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gunebakan
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[*] posted on 27-5-2010 at 15:25
Henry reaction


Hii

Hi friends !

I'm trying condensation of benzaldehyde with Nitromethane for nitro alcohol.I used Zn(OAc)2. H2O. The product not perform. I use hexane:EtOAc for TLC solvent.

Can anyone pls suggest me how to perform this reaction ?
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azo
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[*] posted on 28-5-2010 at 03:20


? Are you sugesting that you have formed the nitroalcohol and trying to reduce it with zn and acetic acid .

if not use 100ml glaciel acetic acid per mole benzaldehyde 10% ammonium acetate based on benzaldehyde this should work ok.


You might get more of a responce if you provide more clearer information,or should i say if it was not about in this case phenylethylamines or amphetamines it is not liked very mutch on this site ? I OFTEN WONDER WHY WHEN THE TOPICS WITH THE MOST POSTS AND VIEWING ARE PRECURSER CHEMICALS ALTHOUGH THE ONES IN COGNETO WILL DEFEND. THIS. THERE LIKE SHEEP IN WOLFS CLOTHING BUT I WONT MENTION NAMES THEY NO WHO THEY ARE .

JUST LOOK YOUR SELF
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[*] posted on 28-5-2010 at 03:45


Quote: Originally posted by azo  
? Are you sugesting that you have formed the nitroalcohol and trying to reduce it with zn and acetic acid .

if not use 100ml glaciel acetic acid per mole benzaldehyde 10% ammonium acetate based on benzaldehyde this should work ok.


You might get more of a responce if you provide more clearer information,or should i say if it was not about in this case phenylethylamines or amphetamines it is not liked very mutch on this site ? I OFTEN WONDER WHY WHEN THE TOPICS WITH THE MOST POSTS AND VIEWING ARE PRECURSER CHEMICALS ALTHOUGH THE ONES IN COGNETO WILL DEFEND. THIS. THERE LIKE SHEEP IN WOLFS CLOTHING BUT I WONT MENTION NAMES THEY NO WHO THEY ARE .

JUST LOOK YOUR SELF


sheep in wolfs clothing? That is one smart sheep...




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-Vogels Textbook of Practical Organic Chemistry
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azo
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[*] posted on 28-5-2010 at 03:52


sorry wolf in sheeps clothing.
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Barium
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[*] posted on 28-5-2010 at 08:42


http://www.orgsyn.org/orgsyn/prep.asp?prep=cv1p0413
Instead of adding the aqueous solution of the nitronate to hydrochloric acid, add acetic acid slowly to the aqueous solution of the nitronate while keeping the temp at 10-15 deg C. The oil that falls out is the nitroalcohol.
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gunebakan
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[*] posted on 28-5-2010 at 11:00


thanks
but I want to synthesize nitro alcohol (2-nitro-1-phenylethanol)
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Barium
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[*] posted on 28-5-2010 at 11:32


Did you read the last sentence in my previous post?

[Edited on 28-5-2010 by Barium]
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[*] posted on 28-5-2010 at 11:47


ooooooooo, sorryyyyyy
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[*] posted on 28-5-2010 at 11:58


Quote:
WHY WHEN THE TOPICS WITH THE MOST POSTS AND VIEWING ARE PRECURSER CHEMICALS


No kidding. That's because in most cases these are useful for things other than illicit drug production, and people who aren't drug chemists are frustrated by their unavailability (or by the suspicion that might fall on them if they ordered them). When you find a long thread devoted to phenyl-2-propanone, let me know.
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[*] posted on 28-5-2010 at 14:08


Quote: Originally posted by bbartlogpeople who aren't drug chemists are frustrated by their unavailability[/rquote  


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[*] posted on 28-5-2010 at 17:53


Quote: Originally posted by azo  

You might get more of a responce if you provide more clearer information,or should i say if it was not about in this case phenylethylamines or amphetamines it is not liked very mutch on this site ?


What do you mean by "this site"? There are only a few members who have problems with the discussion of certain topics. If you want to speak about cocaine, heroin or amphetamine you are free to do so loud and clear. As for the topic, there is one recent paper employing imidazole as catalyst:

EXPERIMENTAL

General Method for Henry Reaction in Aqueous Medium

A mixture of 2-nitrobenzaldehyde (1 mmol), nitromethane (3 mmol), and imidazole (0.25 mmol) was charged with 2 ml of distilled water. The heterogeneous reaction mixture was stirred at ambient temperature and monitored by thin-layer chromatography (TLC). After completion of the reaction, the product was extracted with 10 ml of diethyl ether. The organic layer was dried over anhydrous sodium sulfate and filtered. The organic filtrate was evaporated under reduced pressure and dried under vacuum to give the crude product, which is reasonably pure (> 95% purity by 1H NMR) for aromatic aldehydes. However, the residue was further purified by preparative TLC on silica gel to give the desired analytically pure products.


