Ch. 18 - Reactions of Aromatics: EAS and BeyondWorksheetSee all chapters
All Chapters
Ch. 1 - A Review of General Chemistry
Ch. 2 - Molecular Representations
Ch. 3 - Acids and Bases
Ch. 4 - Alkanes and Cycloalkanes
Ch. 5 - Chirality
Ch. 6 - Thermodynamics and Kinetics
Ch. 7 - Substitution Reactions
Ch. 8 - Elimination Reactions
Ch. 9 - Alkenes and Alkynes
Ch. 10 - Addition Reactions
Ch. 11 - Radical Reactions
Ch. 12 - Alcohols, Ethers, Epoxides and Thiols
Ch. 13 - Alcohols and Carbonyl Compounds
Ch. 14 - Synthetic Techniques
Ch. 15 - Analytical Techniques: IR, NMR, Mass Spect
Ch. 16 - Conjugated Systems
Ch. 17 - Aromaticity
Ch. 18 - Reactions of Aromatics: EAS and Beyond
Ch. 19 - Aldehydes and Ketones: Nucleophilic Addition
Ch. 20 - Carboxylic Acid Derivatives: NAS
Ch. 21 - Enolate Chemistry: Reactions at the Alpha-Carbon
Ch. 22 - Condensation Chemistry
Ch. 23 - Amines
Ch. 24 - Carbohydrates
Ch. 25 - Phenols
Ch. 26 - Amino Acids, Peptides, and Proteins
Sections
Electrophilic Aromatic Substitution
Benzene Reactions
EAS: Halogenation Mechanism
EAS: Nitration Mechanism
EAS: Friedel-Crafts Alkylation Mechanism
EAS: Friedel-Crafts Acylation Mechanism
EAS: Any Carbocation Mechanism
Electron Withdrawing Groups
EAS: Ortho vs. Para Positions
Acylation of Aniline
Limitations of Friedel-Crafts Alkyation
Advantages of Friedel-Crafts Acylation
Blocking Groups - Sulfonic Acid
EAS: Synergistic and Competitive Groups
Side-Chain Halogenation
Side-Chain Oxidation
Birch Reduction
EAS: Sequence Groups
EAS: Retrosynthesis
Diazo Replacement Reactions
Diazo Sequence Groups
Diazo Retrosynthesis
Nucleophilic Aromatic Substitution
Benzyne
Additional Practice
EAS: Sulfonation Mechanism
EAS: Gatterman–Koch Reaction
EAS: Total Benzene Isomers
EAS: Polycyclic Aromatic Hydrocarbons
EAS: Directing Effects
Resonance Theory of EAS Directing Effects
EAS: Badass Activity Chart
Activated Benzene and Polysubstitutions
Clemmensen Reduction
EAS: Dueling Benzenes
Hydrogenation of Benzene
EAS: Missing Reagent
EAS: Synthesis
Diazonization of Aniline
Diazo Coupling Reactions
SNAr vs. Benzyne
Aromatic Missing Reagent
Aromatic Synthesis
Aromatic Retrosynthesis
EAS on 5-membered Heterocycles

So it turns out, you may be asked to propose an aromatic synthesis starting only from benzene or other benzene derivatives. We will use our previous knowledge of sequence groups to plan synthetic steps in the correct order

Concept #1: Aromatic synthesis starting with benzene/benzene derivatives

Transcript

All right guys, so now we're going to get some practice with proposing aromatic synthesis. So at some point in your course work you're going to be asked to propose an aromatic synthesis starting only from benzene or other benzene derivatives. You're going to have to turn that benzene into something more complicated.
In order to make this work, you're going to have to use your knowledge of sequence groups so that you can add the groups in the right positions. It's never going to be that easy that you don't need to use sequence groups.
Let's do this first example kind of as a worked example where I'm going to give you some hints and the second one you'll be completely on your own. For this first one, it says synthesize the target molecule from acetophenone and any other reagents. In this case, acetophenone is given to you as the molecule. But, you should be aware of what the name acetophenone means from the naming benzene area of our Clutch videos.
So what's going on here? What are the different transformations that are taking place? One thing that's happening is that I have a ketone that at some point needs to become a benzoic acid. So that's interesting. I've also got to add a nitro group in the para position so that's p, para substitution. So there's kind of a lot going on here. I've got a few different things.
One thing that I know for sure is that to put a nitro into the para position, at some point, my ketone is going to have to become what? An ortho, para director. Right now what type of director is it? Meta. Right now this is a meta director. If I were to nitrate this ketone right now, or this acetophenone, I would actually get a nitro here. Is that right? No. So I'm going to have to use my knowledge of sequence groups to figure out how can I turn that into an ortho, para director.
Now benzoic acid. Is this an ortho, para director? No, this is also a meta director. That means that I have to turn this into a benzoic acid sometime after I've added the nitro group because if I just turn it straight into benzoic acid, then I'm going to get a meta nitro group again. So this is kind of already outlining all the things we need to do.
So now I'm going to let you guys get creative. This is the part that I can't do for you. You just have to get creative with all the reactions we've learned and see if you can figure out the right sequence of reagents to make this final product. So go ahead and try your best and then I'll answer it for you. 

