A compound I wish to synthesize requires a preliminary nitration step, and I have several questions about how to best do this with my available reagents, as well as general guidelines for doing these reactions.
Regarding the nitrating reagents, red or white fuming nitric acid is not available in our laboratory, and we only have access to 70% nitric acid, as well as KNO3, NaNO3 and NH4NO3
The only literature procedure available for this compound requires the use of fuming nitric acid, and acetic anhydride as solvent. I attempted it using our 70% solution and it gave very poor results. My aromatic system is moderately deactivated with no electron donating groups, and I suspect that the water in the 70% solution is problematic here.
Using the 70% solution, I am under the impression that with concentrated H2SO4 as solvent/acid/dehydrating agent, the mixture should be strong enough to allow the reaction to take place.
1) About how many molar equivalents of HNO3 would you generally add, and about how many milliliters of concentrated H2SO4 do these reactions require per milliliter of 70% HNO3 to get adequate dehydration? Just looking for a general range.
2) When quenching the reaction, about how many milliliters of ice water do you pour the reaction mixture into per milliliter of concentrated H2SO4? Again, I'm just looking for a general range.
Additionally I've seen a number of procedures for nitration using either KNO3, NaNO3 or NH4NO3, in conjunction with Concentrated H2SO4 to produce anhydrous nitric acid in situ.
3) Which of the Nitrate salts do you prefer/which have given you the best results?
4) Most procedures I've seen with the in situ generated HNO3 are as follows:
a) premix H2SO4 with 1.1 equivalents of the nitrate salt and add this solution to the substrate in H2SO4 at 0˚C,
b) portionwise add 1.1 equiv. of the solid Nitrate salt to the substrate in H2SO4 at 0˚C
c) Slurry the substrate in CH2Cl2 with 1.1 equivalents of the Nitrate salt at 0˚C, and then dropwise add H2SO4.
If you have done one of these, which ones worked well for you?
I attempted procedure "b" with NaNO3 but it seems to dissolve very very slowly in the H2SO4 solution at 0˚C, and is still pretty slow even at ambient temperature, and it seems likely I could get a large temperature spike on larger scales if the heat of the reaction rises too quickly causing the undissolved NaNO3 to dissolve and then react, making me hesitant about using this procedure.
5) For these reactions done in a chlorinated solvent with H2SO4, Will there be any issues with the slight (0.1 equiv.) excess of HNO3 / NO2+ reacting with the solvent that I need to worry about? Or is CH2Cl2 relatively inert under these conditions?
Thanks in advance!
-RL
What about trying with Nitronium Tetrafluoroborate CAS#13826-86-3 the reagent is commercially available from Sigma-Aldrich, Alfa Aesar and Acros (shop around you might even be able to find it cheaper). There is an Organic Syntheses procedure for its use, (Organic Syntheses, Coll. Vol. 5, p.480 (1973); Vol. 47, p.56 (1967)) see links.
http://www.sigmaaldrich.com/catalog/product/aldrich/366153?lang=en®ion=US
https://www.alfa.com/en/catalog/B20167/
http://www.orgsyn.org/Content/pdfs/procedures/CV5P0480.pdf
http://www.acros.com/DesktopModules/Acros_Search_Results/Acros_Search_Results.aspx?search_type=CAS&SearchString=13826-86-3
you may need to heat the reaction if your aromatic compound has electron withdrawing groups but this must be carefully done as you have noted that the reaction is exothermic in nature and a lot of toxic gases too,,, Typically start at 0oC then raise to 50oC. Have to experiment to find the optimal temperature.
It may be easier to just see if there are other similar compounds to purchase unless your compound is highly substituted.
I think I use NaNO3 + H2SO4 before but the yield was not good either, but I didn't optimise it further.
I think both KNO3 and NaNO3 (or ammonium nitrate) plus cc. H2SO4 could be nice for you. Maybe KNO3 is the better choice, because it is less hygroscopic, than NaNO3. Eugene has right, perhaps you should let the tempereture rise a little bit, but be very careful . About ratio of HNO3/H2SO4... Typically from 1:1 to 1:2 (V/V), you should optimize.
I have had some frustrating experience with aromatic nitrations. In my case, I was nitrating 2-aminopyridine to give a mixture of 3 and 5-nitro-2-aminopyridine. Nitration first occurred on the amine and then a thermal rearrangement of the nitroamine gave the aromatic nitrated product. While nitrate salts appeared to work, they unfortunately did not improve the overall yield of the reaction. I think one of the problems is the relative insolubility of the nitrate salt in neat H2SO4 but I also think this nitrating mixture is just inconsistent in its results (i.e. variable yields).
There shouldn't be any incompatibilities with using DCM as a solvent but in my experience nitrations are generally done 'neat.' DCM will only dissolve your nitrate salts very minimally and adding a solvent will probably decrease the rate of your reaction. Also, I think acids and DCM don't mix/dissolve one another (i.e. your DCM reaction may be biphasic). I would investigate other nitrating salts that are organic soluble such as copper nitrate or iron nitrate which may give you better results. I have used copper nitrate as a nitrating source for the nitration of porphyrin derivatives and it provided ~50% yields.
The think that the nitration of pyridine and pyridine analogs require the use of the mixture of nitric acid and trifluoroacetic anhydride.
The nitration of five membred ring systems like furan, pyrrole, thiophene, imidazole, thiophene, etc.... , has usually been carried out either a mixture of nitric acid and sulfuric acid, or in some cases with the mixture of nitric acid and acetic anhydride in lower temperature (- 10 ° C).
I've done nitrations using fuming sulfuric acid (oleum) and solid sodium nitrate. Dissolving the nitrate salt first is a good idea, as you can do that at room temperature, then cool to 0ºC. The nitrating strength is a function of the water content, and you can "tune" the reagent by adding water to moderate it, or SO3 to boost it.
it is an ideal case for statistical modelling like - DoE (design of experiment). If you can do that, or you have someone who can help you, this tool will give you all the answers. I use DoE in this kind of problems and I must admit this tool is very nice !
Fuming nitric acid can be easily prepared by distillation, from the mixture of inorganic nitrate and sulfuric acid. As a convenient method of aren's nitration can try a mixture of trifluoroacetic anhydride and NH4NO3 or KNO3. Our article "Trifluoroacetyl nitrate" will soon be published in the journal "Mendeleev Communication", which was described the method of nitration of arens.
Thank you to everybody for your input! Following James' suggestion I was able to improve the yield from below 20% to ca 40%, Time permitting I will re-attempt the reaction with the trifluoroacetyl nitrate, and other nitration reagents. It seems the substrate reacts slowly with the H2SO4 as a solvent so the next experiments will aim at reducing reaction time, reducing amount of H2SO4 in the NaNO3, as well as testing DCM as solvent, and I'll post the results here within the next couple weeks.
Again, thank you very much
-RL
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