Chemical Forums
Chemistry Forums for Students => Organic Chemistry Forum => Topic started by: SinkingTako on December 10, 2014, 11:23:58 AM
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So problem of the week has been dead for quite a while, and Borek is not very not keen on having something new. So let's start a organic synthesis revival!
Each week someone will post a molecule (I can do this for the first few weeks), and anyone can propose a total synthesis. The feasible submission with the least number of steps wins!
The Rules:
- Unless otherwise stated, the starting material(s) should be something relatively affordable and easily accessible in labs. To check, look up the price of the molecule on the Sigma Aldrich website. Something like
http://www.sigmaaldrich.com/catalog/product/aldrich/586366?lang=en®ion=SG
is not allowed. - "Feasibility" is defined as reactions that are known to have a moderate yield, and can take place without difficulty. Reactions that may occur by chance during a reaction, but is not part of the main reaction, are not allowed. (the definition of this is also so iffy)
- All intermediate compounds, reactants and conditions should be stated clearly, either written or typed.
- That's all for now, rule suggestions welcome!
The First Problem
Let's start with something really really easy:
Using benzene as the starting material, propose a synthesis of aspirin.
To start the ball rolling, see below for my proposal. I have done it in 6 steps. How many steps will you take?
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Kolbe-Schmitt carboxylation of phenol via base-promoted reaction of phenol with CO2 works very nicely at 125 degrees C and 100 atm. pressure. Do these conditions qualify as "feasible" and "take place without difficulty" when performed in a student laboratory in the absence of an autoclave?
"Efficient regioselective carboxylation of phenol to salicylic acid with supercritical CO2 in the presence of aluminium bromide" has been reported (Iijima, T.; Yamaguchi, T. J. Mol. Catalysis A: Chemical, 2008, 295, 52-56). But the use of supercritical CO2 once again requires an autoclave.
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Kolbe-Schmitt carboxylation of phenol via base-promoted reaction of phenol with CO2 works very nicely at 125 degrees C and 100 atm. pressure. Do these conditions qualify as "feasible" and "take place without difficulty" when performed in a student laboratory in the absence of an autoclave?
Can you do a 100 atm reaction at all without an autoclave?
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Kolbe-Schmitt carboxylation of phenol via base-promoted reaction of phenol with CO2 works very nicely at 125 degrees C and 100 atm. pressure. Do these conditions qualify as "feasible" and "take place without difficulty" when performed in a student laboratory in the absence of an autoclave?
Okay then shall we change the rules to "something that can only be done in a student lab"?
Actually for feasibility I'm thinking more towards the lines of anything that can be done in a synthesis lab (not a student lab), where there's more equipment. So reactions that may require high temperature and pressure are acceptable unless it really require some special piece of equipment that only exist one copy in the world or something. And non-feasible stuff are also like making buckyballs through flash vacuum pyrolysis (something like http://www.synarchive.com/syn/100) where the yield is like 0.1%.
Back to the initial problem I've actually come up with something that only require 3 steps, but meanwhile we shall wait for the rest to come up with more interesting stuff :)
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Well, there are shorter routes for the synthesis of phenol, but they involove organometallic catalysis and not classic "old" reactions.
For example, you can borylate the benzene by Hartwig-Miyaura reaction and then make hydrolysis with hydrogen peroxide and water to get the phenol.
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Wow dude, I realy like this :) (we can take turns in who propose the next exercise)
anyway my attempt
(https://www.chemicalforums.com/proxy.php?request=http%3A%2F%2Fi.imgur.com%2FM6XMPKm.png&hash=400ab72a00fd8d5c680ee78cdb2444d360545b6a)
btw I realy like that fulerene syntesis, that last step.. :-D
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Wow dude, I realy like this :) (we can take turns in who propose the next exercise)
anyway my attempt
Wow glad you like this:) Let's make it such that the winner propose a new compound to synthesize every week!
Oh one thing: wouldn't the conditions for haloform destroy the ester? Or what base will you use such that the ester won't be destroyed? So probably need another step to reinstall the ester right?
Yay:D
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I was trying to think of a non-classical approach to mix things up a bit. Here's a route using Pd catalysis.
This may of course not qualify on the grounds that only half of the aromatic carbon in the final product is derived from benzene (the other half comes from styrene).
References:
For styrene coupling: Shi Chem. Commun., 2012, 48, 7028-7030 Link (http://pubs.rsc.org/en/content/articlelanding/2012/cc/c2cc33100d#!divAbstract)
For hydroxylation: Yu J. Am. Chem. Soc., 2009, 131, 14654–14655 Link (http://pubs.acs.org/doi/abs/10.1021/ja907198n)
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Wow dude, I realy like this :) (we can take turns in who propose the next exercise)
anyway my attempt
Wow glad you like this:) Let's make it such that the winner propose a new compound to synthesize every week!