They try a variety of solvents (DCM, 1,4-Dioxane, Chloroform, THF, Acetonitrile, Methanol...) and get yields above 90% in all cases. See the article for more details: DOI: 10.1080/00397910802045592

Synthetic Communications, Volume 38, Issue 18 January 2008, pages 3068 - 3073




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[*] posted on 28-5-2010 at 20:47


Hmm.. "...imidazole as a mild Lewis basic catalyst..." I think these authors are confused, seeing as how they drew the nitronate as an intermediate in the reaction. I suppose catalytic aqueous base might also work based on pKa's. What do you think Sandmeyer, magic imidazole?
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[*] posted on 29-5-2010 at 08:28


Quote: Originally posted by Arrhenius  
Hmm.. "...imidazole as a mild Lewis basic catalyst..." I think these authors are confused, seeing as how they drew the nitronate as an intermediate in the reaction.


IMO that paper is a typical Indian synthetic communication :D. They have these cheesy introductions/discussions and often contain funny errors, but the practical methods have (at least in my experience) often worked as claimed (or close to) and that's all I care about. I haven't tried this one though.

Quote:
I suppose catalytic aqueous base might also work based on pKa's. What do you think Sandmeyer, magic imidazole?


There is a Chinese paper* from 2007 in which they describe the reaction carried out in water too. They use 30 mol % K2CO3 as a base together with I2 and KI [mmol ratio of aldehyde/nitromethane/I2/KI/K2CO3 being 1.0/5.0/0.3/0.3/0.3; H2O: 2 mL]. Interestingly, when no iodine is added they say that the yield of nitroalcohol drops dramatically (from 95% to 20%). If we are to trust these papers I would conclude that we can't replace cat. imidazole with cat. K2CO3 and get as high yields. I should add that I have no practical experience with nitroaldol reaction.

*Iodine Catalysis in Aqueous Medium: An Improved Reaction System for Knoevenagel and Nitroaldol Condensation.

Catalysis Letters (2007), 118, (1-2), 134-138.

Typical Procedure Condensation of p-Nitrobenzaldehyde with Nitromethane in Aqueous Media:

A solution of p-nitrobenzaldehyde (1 mmol) and nitromethane (5 mmol) was stirred at room temperature for 3 min, then an aqueous solution (2 mL) of KI (0.3 mmol), K2CO3 (0.3 mmol) and I2 (0.3 mmol) was added and the mixture stirred for 2 h at room temperature. The mixture was treated with aqueous Na2S2O3 (10%, 5 mL). Then the solution was extracted with Et2O (3 X 10 mL). The organic layer was dried and concentrated, and the crude product was purified by column chromatography on silica gel (EtOAc:petroleum ether = 2:9) to afford 190 mg (90%) of pure product 2-Nitro-1-(4-nitrophenyl)ethanol. m.p. 82�84 �C (Lit [16b].m.p. 83�85 �C);

There are literature examples of nitroaldol using bases such as alkali metal hydroxides, carbonates and alkoxides but practically most convenient procedure is IMO to just mix aldehyde, nitromethane and 10% triethylamine as base, one such example is:

Preparation of the racemic nitroaldols:[24]

A mixture of benzaldehyde (1.0 mmol), MeNO2 (2.0 mmol), and Et3N (3 drops) in ethanol (2.0 mmoL) was stirred at room temperature for 10 h. Volatiles were removed in vacuo and the residue was purification by column chromatography on silica gel with elution with ethyl acetate/petrol ether to afford the racemic nitroaldol adduct. yield of Ph-CH-OH-CH2-NO2 = 98%

Chemistry - A European Journal
Volume 13, Issue 6, Pages 1863-1871
doi: 10.1002/chem.200601220

emphasis mine...




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Arrhenius
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[*] posted on 29-5-2010 at 11:04


Quote:
There is a Chinese paper* from 2007 in which they describe the reaction carried out in water too. They use 30 mol % K2CO3 as a base together with I2 and KI

I don't have a guess on a mechanism for this rate enhancement. Do you?


