Chemical Forums
Chemistry Forums for Students => Organic Chemistry Forum => Organic Chemistry Forum for Graduate Students and Professionals => Topic started by: Babcock_Hall on December 10, 2024, 11:06:28 AM
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In a month or so, we will be using fuming nitric acid for the first time. We will nitrate a derivative of thiophene on a small scale (50-100 mg?) based on a similar reaction in the literature. If it goes well, we will scale the reaction up to 250-500 mg. We will use oven-dried glassware and a nitrogen atmosphere.
(1) Is there anything special in handling this reagent?
(2) After we open the reagent container, how should we store it? I was thinking of using a small desiccator with some calcium sulfate (Drierite), to minimize its picking up water.
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I have used it, there is nothing to it except good ventilation and gloves. It's not a problem with moisture.
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One problem I now see is that the authors used 98%, not 90%, fuming nitric acid. ThermoScientific has discontinued it. I can only find one supplier (Honeywell), and the price is very high. The quantity is also much more than I need. I don't suppose that anyone has a suggestion for a supplier.
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Interesting. Thiophene is very reactive, so 90 % is maybe enough? 98% is the "red" version. I don't remember which one I used. Sigma has 99,5%:
https://www.sigmaaldrich.com/SE/en/product/vetec/v001092?utm_source=bing&utm_medium=cpc&utm_campaign=all+product_dsa_WW_%28bing+ebizpfs%29&utm_id=626946489&utm_content=1166583023365595&msclkid=e3ea5b7c185d1f72401c3ccfe71111c4&utm_term=%2Fproduct%2F
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doi:10.1016/j.dyepig.2007.09.006
Thank you, although they may have discontinued this compound in my region. Two other possibilities are to make my own, by distilling nitric acid from magnesium nitrate, or to find a different protocol altogether. A more experienced synthetic person than I am suggested the latter approach. The compound we are trying to nitrate is a thiophene derivative with one aldehyde and two alkoxyl groups, and we had been planning to follow a protocol for a similar compound (45-50% yield). The electron-donating ability of the alkoxyl groups suggested to my colleague that nitration will be relatively facile.
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Yes, its probably OK, the aldehyde is of course deactivating. I found this, they use acetic anhydride instead of sulphuric acid. It's interesting that they get the dinitro also, this shows how activated the thiophene ring is.
https://orgsyn.org/demo.aspx?prep=CV2P0466&utm_source=chatgpt.com
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At your suggestion I found that reference yesterday. My understanding is that acetyl nitrate is the species that is reacting with the substrate.
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At your suggestion I found that reference yesterday. My understanding is that acetyl nitrate is the species that is reacting with the substrate.
My mistake. A colleague of mine suggested looking at old Organic Syntheses preparations.
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GPT4o gave me the reference, it seems this improved GPT is much more useful than the old one.
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https://www.handymath.com/cgi-bin/nitrictble2.cgi?submit=Entry
The Organic Syntheses prep indicates that the fuming nitric acid they used had a specific gravity of 1.51. I have found various densities for both 90% and 98% nitric acid, and I am not sure which value is correct.* Just now I found a table on line. At 25° C, 70% has a density of 1.406; 90% has a density of 1.483, and 98% has a density of 1.501. Therefore, I am not sure whether this protocol is for 90% or 98% nitric acid, but l lean toward the hypothesis that the author used 98%.
*A ThermoFisher web page gives the density of 90% nitric acid as 1.5110, which is questionable. At a FisherSci web page there is 90% nitric acid from Thermo Scientific and the density is given as 1.41, which is very questionable.
By the way, there is also uncertainty regarding the names of the various concentrations of nitric acid. One source indicated that red fuming nitric acid is 98% and white fuming nitric acid is 90%, but I do not think that everyone adheres to this convention. For example Sigma Aldrich has a product "nitric acid, red fuming" that they list as >90%, but it is unclear what the exact percentage is.
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This is from my CASC concentration calculator, but I am not entirely sure where I got this density table from. Most likely either Polish CRC Handbook-like collection of tables, or Knovel International Tables (which were both based on some earlier data, published elsewhere, from what I remember sometimes their densities were identical, sometimes not).
