Author Topic: Question about nitrosation  (Read 46746 times)

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  • Guest
Question about nitrosation
« on: April 25, 2003, 06:12:00 PM »
In all the articles I've seen where a ketone is nitrosated to a oximoketone like e.g. propiophenone to isonitrosopropiophenone with a alkylnitrite, the alkylnitrite is always added to the reaction mixture either as a gas (methyl- and ethyl nitrite) or as a liquid (butyl- and pentyl nitrites).

I wonder if there is a known reason why the alkylnitrite isn't generated in situ in the reaction mixture? For example: to a solution of propiophenone in IPA is added a saturated solution of sodium nitrite in water followed by a dropwise addition of 50% aq H2SO4. If the water content in the reaction is to be kept to a minumum one could possibly omit the aqueous solution of sodium nitrite and use solid sodium nitrite since water is added with the acid.

This simple change would make such a procedure much easier. Does someone have good reason why this wouldn't work or give lower yields compared to the known methods?


  • Guest
« Reply #1 on: April 25, 2003, 06:53:00 PM »
That wouldn't by any chance happen to be a 4-methylpropiophenone would it? ;)  Something that crossed my mind too, but I don't know of any simple ways to reduce the oxime to the amine without affecting the ketone, or at least causing dimerisation due to heat. I'm guessing you do though, and I'm very much looking forward to seeing the results.

Anyway, as to references, the first thing that came into my mind was an old post by Assholium, now archived at

, claiming an average 65-70% yield in the articles cited. Here is the link to the Orgsyn article mentioned:

; although sodium nitrate is used, the generated methyl nitrite isn't actually used in situ, but it's a start I suppose. If I can get access to the JACS articles I'll try and post them. I'm not sure if such old documents are available online, but I did manage to retrieve a 1952 J. Org. Chem. article online a couple of days ago.


  • Guest
This proposal works
« Reply #2 on: April 25, 2003, 10:04:00 PM »
The scientific literature has several examples, one was available to Lego:

Journal of the Chemical Society, Chemical Communications,(1987), (2), 45-7


A solution of NaNO2 (35 g, 0.51 mol) in H2O (70 ml) was added dropwise (hood!) to an ice-cooled, magnetically stirred solution of N,N-diethylacetoacetamid (3b) (78.6 g, 0.5 mol) in glacial acetic acid (100 mL), over ca. 30 min. Upon standing, the product crystallized. Water (100 mL) was added, and the solids were recovered by filtration, washed with H2O, and dried. (The filtrates were discarded.) Yield: 65.3 g (70%), mp 116-118°C. The dense with chunks proved indefinitely stable at room temperature. A sample was recrystallized from aqueous ethanol for analysis, [...]

Another examples were:

NaNO2 + H2SO4
NaNO2 + HNO3
NaNO2 + HCl


  • Guest
« Reply #3 on: April 26, 2003, 08:08:00 AM »
Since the actual reagent in all nitrosations is NO+, any source of nitrite will do - the examples in the literature are multiple.

It's always been my impression that alkyl nitrites were used with a sole intent to provide anhydrous conditions of the reaction, and i have no clue if they are really important for propiophenones' nitrosation.

They aren't needed for phenols or anilines, e.g.



  • Guest
« Reply #4 on: April 26, 2003, 07:45:00 PM »
Ok, what else could I do but try it myself?

To a 500 ml roundbottom flask equipped with a magnetic stirrer, a thermometer and a addition funnel was added 250 mmol propiophenone (33,5 g), 350 mmol HCl (70 ml of a 5N HCl/IPA) and 100 ml IPA. The addition funnel was charged with a solution of 300 mmol sodium nitrite (20,7 g) dissolved in 30 ml water. The sodium nitrite solution was added dropwise during two hours while the temperature was kept at 25°C by mild cooling. Immediately when the nitrite solution was added sodium chloride started to preciptitate and the temperature rose mildly. The color of the reaction mixture changed from almost colorless to clear yellow. There was never any red fumes from NO2 visible throughout the reaction.

