| Pages:
1
2 |
JnPS
Hazard to Self
Posts: 90
Registered: 29-7-2016
Location: PA, USA
Member Is Offline
Mood: Umpolung
|
|
The road to methyl anthranilate
I'm doing a methyl anthranilate synthesis from toluene and need o-nitrotoluene. I ran the classical mixed acid nitration and expected to get a mixture
of ortho and para products. My plan was to freeze the mixture to -15C and I heard that the para isomer would crystallize out of solution via the
chemplayer video ( https://www.youtube.com/watch?v=nBFjdf1s8fQ ) I ran a smaller scale experiment to test out my reagents (home made HNO3, hardware store toluene,
etc...)
10mL Toluene
4.5mL "conc" HNO3
5.4mL "conc" H2SO4
5.8mL of product obtained, 52.7% yield based on toluene
everything went fairly well but I didn't get any crystals precipitating out at -15C, I'm awaiting an IR spectra on my product but is it possible to
get only the one isomer through the mixed acid nitration? Could I have done something wrong and maybe I don't have nitrotoluene at all? Maybe my acids
weren't as concentrated as I thought? Any thoughts?
[Edited on 30-7-2016 by JnPS]
|
|
|
Cryolite.
Hazard to Others
Posts: 269
Registered: 28-6-2016
Location: CA
Member Is Offline
Mood: No Mood
|
|
I've done this reaction before. Try leaving the bottle of nitrotoluenes in the freezer for 24 hours. The crystals don't settle out immediately, but
you should see some on the bottom and sides of the container after a day.
As far as the product not being nitrotoluenes, what is the color like? How does it smell?
|
|
|
JnPS
Hazard to Self
Posts: 90
Registered: 29-7-2016
Location: PA, USA
Member Is Offline
Mood: Umpolung
|
|
It's a pale yellow liquid but when I did the washing steps either i mixed up which layer I drained into which beaker but I could have sworn it was the
top layer in the water washes which makes me think it's not nitrotoluene, and I don't really know how to describe the smell...especially since when I
tried to smell it I wafted a bit too much and it burned my nose. I'll try leaving it in the freezer,
As a side-note do you have any ideas of what to do with the p-nitrotoluene? I don't really have a use for it but it'd be a shame for it to just sit
and collect dust
[Edited on 30-7-2016 by JnPS]
|
|
|
Cryolite.
Hazard to Others
Posts: 269
Registered: 28-6-2016
Location: CA
Member Is Offline
Mood: No Mood
|
|
Yeah, nitrotoluenes are denser than water.... what you have is probably so contaminated with toluene that the density of the resulting mixture is less
than that of water. How long did you run the nitration for? I ran mine (on 40 ml toluene) for 30 minutes of weak stirring during addition plus an hour
of strong stirring, until the reaction had stopped generating its own heat. The reaction temperature was held at 25-30 C during this later strong
stirring phase with a cool water bath. Mixed nitrotoluenes are a pretty bright yellow color, with a smell very reminiscent of bitter almonds.
o-nitrotoluene is probably the more useful isomer (for anthranilic acid, o-toluidine, methaqualone... forget i said that last one), but the para
isomer is good for some things as well. It can be oxidized to p-nitrobenzoic acid, reduced to p-amino benzoic acid, and esterified with ethanol to
form benzocaine. It is also a good substrate for reduction to p-toluidine and a subsequent Sandmeyer reaction, forming a p-substituted toluene.
Finally, you could always nitrate it further to TNT, if you're interested in explosives. These are just some ideas off the top of my head-- there are
probably more interesting reactions you could try.
|
|
|
JnPS
Hazard to Self
Posts: 90
Registered: 29-7-2016
Location: PA, USA
Member Is Offline
Mood: Umpolung
|
|
I ran the nitration for 45 minutes after addition but I added the acids probably quicker than I should have, only over the course of 10 minutes. I
thought maybe on a 10mL scale I could be more lenient with the addition time. Although during the 45 minute period I kept my reaction mixture around
15-20C with an ice bath, is that too cold?
|
|
|
Magpie
lab constructor
Posts: 5939
Registered: 1-11-2003
Location: USA
Member Is Offline
Mood: Chemistry: the subtle science.
|
|
Recommendations:
1.ut[forum]se
2. follow a published procedure 
http://www.sciencemadness.org/talk/viewthread.php?tid=29111
The single most important condition for a successful synthesis is good mixing - Nicodem
|
|
|
JnPS
Hazard to Self
Posts: 90
Registered: 29-7-2016
Location: PA, USA
Member Is Offline
Mood: Umpolung
|
|
Thank you! I'm assuming I can scale your procedure down as long as I keep the molar ratios the same right?
|
|
|
Magpie
lab constructor
Posts: 5939
Registered: 1-11-2003
Location: USA
Member Is Offline
Mood: Chemistry: the subtle science.
|
|
That should work.
The single most important condition for a successful synthesis is good mixing - Nicodem
|
|
|
chemplayer...