Oh one thing: wouldn't the conditions for haloform destroy the ester? Or what base will you use such that the ester won't be destroyed? So probably need another step to reinstall the ester right?
Yay:D
Keep it up Ms. +1
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I was trying to think of a non-classical approach to mix things up a bit. Here's a route using Pd catalysis.
This may of course not qualify on the grounds that only half of the aromatic carbon in the final product is derived from benzene (the other half comes from styrene).
References:
For styrene coupling: Shi Chem. Commun., 2012, 48, 7028-7030 Link (http://pubs.rsc.org/en/content/articlelanding/2012/cc/c2cc33100d#!divAbstract)
For hydroxylation: Yu J. Am. Chem. Soc., 2009, 131, 14654–14655 Link (http://pubs.acs.org/doi/abs/10.1021/ja907198n)
Love it.
Now I can't think of a way of performing this synthesis in less than 4 steps.
One step should be to form the acetyl group.
So to use less than 4 steps, you need a rxn that allows you to transform benzene directly into phenol or benzoic acid in one step. I know plenty of them to do it in two steps, but no less
BTW, Keep this up!
Wow dude, I realy like this :) (we can take turns in who propose the next exercise)
anyway my attempt
Won't haloform aqueous basic conditions remove the acetyl group?
I love LSD synthesis, got Woodward's on the wall of my room :D
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Hm yeah there is a possibility that haloform would hydrolyze the ester (I didnt think of that when I posted it). Im thinking maybe it could be possible to use hypobromite and other base than NaOH? But it seems like a wish :-D
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you need a rxn that allows you to transform benzene directly into phenol or benzoic acid in one step. I know plenty of them to do it in two steps, but no less
There are methods to make benzoic acid from benzene in one step - transition metal catalysis with CO or CO2, but I couldn't find an example with a commercially available catalyst/ligand.
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Just don't put vitamin B12 as the next challenge >:D.
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Just don't put vitamin B12 as the next challenge >:D.
Well that would be something.. :-D
Ok well since not much happened here since last week, I take the liberty of giving another POTW, this one is more difficult (much more?):
(https://www.chemicalforums.com/proxy.php?request=http%3A%2F%2Fi.imgur.com%2FqkxAiSt.png&hash=c059c9d18e901c9d52819533fe3cba985a004f69)
Enjoy
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yes! thanks kriggy! okay we can make it such that new problem is posted every Saturday then?
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I tried though it isn't great. A lot of the steps (eg step 2) are very iffy.
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What about the stereochemistry control?
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What about the stereochemistry control?
Good point :) I forget about it. I think if you want to torture yourself a bit then go for it :)
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Sinking: I think the third reaction will not have a problem with regio because the ring spacing of the different diols make it very different in energy, and it could be done with a lewis acid possibly increasing the yield instead of H: I think Zn can be used.
The enolate with NaH will cause ~10% theoretical yield (elimination product unless in a solvent carefully chosen which stabilizes the anion making it less reactive, which is a solvent with hydrogen bond donors and low polarity.
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Hey phth, I don't think you need to start from hydrocarbons, just cheap starting materials. So your synthesis is actually a lot shorter that what you have written out here!
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I'm trying for the chiral synthesis. I dislike enolate chemistry, so I am attempting to go from a different route. This is only my first pass attempt, but as I put my retrosynthesis down to (electronic-) paper I've realized I have the disfavored regioisomer from the Diels-Alder reaction. Oops. I'm going to come back and try to improve it, but other criticism are welcome.
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(I'm here to learn)
Why do you hydrolize acetyl groups with LiOH? Any reason to choose it instead of NaOH or other option?
Great post!
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Without the Diels-Alder, I think that this is a great synthesis. +1
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I also gave it a try, but I just devised a route without really thinking about stereocontrol.
It's fun to see all these other approaches here.
I'm just not really sure about the first step..
Any thoughts?
(https://www.chemicalforums.com/proxy.php?request=http%3A%2F%2Fi59.tinypic.com%2Fdmuxyh.gif&hash=5c063a59e7840a93843f8f7d59155315ac3e0c2a)
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I'm just not really sure about the first step..
Any thoughts?
Maybe an enamine michael addition would work better?
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(I'm here to learn)
Why do you hydrolize acetyl groups with LiOH? Any reason to choose it instead of NaOH or other option?
Great post!
Thanks! Doing these types of problems is definitely the best way to learn o-chem!
