to a specific spot. Electron withdrawing groups usually direct new groups to the meta position and electron donating groups direct new groups to the ortho and para positions. Although we didn’t mention it in that episode, we usually want either the ortho or para product, not both.

 So, in the lab, we’ll need to purify one compound from this mixture before moving onto the next step of our synthesis. If we want the para product exclusively, sometimes we can block the ortho positions with a bulky group. Let’s take a peek at the synthesis of sulfanilamide, one of the first broadly used antibiotics, to see this in action. We start with aniline, which is a benzene ring with an N-H-2 group. By adding a somewhat bulky and easily removable acetyl group to the nitrogen, we block access to the adjacent ortho position, and we can add an electrophile to just the para position.

One way to acetylate our aniline is using acetyl chloride and pyridine as a base to accept the proton on the N-H-2 group. So, let's say our chemist heads to the chemical shelf to locate the acetyl chloride! But they only find a really old bottle. Acid chlorides are very reactive, so will this old bottle that's been opened a lot still do the trick? Well, the air contains water vapor… and acid chloride undergoes hydrolysis with water. So, the acetyl chloride is likely contaminated with acetic acid and hydrochloric acid, and they'd need to purify it before doing anything else.

 

 So, let's hit pause on our aniline reaction and do that! The acid chloride would be really difficult to purify using flash chromatography because it’s so reactive. But both of these compounds are liquids. So instead of using flash chromatography and polarity to purify the acetyl chloride, we can use a method called distillation. If the boiling points of the components in a mixture differ by about 25 degrees Celsius or more, we can separate them by distillation. The boiling point of acetyl chloride is 51 degrees Celsius, and acetic acid’s boiling point is 118 degrees Celsius. So that’s a nice 67 degrees difference! In distillation, the liquids are heated, and the one with the lower boiling point evaporates more readily.

 The vapors travel up a tube, and when they hit a hollow tube surrounded by chilled water called a condenser, the vapors condense back into the liquid phase into a receiving flask. So, we'll be able to collect the liquid with a lower boiling point before the one with a higher boiling point even evaporates. The rotovap, which we used to remove the extra solvent from our fractions after chromatography in episode 25, is an example of vacuum distillation.

 Vacuum distillation is good for separating liquids with high boiling points, because the vacuum lowers the boiling point. That way, we can use gentler warming to make the liquids boil. In the rotovap, we’re usually just getting rid of solvent from a less volatile or non-volatile compound. But with other distillation equipment, we’re collecting all the evaporated-then-condensed liquid in a clean receiving flask to use later. Got it?

Okay, let's go back to our aniline reaction with our now-purified acetyl chloride from that old bottle. We can use an amide forming reaction to turn aniline into acetanilide, and once we've done this, we'll need to purify our new product. Acetanilide, like many aromatic compounds, is a crystalline solid. So, to purify this, we need a method based on solubility, called recrystallization. This involves heating up a mixture of compounds in a solvent until they all dissolve, and having one selectively crystallize back out – that’s where recrystallization gets its name. The recrystallization solvent has to meet two criteria: Number 1: The solid has to be soluble in the solvent when heated, but insoluble or slightly soluble at room temperature Number 2: The impurities must be soluble in the solvent at any temperature There can be a lot of trial and error when picking a recrystallization solvent. But if we identify a suitable solvent (or combination of solvents) it’s pretty awesome because we often get really pure compound without a lot of solvent waste, which is a big advantage compared to column chromatography. Plus, no switching test tubes!

Our chemist can use their time efficiently and work on another reaction while the chemical crystallizes. We can collect the pure crystals using a technique called vacuum filtration. A special flask with a sidearm lets us rapidly suck the crystals and recrystallization solvent through a flat-bottomed Buchner funnel. And we collect the pure crystals on top of a piece of filter paper in the funnel. Now that we've purified our crystalline solid acetanilide, it's a big moment! We can finish off our synthesis of the antibiotic sulfanilamide. Our EAS reaction is a modified sulfonation reaction called chlorosulfonation, which adds an S-O-2-C-L group instead of the S-O-3-H group we saw with plain old sulfonation. The chloride leaving group is turned into an amine using ammonium hydroxide in a substitution reaction. Since that bulky blocking group that we used to direct new groups to the para position is an amide, it can be removed in the last step through an acid-catalyzed hydrolysis reaction – and then neutralized with base. Practice is so important in organic chemistry, so let’s do some synthesis problems to reinforce what we’ve learned about EAS and benzylic reactions.

