[kaycee08]

Hello. We were asked to figure out reactions to obtain the final product. I'm not quite sure how to start the reaction and was wondering if anybody could give me hints or ideas on how to proceed. Any help would be appreciated. Thanks!

[gfunk]

What level of chemistry is this for?  There are many ways to accomplish this synthesis.  However, it really depends on what kind of chemistry you're expected to know/use.  For example, I'm sure you've learnt about Friedel-Crafts, but what about ortho-metallation, etc.?

[kaycee08]

I have the following reactions so far. I'm not sure if they're right, but I was hoping if you could check them for me. I would greatly appreciate it!

1. Mg, THF
2. O=CH-CH3
3. H2O, H2SO4
4. MnO2, heat
5. Na2Cr2O7, H2SO4, heat
6. HCl
7. HNO3, H2SO4
8. Ni, H2
9. NaNO2, HCl, 0 degrees celsius
10. H2O

Thank you!

I modified it. I replaced KMnO4, heat, and H2SO4 with Na2Cr2O7, H2SO4, and heat so it could be done in one step. Also removed ZnCl2 from step 6.

[gfunk]

Let's see how well I can follow this lol.

1: Create Grignard
2,3: Attack on acetaldehyde, quench to form secondary alcohol
4: Oxidize benzylic secondary alcohol to ketone
5: Chromate oxidation to oxidize benzylic position of ethyl group
6: HCl is just chillin'...
7: Nitration, most likely will not end up in the desired location
8: Reduction to amine, not sure if that won't take out the ketone
9: Turn into azide
10: Hydrolyze azide (might require aqueous acid)

A couple things I would change:
2,3: Make the attack on formaldehyde, not acetaldehyde.  That way you can oxidize to the carboxylic acid and change that into the acid chloride, and not be stuck at a ketone.
6: I'm assuming you're trying to make the acid chloride.  You should use thionyl chloride (SOCl₂) instead.  And save this to the end because the acid chloride will be really reactive
7-10: Interesting set of reactions, though might not really work out as well as you hope... I'll have to think about this one!

[kaycee08]

I attached 2 images below showing my reactions in detail. Would this be feasible or will the reactions affect the other substituents that's already on the benzene? Thanks again for all the help. I truly appreciate it!

[Squirmy]

Acid chlorides are reactive electrophiles...generally they won't survive an aqueous workup because they react with water (a weak nucleophile). So, making a Grignard (a very strong nucleophile) in the presence of an acid chloride is a no-go...as gfunk said, save the SOCl2 step to the last.

You should look back at your notes regarding installation of the -OH. Where is the -NH2 coming from with the reagents Ni, H2...careful, Ni is not N. Also, reacting the -NH2 with NaNO2/HCl does not give -NO2.

[kaycee08]

Acid chlorides are reactive electrophiles...generally they won't survive an aqueous workup because they react with water (a weak nucleophile). So, making a Grignard (a very strong nucleophile) in the presence of an acid chloride is a no-go...as gfunk said, save the SOCl2 step to the last.

You should look back at your notes regarding installation of the -OH. Where is the -NH2 coming from with the reagents Ni, H2...careful, Ni is not N. Also, reacting the -NH2 with NaNO2/HCl does not give -NO2.

Hello. Sorry about the last few steps. I believe I missed a very important step and had the wrong images as they were mixed up a little bit..

I believe it should have been:

1. HNO3, H2SO4 to form the NO2
2. Ni, H2 to react with the NO2 and form NH2
3. NaNO2, HCl, 0 degrees Celsius
4. H2O

For the first part, in what order would you suggest doing the reaction? Would adding the SOCl2 right after the "NaNO2, HCl, 0 degrees Celsius" reaction be more feasible? I would really appreciate the feedback. Thank you so much!

[kaycee08]

I have the following sequence of reactions so far:

1. Na2Cr2O7, H2SO4, heat to convert the ethyl group to a carboxylic acid
2. Mg, THF - to create a Grignard
3. (1) acetaldehyde (2) H2O, H2SO4 to convert the Grignard and form a secondary alcohol
4. MnO2, heat to oxidize the benzylic secondary alcohol to ketone
5. HNO3, H2SO4 to form NO2 (para position relative to the F)
6. Ni, H2 to react with the NO2 and form NH2
7. NaNO2, HCl, 0 degrees Celsius to form the azide from the NH2
8. SOCl2 to react with the carboxylic acid group and form the acid chloride
9. H2O to react with the azide and form the alcohol

Is this correct?

[kaycee08]

I attached the reactions that I have so far. Hopefully the reaction sequence is ok now  .

[Squirmy]

Looking much better. You probably want to change the order a little, though:

1. Your Grignard is a strong base as well as a strong nucleophile. There is a functional group in your starting material that's non compatible with the strongly basic Grignard.

2. The acid chloride is still too reactive to survive the last step. It will hydrolyze back to the carboxylic acid.

[kaycee08]

I'm unsure how or where to react the SOCl2.. if I add it at the very last step, would it react with the other -OH group or would the "phenol" group be stable enough that SOCl2 wouldn't affect it?

I'm still trying to figure out what you said about the Grignard.. hopefully it will come to me soon! Haha. Thanks for the feedback!

Sorry, I'm still a little new at this. I'm still trying to learn the ins and outs of these reactions.

[kaycee08]

Oh, I see.. The Grignard would react with the carboxylic acid reducing it to alcohol.

If I switch the first 2 reactions and switch the last 2 reactions, would this yield the desired product?

1. Mg, THF
2. Na2Cr2O7, H2SO4
...
8. H2O
9. SOCl2, pyridine

[Squirmy]

You're doing fine.

The SOCl₂ - phenol question is a good one. The phenol OH wouldn't give chloride substitution the way an aliphatic OH would (no Sn2 on benzene), but it might react to give a sulfur ester (ClSO₂R).

Who knows what that'll do? You might need a little hand-waving at that step On the other hand, treating the acid chloride with water, especially with the heat required to react with the diazonium salt, WILL hydrolyze the acid chloride, so the hand-wavy route seems preferable.

The Grignard will react with the carboxylic acid, putting a hydrogen where the bromide once was. The same reason you have to keep water out when you run a Grignard.

[Squirmy]

Saw your post after I put mine up...looks good!

[kaycee08]

Squirmy, THANK YOU SO MUCH for all the *delete me* I appreciate it dearly.