The reaction mixture was allowed to stir for a additional two hours after the addition was complete and was then left over night without stirring at room temp. In the morning the two phases was separated first by decantation then with the aid of a separatory funnel.

The acidic solution was slowly poured poured into 750 mmol NaOH (30 g) dissolved in 200 ml water with cooling and violent stirring. The alkaline solution was extracted with 3x50 ml toluene and the toluene discarded. The alkaline aqueous solution was cooled to 10°C and slowly added to a ice cold solution of 800 mmol HCl in 500 ml water. Isonitrosopropiophenone precipitated out immediately as white crystals and was isolated by filtration.

The still wet isonitrosopropiophenone was divided in two equal portions. One portion (A) was set aside to dry and the other portion (B) hydrolyzed in the following manner:

The wet isonitrosopropiophenone (B) was added to a solution of 400 mmol sulfuric acid (40 g) in 300 ml water and steam distilled until no more oily drops came over. This took about 2 hours. The distillate (little less than 1L) was saturated with NaCl and extracted with 2x100 ml toluene. The combined toluene extracts was dried over MgSO4 and the solvent removed by distillation.

Portion B gave 12,6 g 1-phenyl-1,2-propanedione (68% calculated from propiophenone)
Portion A is not dry yet but I'll add the yield tomorrow.

Ok what have we learned by this?
The alkyl nitrite can very well be generated in situ. Since the yield of the 1,2-diketone isn't too shabby I don't see any reason whatsoever to make any alkyl nitrite separately and add it to the reaction. Unless one wants some amyl nitrite to sniff right before orgasm  ;)

Now with 1-phenyl-1,2-propanedione in hand I will give in to my curiosity of the effects of alpha-pyrrolidinopropiophenone and 2-tert-butylamino-1-phenylpropan-1-one.


  • Guest
Further thoughts
« Reply #5 on: April 26, 2003, 10:21:00 PM »
Acetophenones and propiophenones can be oxidised to the corresponding 1,2-dicarbonyl compounds using SeO2(seriously nasty) or a nitrite. There is a example in Vogel using SeO2 in aqueous 1,4-dioxane to make phenylglyoxal from acetophenone. I've seen somewhere a method which used excess methyl nitrite in MeOH to make a acetophenone dimethylacetal which is was not isolated but hydrolysed to the phenylglyoxal immediately.

Couldn't Oxone be used to oxidise propiophenone to 1-phenyl-1,2-propanedione or a acetophenone to a phenylglyoxal? I can't see any reasons why a PTC oxidation of propiophenone/oxone/DCM/water or perhaps even propiophenoneOxone/MeOH/water without a PTC shouldn't work.

Comments, pretty please..


  • Guest
Here is another toxic method
« Reply #6 on: April 26, 2003, 11:40:00 PM »
Here is another toxic method:

Post 423929 (missing)

(Rhodium: "P1P to P2P - no go.", Newbee Forum)


  • Guest
From US Pat. 2,248,035..
« Reply #7 on: May 04, 2003, 09:53:00 PM »
..entitled "Process of Nitrosating Aromatic Alkyl Ketones", by Walter H. Hartung and Frank S. Crossley, patented July 1, 1941:

