Helional

[baffler]

So I believe I remember there being a patent on the hoffman stating like up to 6 or so carbons in a molecule had been tested, like you think this would work with 11?? Sounds pretty kick ass and OTC and all, so I may get my imaginary friend to give this a whirl this summer. Do work

[Aperson444]

I'd be interested to see that patent. I think it should work. The Hofmann does not seem to be too dependent on chain length, though free movement of electrons is a must for the rearrangement steps to occur. Otherwise yields will be horseshit.

EDIT: this paper is quoted a lot by some friends of mine: "The Hofmann Rearrangement Using Household Bleach: Synthesis of 3-Nitroaniline" (J. Chem. Educ., 1999, 76 (12), p 1717)

They use 5.25% bleach and 1 M NaOH.

Also, see "J. Org. Chem., 1958, 23 (12), pp 2029–2032". They state that the yields for Hofmann on longer carbon chains drop off due to side reactions of some sort.

[baffler]

Originally Posted by Aperson444

I'd be interested to see that patent.

http://www.google.com/patents/US7205440 and http://www.google.com/patents/US5410082 but actually this states that up to 10 C (alkyl) has been tested, and also aryl/heteroaryl works well so I don't doubt ya

Originally Posted by Aperson444

EDIT: this paper is quoted a lot by some friends of mine: "The Hofmann Rearrangement Using Household Bleach: Synthesis of 3-Nitroaniline" (J. Chem. Educ., 1999, 76 (12), p 1717)

They use 5.25% bleach and 1 M NaOH.

Bitchin. So have they tried this hydroxylamine then Beckman then Hoffman to MDA with helional??

Originally Posted by Aperson444

Also, see "J. Org. Chem., 1958, 23 (12), pp 2029–2032". They state that the yields for Hofmann on longer carbon chains drop off due to side reactions of some sort.

And with more research it seems wiki (http://en.wikipedia.org/wiki/Oxime) it states the same--biurets and cyanate polymers... Says also solvation of the substrate, careful temperature control can decrease these.

[Stasis]

Originally Posted by Aperson444

Also, see "J. Org. Chem., 1958, 23 (12), pp 2029–2032". They state that the yields for Hofmann on longer carbon chains drop off due to side reactions of some sort.

Interestingly, "When the amide is not derived from a simple fatty acid, the limitations are somewhat different, numerous phenethylamines being satisfactorily obtained from the corresponding hydrocinnamic amides."

Mmm, phenethylamines... So what they effectively say in the paper is that the side-reactions observed for fatty-acid amide derivatives (i.e. chain length shortening and aminoimide formation) do not occur for molecules with a phenethylamine backbone. The limitation they are referring to is one of solubility.

[Aperson444]

Bitchin. So have they tried this hydroxylamine then Beckman then Hoffman to MDA with helional??

I've only read one success story -- I'm sure you've read it as well. It was that guy on the Tor network. I think he was also on Psychonaut. He went oxime --> amide using nickel acetate, then from amide to amine using bleach. Overall yield was kind of shitty (I calculated around 25%), but I think that was an error of a) the amide forming step and b) sloppy Hofmann rearrangement. The product itself was reported to be quite good. Saw it on the Silk Road, looked pretty legit.

http://www.google.com/patents/US7205440 and http://www.google.com/patents/US5410082 but actually this states that up to 10 C (alkyl) has been tested, and also aryl/heteroaryl works well so I don't doubt ya

Interesting patents. I wish NaOBr was more OTC, or at least more concentrated bleach (+30%). The reason I picked a TCCA method was because you needed a very small volume of moderately pure TCCA to complete the reaction... But TCCA has serious solubility issues. I might just tell my mystical friend that the hypohalide method is for the better.

And with more research it seems wiki (http://en.wikipedia.org/wiki/Oxime) it states the same--biurets and cyanate polymers... Says also solvation of the substrate, careful temperature control can decrease these.

That's why my mystical friend has stressed the need for a one-pot aldehyde to amide. He suggested a no-solvent reaction whereby the aldehyde is heated with NH2OH and a weak base, perhaps sodium acetate or carbonate and a small amount of a metal salt. While the conditions are unsafe for an oxime, the time that the molecule of aldehyde exists as an oxime is shortened. It is almost immediately converted to the amide upon formation. There are a few metal salts that can catalyze this reaction to the amide. The most promising are zinc and copper salts (both in the +2 oxidation state). This works especially well if the aldehyde is a liquid. In the case of helional, any amide should crystallize out of the substrate. Obviously, recrystallization would be necessary to isolate the amide and leave behind unreacted aldehyde and nasty metal salts.