 Here’s our first problem: notice the retrosynthesis arrow. We’re going to make 1-bromo-4-nitrobenzene, or para-bromonitrobenzene, starting from benzene. We know how to do nitration and bromination using EAS reactions, so there’s nothing too wild going on here. But we do need to decide on the order to add the groups to make sure they end up para, so let’s think about the directing effects of each group. The nitro group is an electron-withdrawing group, an EWG that directs groups meta. Halogens like our bromide direct the incoming group to park at the ortho or para positions. If we label the positions that are ortho and para to the bromide, we can see that’s where our nitro group ends up!

But when we label the positions meta to the nitro, there’s no group there. We need to put our bromide on first. In our forward synthesis, we first add bromine to benzene with our ferric bromide catalyst. Then, we nitrate using a mixture of sulfuric and nitric acid. The product is a solid, so we can recrystallize the para-bromonitrobenzene from our mixture of ortho and para products. We’ve solved this puzzle!

 Let’s try another synthesis. Starting again with benzene, we want to make 1-chloro-3-propylbenzene, a meta-substituted product. Again, let’s analyze the effects of our directing groups. The halogen, chloride, is an ortho/para-directing group, and the alkyl group is also an ortho/para-directing EDG. So... we need to get creative here. Chlorines are put onto aromatic rings by EAS halogenation reactions – not much else we can do there. But what about this straight-chained alkyl group? Hmm… chains like this tend to rearrange in Friedel-Crafts alkylation reactions. So, we usually make these in a roundabout way using acylation reactions. Looking at this retrosynthetically, and thinking about the directing effects of these groups, the ketone is actually an electron withdrawing group and a meta director! To do the forward synthesis, we can first acylate the ring, and with that EWG still in place, we chlorinate.

And in our final step, a Wolff-Kishner reduction completely removes the carbonyl, giving our desired product. And we’re done! Okay, let's do one more retrosynthesis problem together. This time our starting material, toluene, has a C-H-three group on the ring. That’s an ortho/para director. And we don’t have an easy way to remove this methyl group, so it needs to be in our product too. The carbon from the methyl has to be one of these two carbon atoms. So which carbon is it?

 Let’s think about which carbon is easier to add through electrophilic aromatic substitution. It's this one! It may look big and complicated, but it’s just an acyl group with another benzene ring attached. Now, we don’t know a reaction to make this SH group directly from our methyl, but we do know benzylic bromination. We also know halides are good leaving groups in SN2 reactions and that sulfur is a good nucleophile. For our forward synthesis, let’s capitalize on the ortho/para directing effect of our methyl group and acylate first. With a purified para product, we can do a benzylic bromination, and then an SN2 reaction on our benzylic substrate with a sulfur nucleophile. And we’ve completed another synthesis! Now that we've walked through a few examples, let’s try some rapid fire problems!

We’re going to put three problems on screen, and you’ll predict syntheses for the first two, and the product for the third. As a hint, the synthesis problems can be done in two steps. Like always, pause the video if you want to practice without seeing the solution. Ready?

Here’s problem number one. We’re turning this ketone into a para-substituted product. The starting ketone is a meta director, so first we’ll reduce that to an ortho/para directing alkyl chain. Then, we'll do the chlorosulfonation reaction we met this episode!

 Onto problem number two. We’re starting with toluene and making a meta-substituted product. As we’ve seen a lot now, alkyl groups direct ortho-para. So, we need to make a meta director first. A benzylic oxidation makes a carboxylic acid. And this carbon atom is directly attached to more electronegative oxygens, so the trick we learned in episode 38 tells us this is an EWG and a meta director. For our second step, let's do a nitration. And we’re done!

 And finally, here's problem number three. Let's predict the product of this Friedel-Crafts acylation reaction. In episode 39, we learned that the more activating group is our parking lot attendant when we have multiple substituents. So, the hydroxyl group is the activating group here, and directs ortho-para. And our electron withdrawing sulfonic acid is a meta director and reinforces the positioning – so this is our product!

 In this episode, we: Used distillation to separate compounds based on boiling point Used recrystallization to purify crystalline solids, and Practiced EAS reactions, benzylic reactions, and directing effects through lots of synthesis problems in the next episode, we’ll look more at conjugated compounds and learn about UV/Vis spectroscopy. Until then, thanks for watching this episode of Crash Course Organic Chemistry.

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