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Organic Chemistry: Mechanism
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File: methylphenidate.png (19 KB, 545x300) Image search: [iqdb] [SauceNao] [Google]
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Here is one step of a possible synthesis of methylphenidate.

I get it that tert-butoxide removes a proton from piperidine, alpha to the nitrogen.

Then the carbanion hits the tosylhydrazone, a pair of electrons shift from the C=N to a N=N double bond, but then...

Does the tosyl moiety leave? 'Cause tosylate is a good leaving group, but the tosyl doesn't look like one. What else could happen?

>Also feel free to recycle this thread into a general orgo question thread once we're done with this particular question.
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>>7799815
maybe the conj. base of tosylhydrazide is the leaving group
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>>7799856
>conj. base of tosylhydrazide
That's a dianion, right?
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File: mephe.png (15 KB, 401x328) Image search: [iqdb] [SauceNao] [Google]
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Same question in picture form.
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>>7799890
where the fuck do those two electrons come from again, anon?

thats a fully bonded sp3 carbon, it doesnt have any fucking extra electrons.
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>>7799894
Potassium tert-butoxide (tBuOK) is a base. It strips the relatively acidic proton from the piperidine ring.
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>>7799890
Also, assuming you typod and those are from the N, you are going to attack the ketone group and go from there.
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>>7799899
>strips the acidic proton
>two electrons
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>>7799903
>>7799904
Are you even chemists?
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>>7799862
>That's a dianion, right?
no, tosylhydrazide is just another name for tosyl hydrazine
>>
a) The tosylhydrazone is converted to the alpha-diazoamide.
b) The diazo group decomposes to N2 and the alpha-oxo-carbene. Thermally, this is why it is refluxing toluene.
c) The carbene undergoes C-H insertion to form the 4-membered ring.

Procedure here.
http://pubs.acs.org/doi/suppl/10.1021/jo982214t/suppl_file/jo982214t_s.pdf
>>
Freshman in university, potentially majoring in chemistry.

Do you guys find it fulfilling? What do you do on a day to day basis?
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>>7800260
>a) The tosylhydrazone is converted to the alpha-diazoamide.
What becomes of the tosyl moiety?

>>7800389
Orgofag here.

>Do you guys find it fulfilling?
I find it intellectually rewarding, with few technical skills that you can greatly improve with practice.
The many frustrations in the lab make any success particularly enjoyable.

>What do you do on a day to day basis?
I am jobless. Organic chemistry's halcyon days are over. Pick something else (analytical, material science)?
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>>7801658
tosylsulfinate (and the initial N-H ends up as t-BuOH)
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>>7799815
Havent started my degree in Chemistry yet but fuck this looks complicated
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>>7801700
Makes sense. Thanks!
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>>7799903
>>7799904
Premeds pls go
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>>7801658
>Organic chemistry's halcyon days are over.
so as someone who's studying molbio and is exceedingly interested in chemistry or even switching to something more chem-y, I should look for something else?
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>>7799904
w e w
e
w

>>7801828
if you're in it for the money, then probably
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>>7799890
this is beyond retarded do you honestly think kotbu could pull off one of those?

>>7799815

Did whoever gave you that problem specify that the stereochemistry is absolute?

Are you sure they shouldn't be "squiggly lines"?
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>>7800389
I'm a syn org dude in drug design

you will not find a job

don't do it. I'm not kidding. look for a blog called chemjobber and wait for your hopes to be crushed.

If you are a phd, dont put it on your resume. nobody hires above bs these days
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>>7801828
>I should look for something else?
Definitely. I know this is hard if you're passionate about chemistry, because this isn't one of those field you can keep as a hobbie (unless you're happy with pen-and-paper synths, or live in a country that doesn't prohibit owning glassware and chemicals).

>>7803652
>do you honestly think kotbu could pull off one of those?
Reaction happens. Whether or not you saw it coming. Propose a different mechanism, if you like.

>Did whoever gave you that problem specify that the stereochemistry is absolute?
Axten JM, Krim L, Kung HF, Winkler JD (1998). "A Stereoselective Synthesis of dl-threo-Methylphenidate: Preparation and Biological Evaluation of Novel Analogues". The Journal of Organic Chemistry 63 (26): 9628–9629. doi:10.1021/jo982214t.
via https://en.wikipedia.org/wiki/Methylphenidate#Physical_and_chemical_properties

I don't care about the stereochemistry for now, only what happens when a tosylate get kicked in the teeth.