For the Hofmann, I've advised my mystical friend to ensure the product is as clean as possible. If this is true, it should react quite nicely with the halogenating agent (hypohalide, halogen or other agent) to form the N-haloamide. The beauty with TCCA is that TCCA will form a very cloudy, nasty solution (might actually end up a slightly cloudy suspension), but when the chloramide forms, it should clear up nicely, signalling the necessary temperature hike to encourage rearrangement to the amine.

[Stasis]

Here is the paper from Tetrahedron on aldehyde --> amide if anyone is interested:

http://www.4shared.com/office/kl5GYblh/1-s20-S0040403912000536-main.html

[baffler]

Originally Posted by Aperson444

I've only read one success story -- I'm sure you've read it as well. It was that guy on the Tor network. I think he was also on Psychonaut. He went oxime --> amide using nickel acetate, then from amide to amine using bleach. Overall yield was kind of shitty (I calculated around 25%), but I think that was an error of a) the amide forming step and b) sloppy Hofmann rearrangement. The product itself was reported to be quite good. Saw it on the Silk Road, looked pretty legit.

Aight, I think I either read this a while back or am experiencing some interesting De ja vu trippy sorta memory lapse shit... Anyhow, I checked this out and yeh, I bet this could be cleaned up a fair bit. Haha essentially all he did well was the oxime formation, but the Beckman and then Hoffman could be bettered.

Originally Posted by Aperson444

Interesting patents. I wish NaOBr was more OTC, or at least more concentrated bleach (+30%). The reason I picked a TCCA method was because you needed a very small volume of moderately pure TCCA to complete the reaction... But TCCA has serious solubility issues. I might just tell my mystical friend that the hypohalide method is for the better.

I mean calcium hypochlorite is readily available, but that's not an alkali metal salt that I've seen these typically called for... will look into it.

Originally Posted by Aperson444

That's why my mystical friend has stressed the need for a one-pot aldehyde to amide. He suggested a no-solvent reaction whereby the aldehyde is heated with NH2OH and a weak base, perhaps sodium acetate or carbonate and a small amount of a metal salt. While the conditions are unsafe for an oxime, the time that the molecule of aldehyde exists as an oxime is shortened. It is almost immediately converted to the amide upon formation. There are a few metal salts that can catalyze this reaction to the amide. The most promising are zinc and copper salts (both in the +2 oxidation state). This works especially well if the aldehyde is a liquid. In the case of helional, any amide should crystallize out of the substrate. Obviously, recrystallization would be necessary to isolate the amide and leave behind unreacted aldehyde and nasty metal salts.

I think you misunderstood my poorly written citing/post (maw bad). I was actually talking about the biproducts that form during the Hofmann (not the Beckman or the oxime formation) that were cited (for whatever fucking reason) in that wiki article about oximes. This is interesting though and I'll look into specs for oxime creation/Beckman one-pot. Also, yes about the amide isolation, but what's important also is that an acid/base workup on MDA is performed (thus leaving behind the organic shit that ain't amine) for purification.

Originally Posted by Aperson444

For the Hofmann, I've advised my mystical friend to ensure the product is as clean as possible. If this is true, it should react quite nicely with the halogenating agent (hypohalide, halogen or other agent) to form the N-haloamide. The beauty with TCCA is that TCCA will form a very cloudy, nasty solution (might actually end up a slightly cloudy suspension), but when the chloramide forms, it should clear up nicely, signalling the necessary temperature hike to encourage rearrangement to the amine.

Originally Posted by Stasis

Interestingly, "When the amide is not derived from a simple fatty acid, the limitations are somewhat different, numerous phenethylamines being satisfactorily obtained from the corresponding hydrocinnamic amides."

Mmm, phenethylamines... So what they effectively say in the paper is that the side-reactions observed for fatty-acid amide derivatives (i.e. chain length shortening and aminoimide formation) do not occur for molecules with a phenethylamine backbone. The limitation they are referring to is one of solubility.