Example #1: Synthesize the target molecule

Transcript

Alright so this was a three step reaction so if you got three steps you're on the right track the first step would be to turn this ketone into an ortho para director and we learned that we could do that through clemmensen reduction so my first regent would be a zinc mercury amalgam and what that's going to give me is in alkyl benzene I'm going to wind up getting specifically ethyl benzene. Now this is an ortho para director so since it's an ortho para director now I can use a nitration to put a nitro group in the pair position so I'm going to use H N O 3 and H S O 4 and that's going to give me my active electrophile which is going to attack the pair position predominantly and I'm going to get a nitro group. Why did I have to do a nitration next because now I have an ortho para director. Now do I have a one step way to turn this molecule into a benzoic acid? Yeah I do guys I can use K M N O 4 I can use another sequence group which is using K M N O 4 to oxidize the ethyl. Now remember that there's quite a few regents you have to write down so there's K M N O 4 which I mean some professors will be absolute fine with that but we have to be cautious. So the real the right way to write it would be K M N O 4 in the presence of base and heat and then I guess I said 3 steps it could technically be 4 but the way you could draw is you could also write like 3 A and 3 B since it's still the same reaction right so three B would be our acid H 0 + and what that's going to do is it's going to create a benzoic acid and that's our final product it does nothing to the nitro group so our final product ends up being this if we had to name it right it would be P nitro benzoic acid.

So guys I that was a good little introduction to sequence groups notice that there's no other order of regents that would've work I had to use those regents in specifically those borders because those are the specific sequence groups that I needed. Awesome guys so now you have another question go ahead and read it for yourself try your hardest and then I'll come in and I'll solve it for you.

Example #2: Synthesize the target molecule

Transcript

Alright guys there was a lot going on in this question notice that pretty much the only thing that stayed the same was the ethyl group but a lot of other stuff changed. First of all I'm going to need to find a way to put a methyl group in the pair positions this is para substitution. Even harder than that I'm going to have to put it in an annulene in the ortho position so ortho substitution. Now I've got a few issues here first of all is ortho substitution very favored? In most cases no so the only way that I'm going to get a high yield of the ortho position is to make sure that this methyl group is there first or something is there blocking the pair position I need to block it so that it's going to be forced into the ortho. On top of that ideally this should be a meta director when I add the annulene because I want it to be synergistic with the ethyl group to face towards the top so we should be thing are there any groups that I can add that could be a meta director and then be turned into an ortho para director later, so that's one thing another thing is do we even know how to add annulene to benzene did I ever teach you how to add N H 2 specifically to a benzene an A E S reaction? No but did I teach you a precursor that can be easily turned into annulene? Yes guys remember reduction of nitro groups we can use nitration to make annulene which is why it's so popular, so at some point I need to nitrate that position but only after I already have some kind of meta director in this position, see where this is going alright you might not but let me just step in and try to help and guys this is just you have to just start getting a feel for these. So the first direction we're going to do is a friedel crafts acylation because we know that acylation can be turned later on into alkylation using a clemmensen reduction so I'm going to use I'm just going to erase this I'm going to use an acid chloride right. Now this part is important guys your acid chloride needs to contain the number of carbons that you want in your end product so since I'm adding it here how many carbon should this acid chloride have? Just one because I only have one carbon here that means that I should have an H on the other side because I only want one carbon total and that's the carbon on the carbon yield I'm going to combine that with A L C L 3 and I'm going to get a molecule that looks like this.

Now see so I got an aldehyde now notice that it attached to the pair position because we said that para is pretty much predominately favored especially when you have larger groups like the A silk groups cool. So now what can we do, well now I have a meta director here and an ortho para director here now is the time to nitrate because they're both synergistically pointing to that top position so now we would take my nitric acid and myself sulphuric acid and I would now make my nitrated my nitro group along with my aldehyde at the bottom, cool. Awesome guys so now what do you want to do? Well we have two more things we have to do, we have to do a clemmensen reduction and we need to do a nitro reduction. Now these you split slightly different regents so I'm just going to draw both of them and it doesn't really matter the order because both things need to happen and we don't have any more groups to direct so if you chose to do clemmensen first and then reduce the nitro that's fine or the other way around let's just do that so lets do clemmensen zinc mercury amalgam with H C L that's going to give me a single carbon with an N O 2 and then finally I would use you know any of my reducing agents that work on nitro groups to turn it into an annulene again I've told you a few times now I prefer stannous chloride S N C L 2 and H 2 O because that's the one that's chemoselective if there was anything else here that could be reduced it would only react with the nitro group and that's going to give me my final product. So this was a four step reaction and we got it we have figured it out. So you see how sequence groups are so important awesome guys so let's go ahead and move on.