Quote:
IMO to just mix aldehyde, nitromethane and 10% triethylamine as base, one such example is:

That's what I was taught. I think you can stop at the nitroalcohol if you simply don't heat it.

Given the org syn nitrostyrene prep (which I've done a couple times en route to 1-nitro-2-phenylcyclopropanes), I'm inclined to think any 'medium' base (hydroxide, tertiary amine, pyridine), especially if homogeneous, will allow for the nitro aldol without subsequent condensation. As stated by Barium:
Quote:
...add acetic acid slowly to the aqueous solution of the nitronate while keeping the temp at 10-15 deg C. The oil that falls out is the nitroalcohol.
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[*] posted on 29-5-2010 at 12:00


Quote: Originally posted by Arrhenius  

I don't have a guess on a mechanism for this rate enhancement. Do you?


Iodine can act as a Lewis acid and activate the benzaldehyde carbonyl, indeed, it is sometimes used in Mukaiyama aldol for this purpose. I do not understand why the Chinese scientists also put equimolar amount of KI (relative to I2), this means that I2 could exist in equilibrium with triiodide ion but what is the point of this?




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[*] posted on 31-5-2010 at 00:48


triethylamine

right isomer too that is if your a wolf in sheeps clothing :D

interesting sandmeyer I know they use the triiodide for aromatic iodination of phenols.




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[*] posted on 31-5-2010 at 03:10


i think you need to no this arrhenius

If acidic protons are available (i.e. when R = H), the products tend to eliminate water to give nitroalkenes. Therefore, only small amounts of base should be used if the isolation of the β-hydroxy nitro-compounds is desired.

or you do a dry media reaction with a microwave only takes several minutes for completion.
if you are a wolf in sheeps clothing

regards azo i



[Edited on 31-5-2010 by azo]
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[*] posted on 31-5-2010 at 06:30


Quote: Originally posted by azo  
If acidic protons are available (i.e. when R = H), the products tend to eliminate water to give nitroalkenes. Therefore, only small amounts of base should be used if the isolation of the β-hydroxy nitro-compounds is desired.
[Edited on 31-5-2010 by azo]


This is not true. Hydroxide is not a very good leaving group, and therefor under mild conditions (i.e. room temp or below) the reaction will not proceed to eliminate water. The amount of base only effects the reaction velocity/velocities. Notice the Org Syn prep uses an excess of hydroxide as the catalytic base, and even draws the second nitronate - the delocalized anion alpha to the nitro group - that would be ejecting hydroxide in the condensation reaction! Only upon rapid acidification are they able to protonate the hydroxyl group and eject water, a much better leaving group. As to the exact mechanism here, it may involve double protonation followed by loss of water.

Again: Org Syn - Nitrostyrene


[Edited on 31-5-2010 by Arrhenius]
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[*] posted on 3-6-2010 at 20:16


i don't think all these compounds are necessarily all as unstable as infaously claimed. Just keep in topped off bottle, low light, room temp or cool, etc...
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[*] posted on 10-8-2010 at 06:35


Finding myself a bit confused regarding the stereochemistry here, particulary in relation to 4-methylaminorex..

So (1R,2S) & (1S,2R) PPA goes to trans-4MAR, but the (1R,2R) & (1S,2S) go to the oxazolidinone.

According to this, the reaction of EtNO2 with benzaldehyde using NaOH catalyst ala Kamlet gives ~35% (1R,2S) and the other ~65% (1S,2R).. But no (1R,2R) or (1S,2S)? Therefore all of the PPA produced using Kamlet's method will afford trans-4MAR and no oxazolidinone? If this is the case then why worry about using something like TEA to maximise (1R,2S) content?


Quote:
Phenylpropanolamine can also be manufactured by the reaction of benzaldehyde with nitroethane followed by catalytic reduction of the intermediate nitro-alcohol, 2-nitro-1-phenyl-1-propanol. This process is described by Hoover et al., "Synthesis of 2-Amino-1-Phenyl-1-Propanol and Its Methylated Derivatives," J. Org. Chem., Vol. 12, pp. 506-509 (1947), and has the advantage of almost no waste generation. The process, however, has a serious disadvantage in that the nitro-alcohol intermediate, itself, is produced as an stereoisomeric mixture of (1R*,2S*)-2-nitro-1-phenyl-1-propanol and (1S*,2R*)-2-nitro-1-phenyl-1-propanol having a low fraction of the desired (1R*,2S*)-2-nitro-1-phenyl-1-propanol stereoisomer. Upon reduction, the fraction of the desired phenylpropanolamine stereoisomer, dl-norephedrine, is only about 30-35%, the remaining amount being the other stereoisomer, dl-isonorephedrine.