>>7803654
>syn org dude in drug design
CRO?
>>
Since P and N are in the same group, are there phosphorus analogues of amides? As in R-CO-PR2.
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>>7803917
Yes, but considering things like atomic raduis, bond energies, electronegativity and that delicious access to d orbitals, comparing the two is mostly trivial.
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>>7800389
I originally majored in chemistry because i loved it, but i switched to food science in tech. If youre good in ANY chem field, food sci will be a walk in the and you will be way more valuable to the food industry than someone who can just operate an extruder
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>>7799890
it's probably more likely that you deprotonate the amine on the hydrazone to a nitrogen nitrogen double bond with the negative accumulating on the carbon alpha to the carbonyl, this then picks up a proton from the tert butoxide forming an sp3 centre

the nitrogen group leaves leaving a positive sp3 centre which is very electrophilic and attracts the nucleophilic carbon alpha to the nitrogen
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>>7803901
Is it possible to find employment, perhaps, in Europe? This is assuming you are all Americans, which admittedly is a bad assumption.
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>>7804268
What are they called?

>>7804476
Deprotonation of hydrazone: probable. But why would the electron pair stay on the benzylic position when it can run around the phenyl ring or sit on the oxygen?
If the sp3 center forms, will there be enough incentive for the diazo to break the molecule apart into sulfinate, nitrogen and a benzylic cation? Not sure.
And I don't understand where you think you're going with that last step...

>>7804626
>Is it possible to find employment, perhaps, in Europe?
As much as in the US, I'm afraid. So many chem jobs –R&D included– have been outsourced to Asia! If you're feeling lucky, try Germany, Switzerland or the UK. Maybe France and Ireland.
Don't pretend you don't have a PhD if you do (else you'll get fired the moment they know), and don't expect to be hired to a position you're overqualified for.
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>>7804737
Most hetero atoms are named with an -ane suffix, for their hydrogen bound species. Phosphane, silane, borane etc.
>>
Only one person in this thread posted the right answer, and almost everyone ignored it.
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>>7803901
>Reaction happens. Whether or not you saw it coming. Propose a different mechanism, if you like.

it would be really slow; kotbu sucks in this respect.

I would propose n buli
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>>7805159
tert-butoxide is good enough for this, but that guy has the mechanism all wrong. Look up the Bamford-Stevens reaction.
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>>7805169
no dude, tbutoxide is fine as the anion, but you need a stronger cation. Litium vs potassium is a big difference to grab the alpha off of a cyhex with any selectivity at all.

i won't argue that kotbu would work, but it would be a shitshow.
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>>7805175
I'm not sure we're on the same page here. You're not deprotonating on any carbon, you're deprotonating at the nitrogen. Any strong enough non-nucleophilic base would be fine.
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>>7805190
I have no idea why on earth anyone would use kotbu instead of buli in this case. It seems like it would just increase rxn time, complicate the quench, and disallow other potassium reagents during workup.
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>>7805191
Because not everyone likes working with a glove box.
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>>7805191
Not to mention using BuLi would lead to another reaction occurring if the substrate had any alpha protons to the tosylhydrazone.
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>>7801811
>English higher than biochemistry
Oh dear
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>>7799856
Diazo it is.
>The originally yellow solution turned bright orange as the diazo compound is formed.
>http://pubs.acs.org/doi/suppl/10.1021/jo982214t/suppl_file/jo982214t_s.pdf

>>7805140
You mean this guy?
>>7805169
>Look up the Bamford-Stevens reaction
Interesting. This concurs with >>7800260's explanation. Last step 'c' is not obvious to me, but that's sensible.

>>7805159
>>7805175
>>7805213
https://en.wikipedia.org/wiki/Shapiro_reaction
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>>7806381
Ayy, both of those were me. I posted the first one before I spotted this >>7800260, which correctly pointed out the formation of the carbene followed by C-H insertion. C-H insertion is indeed a very common reaction for carbenes. I'm not sure why the reaction ends up giving that diastereomer, but I suspect it's due to the geometry of the carbene itself that forces it to be that way. I did some drawing and it does seem to be so.
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