....Phenylalphaoximinoethyl ketone (alpha oximinopropiophenone or isonitrosopropiophenone) is prepared from propiophenone as follows:
Into a suitable reaction vessel, such as as a one liter three-necked flask, equipped with a dropping funnel, a mechanical stirrer and a thermometer, and immersed in a water bath are placed 67 parts (0.5 mol) of propiophenone, 43.9 parts (0.75 mol) of sodium chloride, 2.4 parts of of conc. hydrochloric acid with 60 parts (1 mol) of isopropyl alcohol.
To this reaction mixture, maintained under vigorous agitation throughout the process, ther is added in portions and in the manner hereinafter described a total of 38 parts (0.55 mol) of sodium nitrite and 64 parts (0.65 mol) of concentrated sulfuric acid. First 9.5 parts, or one quarter of the total required amount, of sodium nitrite is added and then 16 parts, or one quarter of the total required amount, of the sulfuric acid is added through a dropping funnel during a period of  about 30 minutes while the temperature of the reaction mixture is maintained below 35°C.
After the addition of the of the first quarter of sulfuric acid, 30 minutes are allowed to elapse and a second one-quarter of the total required quantity of sodium nitrite and of the sulfuric acid is added in the same manner and with the time interval previously described. Then the third one-quarter of the total required quantity of sodium nitrite and of the sulfuric acid is added in the same manner. The last one-quarter of each of those reagents is then added except that the addition of the last one-quarter of sulfuric acid is extended over a period of sixty minutes, after which the agitation of the reaction mixture is continued for about three hours.
After standing over night at room temperature, a solid mass of crystals phenyl alphaoximinoethyl ketone forms. The product, after recrystallisation from toluene melts at 113°C to 114.5°C. Yields of at least 85-95% of the end product based on propiophenone are obtained. These results indicate that the reaction proceeds so far towards completion as to leave practically no reacted propiophenone to be separated and recovered....

Looks like they combined the in situ formation of isopropyl nitrite with the in situ formation of nitrosyl chloride to boost up their yield significantly, when compared with the yields obtained from HCl, ethyl nitrite and propiophenone, which are in the range of 65-70%, if my memory serves me right.


  • Guest
Re: Isonitrosopropiophenone
« Reply #8 on: May 04, 2003, 10:00:00 PM »

Post 402025

(Rhodium: "Ye olde Benzedrine", Stimulants)


  • Guest
Nitrosation of ketones
« Reply #9 on: October 20, 2004, 12:31:00 AM »
Here is a nice method for the selective formation of either alpha-oximinoketones or 1,2-diketones from ketones, with no alkyl nitrites required:

A Practical and User-Friendly Method for the Selenium-Free One-Step Preparation of 1,2-Diketones and their Monoxime Analogs
Matthias A. Oberli, Matthias Nagel, Christophe Weymuth, Hans-Jürgen Hansena
2004 [The DOI given in the paper does not work, and the pages aren't numbered]

Treatment of alpha-methylene ketones with excess sodium nitrite and aqueous HCl in THF at reduced temperatures provides an effective tool for the preparation of a variety of 1,2-diketones. The diastereoselective synthesis of the corresponding (Z)-1,2-dione monoximes could be accomplished under similar conditions, but by using only one equivalent of nitrosating reagent.

General Procedure for the Prearation of 1,2-Diketones and 1,2-Dione Monoximes
A suspension of the starting ketone (50 mmol) and NaNO2 (10.35 g, 150 mmol) in THF (100 mL) was cooled to 0 °C. To this mixture, concd HCl (65 mL) was added in such a way that the temperature did not exceed 10 °C. In order to avoid the evolution of nitrous gases the acid was added via cannula that was immerged into the reaction mixture. After the addition the cooling bath was removed and the suspension turned dark yellow. The progress of the reaction was monitored by GC. After the starting material had vanished (0.1–12 h) the reaction mixture containing the crude 1,2-diketone was poured into a separatory funnel containing crushed ice (200 g) and Et2O (100 mL). The organic layer was separated, and the aqueous phase extracted with Et2O (3× 100 mL). The combined organic layers were washed with a sat. aq solution of NaHCO3 (100 mL) and with brine (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by filtration over a pad of silica gel (5:1) using hexane–EtOAc (50:1) as eluent. The corresponding 1,2-dione monoximes were prepared accordingly by using only 3.45 g (50 mmol) of NaNO2 and 25 mL of concd HCl. The crude product was purified either by filtration over a pad of silica gel (5:1) using hexane–EtOAc (50:1) as eluent or by crystallization from hexane–EtOAc.