Quote:
Benzaldehyde (106.1 g., 1.0 mole) was agitated with sodium bisulfite (100.6 g., 1.06 mole) in 500 ml of water for 30 minutes. Separately, nitroethane (82.5 g., 1.10 mole) was dissolved, with cooling, in a solution made from 50% sodium hydroxide (90.9 g., 1.13 mole) and 155 ml of water. This mixture was added, over a period of 15 minutes, at 25°C, with vigorous agitation to the addition product of benzaldehyde and sodium bisulfite. After stirring overnight, the lower layer was discarded. HPLC analysis of the upper layer showed a conversion of 125.4 g. (69.3%) of total 2-nitro-1-phenyl-1-propanol with a (1R*,2S*)-isomer content of 43.9 g. (35.1 %).


But then, according to US Patent 5962737..

Quote:
It has been discovered that if a benzaldehyde derivative is reacted with a nitroalkane in the presence of a tertiary amine, the nitroalcohol formed is of a threo configuration rather than a mixture of threo and erythro isomers which results when sodium hydroxide is used as the catalyst.


Which is somewhat contradictory. I'm thinking the reality is actually that TEA produces a mixture of the two desired isomers, and hydroxide affords all four, but in what ratio? It is said above that ~35% is (1R,2S), but what about the rest if it's not all (1S,2R).. Anyone have some insight? Struggling to find a definitive answer.

Also curious what the stereoisometry of Akabori-PPA is, 1:1:1:1 (1R,2S): (1S,2R): (1R,2R): (1S,2S)?


Cheers.
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[*] posted on 24-7-2012 at 12:24


Does anyone know any means of inhibiting dehydratation after Henry reaction? I am currently working on a total synthesis and using Henry reaction with nitroethane I would save three bothersome steps. The aromatic aldehyde used is quite different from benzaldehydes, the product seems to be very prone to dehydratation - RCHO/EtNO2/cat. Et3N or RCHO/EtNO2/cyclohexylamine at -22*C gives nitropropene only.
I am thinking of adding some transition metal complex, titanium maybe so that the nitroalcohol formed is complexed and sterricaly protected, then I would destroy the complex in a two phase system. Something similar to soft enolization. Anyone tried such procedure?

Sorry for digging out a dinasour thread - still better than posting a new one.

[Edited on 24-7-2012 by heksogen]
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[*] posted on 24-7-2012 at 19:10


The Henry reaction is useful for so much more than amphetamines. It opens up a lot of doors from reagents readily available to the amateur.

Consider the Henry-Nef strategy. Starting from nitromethane, it is possible to synthesize a huge variety of asymmetric ketones using two sequential nitroaldol reactions. Subsequent acid hydrolysis affords the ketone product (Nef reaction: http://en.wikipedia.org/wiki/Nef_reaction ).

Anyhow, the discussion about illicit substances and their syntheses may continue.




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[*] posted on 25-7-2012 at 03:59


http://www.erowid.org/archive/rhodium/chemistry/nitroalkene....

there's enough reading material in form of references..... took me <1min with google. so get your lazy ass up! u wont get spoon fed, especially on this kinda topic.

BTW: i wouldnt try combining CH3NO2 with KOH or NaOH!

http://www.youtube.com/watch?v=r3CjogY5T0I&NR=1
http://www.youtube.com/watch?v=LdKrXH4PXqw&feature=watch_res...

nitronate salt deflagrating:
https://www.youtube.com/watch?v=iscHVlucDfI


BTW:
somethings wrong in this thread =)
some MOD, pls fix that!

[Edited on 25-7-2012 by Organicus]
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[*] posted on 25-7-2012 at 07:10



Quote:

there's enough reading material in form of references..... took me <1min with google. so get your lazy ass up! u wont get spoon fed, especially on this kinda topic. BTW: i wouldnt try combining CH3NO2 with KOH or NaOH!


I don't know how is that related to my post. If you took another <1min to read my message carefully, you'd know I'm not a drug chemist. I'm looking for a reliable way to synthesize a nitroalcohol derived from a heterocyclic aldehyde. I didn't come across any publications on in situ complexation of henry reaction products (searched via reaxys). It is more wise to ask than to do numerous experiments, maybe someone did it before. A lot can be found on assymetric henry catalysed by shibasaki, evans or trost catalysts, but nothing on simple addition of transition metal. As soon as i try such procedure I will post the results.
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