Practice: Provide the reaction for each of the following reaction steps

Practice: Beginning from Benzene, synthesize the following compound.

Practice: Beginning from Benzene, synthesize the following compound. 

1-Phenylethanol

Practice: Beginning from Benzene, synthesize the following compound.

Additional Problems
Propose the sythetic plan complete with reagents and proper order of reactions. You must show the product of each step in your scheme, however no detailed mechanism is required. 
Which sequence of reactions would give (some of) the correct product?  1) A and B 2) A and C 3) B and C 4) B only 5) A, B, and C 
Which sequence of reagents will accomplish this transformation?
Which sequence of reagents will effect this transformation?
Provide stepwise synthesis for the following transformation:
Which is the best method for carrying out the following reaction?
Provide the reagents to accomplish the transformation below. More than one step might be required for the transformation. 
Perform a retrosynthetic analysis on the molecules below (work backwards) from the given commercially available starting materials.
Starting with benzene, and using any other necessary reagants, design a synthesis for the following compound. Note: A reaction mechanism (i.e.; arrow-pushing) is not required.
Which set of reagents will best accomplish this transformation?    
Using any necessary reagents, show how you would accomplish the following transformations.  
Predict the major product for each of the following reactions paying attention to the region- and stereochemistry. If there is no reaction, write just “No Reaction.”  
For the reaction below, draw the structure of the appropriate compound in the box. Indicate stereochemistry where it is pertinent. For Friedel Crafts reactions, assume that the major product is the least sterically hindered one.
Propose a multi-step synthetic scheme complete with reagents and proper order of reactions (no mechanisms required) for the following molecule starting from the indicated compounds. You may use any reagents neccessary. Show the product of each step in your scheme.
Provide a scheme for the synthesis of the molecule below, using the indicated starting material and reagents of your choice.
Which sets of reagents would best be used to perform the following reaction?
Using any necessary reagents, show how you would accomplish the following transformations.
Circle the stating material for the following synthetic sequence.  
The following synthetic pathway does NOT sufficiently produce the indicated product. Provide an acceptable synthetic pathway. 
Propose a synthesis of compound B starting from benzene and acetyl chloride (CH3COCl ) as the only sources of carbon. Several steps may be required. Assume that all reagents needed for the synthesis are available. Indicate clearly the reagents used and the products obtained after each step. Mechanisms are not required.  
Propose a synthetic pathway from the indicated starting material to the designated product
Propose a synthetic pathway from the indicated starting material to the designated product
Provide the starting materials and reagents necessary to yield the product below.
Provide the reagents that will accomplish the following transformation. More than one step may be required.
Synthesize the trisubstituted benzene A from benzene.
Propose a synthesis of toulene starting from benzene and any other necessary reagents.
Propose a synthesis of acetophenone starting from benzene and any other necessary reagents.
Suggest a synthetic pathway from the given starting materials to the designated products.
Suggest a synthetic pathway from the given starting materials to the designated products.
Suggest a synthetic pathway from the given starting materials to the designated products.
Suggest a synthetic pathway from the given starting materials to the designated products.
Suggest a synthetic pathway from the given starting materials to the designated products.
Suggest a synthetic pathway from the given starting materials to the designated products.
Give the reagents needed to synthesize the desired products in high yields from the given starting materials
Provide reagent to complete the following chemical transformation.
Provide reagent to complete the following chemical transformation.
Provide reagent to perform the following transformation.
Suggest a synthetic pathway from the given starting material to the designated product.
Suggest a synthetic pathway from the given starting material to the designated product.
Suggest a synthetic pathway from the given starting material to the designated product.
Suggest a synthetic pathway from the given starting material to the designated product.
Suggest a synthetic pathway from the given starting material to the designated product.
Consider the following synthetic sequence and fill in the missing structures and/or reagents (ignore stereochemistry).
Starting with Benzene and using other reagents devise a synthesis for Methoxyphenyl acetamide.
In each reaction box, place the best reagent and conditions from the list below.
In each reaction box, place the best reagent and conditions from the list below.
In each reaction box, place the best reagent and conditions from the list below.
In each reaction box, place the best reagent and conditions from the list below. 
In each reaction box, place the best reagent and conditions from the list below. 
In each reaction box, place the best reagent and conditions from the list below.