As for why I chose LiOH, it was mostly because that's what I used in lab! There are many cases where the difference between Li, Na, and K will give you a change in rates or selectivity. For instance LiBH4 reduces ketones with a ten fold rate increase over NaBH4. The rational I've heard for this is that the lithium binds more strongly to the carbonyl oxygen, thus activating the ketone during the rate-limiting step, addition of the hydride. I've heard a similar argument for the hydrolysis of esters with LiOH/MeOH/H2O. Supposedly it forms a six-membered transition state to help activate the carbonyl (see picture). Take this explanation with a huge grain of salt because I can't find any paper that supports this hypothesis or the fact that LiOH does have a faster rate compared to NaOH or KOH. Maybe some of the more experienced members would know better.
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Maybe an enamine michael addition would work better?
Yes, that would definitely help. Even the correct stereochemistry can be obtained by chosing the right amine auxaliary. :)
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Here's an enantioselective route. Though the chiral Si reagent is quite expensive...
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Any thoughts?
You can probably set the first stereo-center with the right enolate, but I'm not sure about the second. Maybe if you quench the reaction with a chiral acid you can set both! I'm not sure about the desymmetrization with the witting reaction. I think that dooms you to a below a 25% yield for that reaction and then getting the product pure will be a pain.
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Hi Dan,
That seems like a nice proposal. I wonder how did you get to the Si-catalyst procedure?
I have got one question about this route though: does the Grignard reaction give a reliable yield/product here?
And by alkylating the ester you create another chiral center, so only one of the two products (si or re product) has the hydroxyl group in the right position to kick out the -OTBS-group?
I might be missing something here, so feel free to correct me!
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I think the grignard reagent adds from the less hindered side which in this case is the one you want
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Dan: I like your ideas with the alkene metathesis :). I messed up my synth should convert the acid to ketone before the double bond is dihydroxylated.
(I'm here to learn)
Why do you hydrolize acetyl groups with LiOH? Any reason to choose it instead of NaOH or other option?
Great post!
Thanks! Doing these types of problems is definitely the best way to learn o-chem!
As for why I chose LiOH, it was mostly because that's what I used in lab! There are many cases where the difference between Li, Na, and K will give you a change in rates or selectivity. For instance LiBH4 reduces ketones with a ten fold rate increase over NaBH4. The rational I've heard for this is that the lithium binds more strongly to the carbonyl oxygen, thus activating the ketone during the rate-limiting step, addition of the hydride. I've heard a similar argument for the hydrolysis of esters with LiOH/MeOH/H2O. Supposedly it forms a six-membered transition state to help activate the carbonyl (see picture). Take this explanation with a huge grain of salt because I can't find any paper that supports this hypothesis or the fact that LiOH does have a faster rate compared to NaOH or KOH. Maybe some of the more experienced members would know better.
Interestingly when 2,2,2-cryptand or a crown ether is used, the yield drops considerably; LAH reductions wont go without Li, so a logical conclusion is to substitute Li with a lewis acid and it changes the yield from good to quantitative (i.e. 100%). FeCl3, CoCl3, etc. do this with LAH; I think this is an example of the elegance in details, and how they can lead to perfection when textbook reasoning says H-+electrophile will react. Really reducing agents are not H-. Even R-Li compounds are covalently bonded to Li
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Hi Dan,
That seems like a nice proposal. I wonder how did you get to the Si-catalyst procedure?
I was aware of this kind of gamma crotylation reaction with boronates and trifluoroborates, so was googling around and found these commercially available (albeit expensive) "EZ-CrotylMix" reagents.
I have got one question about this route though: does the Grignard reaction give a reliable yield/product here?
And by alkylating the ester you create another chiral center, so only one of the two products (si or re product) has the hydroxyl group in the right position to kick out the -OTBS-group?
I might be missing something here, so feel free to correct me!
The Grignard addition should be fine. I used to do this kind of reaction with 5- and 6-membered lactones routinely in the lab.
The stereochemistry of the Grignard addition doesn't matter. The mechanism of the final step is an acid-catalysed desilylation and then acetal formation in the normal way (not an SN2 reaaction with TBSOH as the leaving group). Since the reaction proceeds via a planar oxonium, the stereochemistry of the hemiketal is inconsequential (see below).
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Ah I see, forgot that silyl-protecting groups are pretty acid-labile (because I mostly see them cleaved using F-). Thanks for explaining!
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I'm going to come back and try to improve it, but other criticism are welcome.
Could you comment on and/or give a reference for the chemoselectivity of the NaBH4/HFIP reduction? I've not seen this modification before and would be interested to read more about it.
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It's Saturday again. The winner for this week is Dan!
Could Dan kindly post a new problem? I think starting a new thread is better, so that the current discussion can go on as well.
So happy for the active participation everyone, and there's so much to learn!