Hazard to Others
Posts: 191
Registered: 25-4-2016
Location: Away from the secret island
Member Is Offline
Mood: No Mood
|
|
It's actually a deceptively tricky reaction to perform and it took us quite a lot of tries and failures before we got it right. Our main suggestions:
1. Add the mixed acid dropwise to the well stirred toluene.
2. The reaction is exothermic - you're going to need a lot of ice to cool.
3. Go slowly - it's boring but be patient.
4. Stir for a long time after all the acid is added.
5. If the temperature starts to rise again once the final mixture is removed from the cool bath, then it's not over yet!
6. Wash and dry the product properly and carefully.
7. Any toluene still present will totally inhibit crystallisation of isomers and hence separation.
8. You'll need to freeze the dry product for a good 48 hours to get a first good yield of crystals.
9. Use a chilled vacuum filter sinter as the p-isomer crystals are somewhat soluble in the liquid o-isomer. Keep the temp low.
10. Crystallise again by freezing and do this 3-4 times to get a highly enriched (but not totally pure) o-isomer.
The p-isomer is actually more interesting in some respects - you can use it to make benzocaine!
|
|
|
JnPS
Hazard to Self
Posts: 90
Registered: 29-7-2016
Location: PA, USA
Member Is Offline
Mood: Umpolung
|
|
After three tries I'm starting to think that my acids aren't as concentrated as they need to be, I'm going to fork out the cash and order the real
stuff rather than use my homemade reagents.
|
|
|
Cryolite.
Hazard to Others
Posts: 269
Registered: 28-6-2016
Location: CA
Member Is Offline
Mood: No Mood
|
|
I got away with 93% sulfuric acid and 50% nitric acid. I used extra sulfuric acid to help dry the nitric acid, but unless you have extremely weak
acids, I don't think this is the problem. Keep in mind that I did end up getting product which was denser than water, and crystals of p-nitrotoluene
did appear relatively quickly.
|
|
|
Texium
Administrator
Posts: 4516
Registered: 11-1-2014
Location: Salt Lake City
Member Is Offline
Mood: PhD candidate!
|
|
I followed Magpie's procedure last year using reagent grade chemicals at my school, and it went flawlessly. I have not tried yet using my home made
nitric acid and technical grade sulfuric acid, but I'm going to have to at some point because I left my bottle of o-nitrotoluene in the freezer at
school, and I'm never going back there, so it's lost. Hopefully it will work.
Side note: I used the p-nitrotoluene that I had to make an azo compound, 4,4'-dimethylazobenzene. I can't remember the exact procedure, but I think I
found it on OrgSyn. It involved rexluxing a mixture of p-nitrotoluene, zinc granules, and sodium hydroxide in methanol for a couple of hours. After
filtering, evaporating down the mixture, extracting with DCM and evaporating it down again, I got a tiny amount of a reddish orange compound.
|
|
|
JnPS
Hazard to Self
Posts: 90
Registered: 29-7-2016
Location: PA, USA
Member Is Offline
Mood: Umpolung
|
|
I know my sulfuric acid is somewhere around 95%, I don't have the available hardware to do an accurate titration, but the density was 1.83g/mL if
memory serves, the problem is my nitric acid. I didn't measure the density but it must be only around 30-40% or lower since after the failed
nitrations I tried doing the simple HNO3+copper -> Cu2+ since its a visual test and I didn't get any noticeable reaction until a good minute or
two.
In hindsight I should have double checked the nitric acid before using it, but I wanted to get the methyl anthranilate ASAP while I still had access
to an IR but now that someone here may be offering NMR services I have the time to be patient.
|
|
|
Cryolite.
Hazard to Others
Posts: 269
Registered: 28-6-2016
Location: CA
Member Is Offline
Mood: No Mood
|
|
Can you take a density of the nitric acid? There are tables to correlate density and temperature to concentration online.
|
|
|
JnPS
Hazard to Self
Posts: 90
Registered: 29-7-2016
Location: PA, USA
Member Is Offline
Mood: Umpolung
|
|
I would, but my third run of the nitration I tried doing it to the scale in Magpie's procedure and I got a better colored product (density is still
way too low so not good enough to get any good NTs) and that combined with the bit I used for the copper test used up the rest of the HNO3 I had on
hand, I only ever keep like 100mL on hand at any time in case my dad knocks something over in my lab. I should probably just get a small safe to keep
my hazardous stuff in.
|
|
|
JnPS
Hazard to Self
Posts: 90
Registered: 29-7-2016
Location: PA, USA
Member Is Offline
Mood: Umpolung
|
|
I finally have a viable sample of fairly pure o-nitrotoluene for use in my methyl anthranilate synthesis. It probably still has some p-NT dissolved in
it but I got out as much as I can through freezing and filtering out the crystals. I may use the p-NT in the future for the suggested benzocaine
synthesis.
However I would like to lay out my synthetic scheme to methyl anthranilate here so I can get some feedback from you guys on whether you think its
viable or if I should adjust it.