These are for 20°C
90.00 1.4826
91.00 1.4850
92.00 1.4873
93.00 1.4892
94.00 1.4912
95.00 1.4932
96.00 1.4952
97.00 1.4974
98.00 1.5008
99.00 1.5056
100.00 1.5129
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https://www.handymath.com/cgi-bin/nitrictble2.cgi?submit=Entry
The Organic Syntheses prep indicates that the fuming nitric acid they used had a specific gravity of 1.51. I have found various densities for both 90% and 98% nitric acid, and I am not sure which value is correct.* Just now I found a table on line. At 25° C, 70% has a density of 1.406; 90% has a density of 1.483, and 98% has a density of 1.501. Therefore, I am not sure whether this protocol is for 90% or 98% nitric acid, but l lean toward the hypothesis that the author used 98%.
*A ThermoFisher web page gives the density of 90% nitric acid as 1.5110, which is questionable. At a FisherSci web page there is 90% nitric acid from Thermo Scientific and the density is given as 1.41, which is very questionable.
By the way, there is also uncertainty regarding the names of the various concentrations of nitric acid. One source indicated that red fuming nitric acid is 98% and white fuming nitric acid is 90%, but I do not think that everyone adheres to this convention. For example Sigma Aldrich has a product "nitric acid, red fuming" that they list as >90%, but it is unclear what the exact percentage is.
Here is a nice chance to write a classic paper! Sort out all this question marks by making all these concentrations and measure density and observe color. A bit dangerous, but it could get a lot of reads and citations. It could end up with that It's not very important for nitration what concentration you use if you try their reactivity on a model molecule.
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Probably worth trying the 90% before screwing around to try to make the 98% yourself. Both are nasty stuff, even in small amounts they spit out NOx smoke in surprising amounts just from being exposed to the air. It lives up to the name "fuming nitric acid" I assure you.
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We have been putting this off in order to pursue some other syntheses, but it is time to move forward. One of my colleagues uses 90%, and he gave us a protocol recently. That is a good starting point for us to develop conditions.
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I used neat TFA with sodium nitrate to nitrate a thiophene before. Yields were... OK. I think I used 1.5 equiv of sodium nitrate. Might be worth a shot. I heated it to like 50 degrees I think. This was years ago so I do not remember the exact conditions.
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We have been trying some test reactions using previously obtained protocols (one from the 1930s), and the preliminary H-1 results from the first protocol is very promising. Today I found the two papers below, which use TFA and a metal-ion salt of nitrate or nitrite. We are looking for references to other TFA-based methods, just in case our first methods fail.
https://pubs.rsc.org/en/content/articlepdf/1978/p1/p19780001076
S Uemura et al., J Chem Soc Perkin I 1076-1079 1978.
https://jcsp.org.pk/ArticleUpload/1368-6161-1-RV.pdf
Munawar and Khalid 2004
From the first reference: "A typical procedure is given. To a stirred solution of toluene (0.184 g, 2 mmol) in trifluoroacetic acid (15 ml) was added solid sodium nitrite (0.414g, 6 mmol) in one portion a t 25 "C. The resulted dark brown mixture was stirred for 8 h at 25 "C during which period the mixture turned orange, water (100 ml) was added, and the solution was extracted with benzene (3 x 50 ml)...Reactions with sodium nitrate were carried out similarly." The substrates in the second reference were haloaromatics, and the conditions were 90 °C. I don't think that their substrates are similar to ours, and I doubt that I would try this method as is.
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Nice! You can do a lot of chemistry with thiophenes that is not possible with benzenes. If you lithiate thiophene you can alkylate it with alkyl iodides, you dont need to make a cuprate like you need with phenyl lithiums for example.
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The thiophenes we have tested so far have modest antimicrobial activity. Our second small-scale nitration using slightly different conditions also went well. We will combine them to test our purification conditions and to work out any bugs. We also have a medium-scale nitration reaction waiting in the wings once the first column is completed.