Toluene -> o-nitrotoluene -> o-nitrobenzoic acid (via chromic acid) -> Anthranilic
acid via Sn/HCl reduction
Then before I do the Fischer Esterification I want to protect the amine group from being protonated during the esterification using M.E.K. to form an
imine. Run the fischer esterification with methanol, and then hydrolyze the imine back to the amine to be left with methyl anthranilate.
Any thoughts on this scheme to get the desired ester?
|
|
|
Metacelsus
International Hazard
Posts: 2531
Registered: 26-12-2012
Location: Boston, MA
Member Is Offline
Mood: Double, double, toil and trouble
|
|
Starting from phthalimide would be easier.
Also, I don't see why protection of the amino group is necessary (why would protonation hinder the esterification?), but if you really care, you could
esterify the carboxylic acid before reducing the nitro group. In any case, an imine is not a good protecting group under these conditions.
|
|
|
byko3y
National Hazard
Posts: 721
Registered: 16-3-2015
Member Is Offline
Mood: dooM
|
|
o-xylene --(chromic acid) --> phthalic acid ---(ammonia)--->phthalimide --->anthranilic acid.
Anyway, o-nitrotoluene is a viable source, if you have the o-nitrotoluene. Otherwise preparing o-nitrotoluene is a pain in the a.
|
|
|
JnPS
Hazard to Self
Posts: 90
Registered: 29-7-2016
Location: PA, USA
Member Is Offline
Mood: Umpolung
|
|
My organic professor thought that if I reduced the nitro group after esterifying the carboxylic acid the HCl might hydrolyze the ester, he's the one
that suggested protecting the amino group, but if the amino group won't be affected by the esterification then I won't bother.
|
|
|
byko3y
National Hazard
Posts: 721
Registered: 16-3-2015
Member Is Offline
Mood: dooM
|
|
HCl will surely hydrolyze the ester. You don't need to protect amino group if you are using acid-catalized esterification (Fischer).
|
|
|
DJF90
International Hazard
Posts: 2266
Registered: 15-12-2007
Location: At the bench
Member Is Offline
Mood: No Mood
|
|
You don't need to use Sn/HCl for the reduction step. From o-nitrobenzoic acid, form the ester and do the subsequent reduction with Pd/C under hydrogen
balloon or use Fe/FeCl3 depending on what you have available and your practical ability. Neither of these methods will risk hydrolysis of the ester.
EtOH will work as a solvent for both reactions (I've used both methods previously using a 5-nitrosalicylate ester)
|
|
|
byko3y
National Hazard
Posts: 721
Registered: 16-3-2015
Member Is Offline
Mood: dooM
|
|
Any links to Fe/FeCl3 route? The only procedure I know is preformed using ultrasonic agitation of Fe+AcOH+EtOH+H2O Aryl Nitro Reduction with Iron Powder or Stannous Chloride under Ultrasonic Irradiation
No iron chloride though, because FeCl3 with lead to HCl production in a protic solvent and will be reduced into FeCl2 by iron. FeCl2 is nonacidic
though.
|
|
|
CuReUS
National Hazard
Posts: 928
Registered: 9-9-2014
Member Is Offline
Mood: No Mood
|
|
Quote: Originally posted by JnPS  | | My organic professor thought that if I reduced the nitro group after esterifying the carboxylic acid the HCl might hydrolyze the ester
|
I have always had this doubt.Can HCl hydrolyse the ester even if there is no water in the reaction mixture (i.e if the water fomed during the
reduction step was continuously removed using a dean-stark trap) ? Don't you need H2O for hydrolysis ?
and if the reduction was run in methanol,there won't be a problem of trans esterification
Actually forming the ester before reducing the nitro compound is better since the electron withdrawing effect of the nitro group facilitates the ester
formation
the reduction can be done easily with sodium dithionite https://youtu.be/1PXmg2OZDmI?t=729
[Edited on 19-8-2016 by CuReUS]
|
|
|
DJF90
International Hazard
Posts: 2266
Registered: 15-12-2007
Location: At the bench
Member Is Offline
Mood: No Mood
|
|
This was the method I used:
http://cssp.chemspider.com/Article.aspx?id=261
Apologies for the omission of acetic acid as a component in my earlier description. I suspect that FeCl2 is the actual reductant in this method
(formed in situ from Fe and FeCl3). Acetic acid is there as a mild proton source (nitro reduction requires 6H+ and 6 e-) and can probably be
substituted out if needed. High yielding with the substrate I was dealing with, but as the author mentions it is a bit messy. Later settled for H2 and
Pd/C as it was spot to spot and only required filtration to remove catalyst and concentration in vacuo to afford the pure product.
|
|
|
byko3y
National Hazard
Posts: 721
Registered: 16-3-2015
Member Is Offline
Mood: dooM
|
|
FeCl3 might be there just to activate the iron. I was unable to find any other rationalization in the internet. FeCl2 forms even if you add NaCl into
mixture.
|
|
|
| Pages:
1
2 |
![[*]](images/xpblue/default_icon.gif){kind=icon}