So yes, a clean substrate and good dissolution is key (pesky dissolution). This is a good find and pretty specific to our substrate (seeing as the amide we're talking about is basically alpha-methylhydrocinnamic amide with the ether bridge instead of two methoxy/ethoxy functions). Oh and it says to make sure the solution of NaOH/NaOCl is cold to aid the "smoothness" of the halogenoamide formation (hypochlorite is said to be better that hypobromite btw and much better than the original Br2 way). Also, stirring is good, and external heating after commencement of the reaction might be bad (these specs are at least applicable to aliphatic amides).

btw there's some talk on SM about forming the haloamide in methanol with TCCA then dripping that into an alkaline soln. In addition there was talk about even forming the haloamide (TCCA) and isolation before rearrangement... Any thoughts anyone?? I can look up some of the SM threads if you want

[Aperson444]

Aight, I think I either read this a while back or am experiencing some interesting De ja vu trippy sorta memory lapse shit... Anyhow, I checked this out and yeh, I bet this could be cleaned up a fair bit. Haha essentially all he did well was the oxime formation, but the Beckman and then Hoffman could be bettered.

The guy's technique was a little sloppy towards the end, especially with the Hofmann. I am starting to think that bleach might actually be a viable halogenating agent after all. The problem with TCCA is its solubility issues, which are a major pain in the ass. The only thing I don't like about bleach is that it is only found in rather dilute solutions. I prefer concentrated reagents myself. Maybe 10% NaOCl.

I mean calcium hypochlorite is readily available, but that's not an alkali metal salt that I've seen these typically called for... will look into it.

I read a paper (it was like chemistry education something I think... it's on scribd) about acetamide to methylamine hydrochloride using CaOCl2, but the yields were not very good. The reaction wasn't really designed for high yields; it was supposed to be a demonstration for O-Chem students. However the case my be different with the helional amide. Who knows?

I think you misunderstood my poorly written citing/post (maw bad). I was actually talking about the biproducts that form during the Hofmann (not the Beckman or the oxime formation) that were cited (for whatever fucking reason) in that wiki article about oximes. This is interesting though and I'll look into specs for oxime creation/Beckman one-pot. Also, yes about the amide isolation, but what's important also is that an acid/base workup on MDA is performed (thus leaving behind the organic shit that ain't amine) for purification.

Stasis has the right journal article for the copper sulfate + aldehyde + NH2OH + NaOAc to amide. The reason the amide should be washed is more because there may be side-reactions during the Hofmann due to impurities in the amide. Could just be paranoid thinking, but hey, there's nothing like freshly isolated amides.

Also, stirring is good, and external heating after commencement of the reaction might be bad (these specs are at least applicable to aliphatic amides).

Huh, I had read that you needed to raise the temp. to ~70oC after the N-haloamide formed in order to provide the required energy for the rearrangement step to the isocyanate. Are you talking about the halogenation step? I had a dream once that a friend told me to maintain 0oC for some time until the solution finished changing (qualitatively) then to jack the temperature up to around 70-80oC, probably in an oil bath or pre-prepared water bath to make the temperature increase more rapidly.

btw there's some talk on SM about forming the haloamide in methanol with TCCA then dripping that into an alkaline soln. In addition there was talk about even forming the haloamide (TCCA) and isolation before rearrangement...

I'd avoid methanol. I've read somewhere that it isolates an intermediate (Yes, Wikipedia, but there was a Journal of Organic Chemistry note that used TCCA/MeOH to isolate some isocyanate in order to make a carboxylate... yes very vague, I have to retrieve the actual article and read it. I did not really understand very much from the abstract). NEED MOAR ACS ACCESS

[BungHole]

Originally Posted by Aperson444

The guy's technique was a little sloppy towards the end, especially with the Hofmann. I am starting to think that bleach might actually be a viable halogenating agent after all. The problem with TCCA is its solubility issues, which are a major pain in the ass. The only thing I don't like about bleach is that it is only found in rather dilute solutions. I prefer concentrated reagents myself. Maybe 10% NaOCl.



I read a paper (it was like chemistry education something I think... it's on scribd) about acetamide to methylamine hydrochloride using CaOCl2, but the yields were not very good. The reaction wasn't really designed for high yields; it was supposed to be a demonstration for O-Chem students. However the case my be different with the helional amide. Who knows?



Stasis has the right journal article for the copper sulfate + aldehyde + NH2OH + NaOAc to amide. The reason the amide should be washed is more because there may be side-reactions during the Hofmann due to impurities in the amide. Could just be paranoid thinking, but hey, there's nothing like freshly isolated amides.



Huh, I had read that you needed to raise the temp. to ~70oC after the N-haloamide formed in order to provide the required energy for the rearrangement step to the isocyanate. Are you talking about the halogenation step? I had a dream once that a friend told me to maintain 0oC for some time until the solution finished changing (qualitatively) then to jack the temperature up to around 70-80oC, probably in an oil bath or pre-prepared water bath to make the temperature increase more rapidly.



I'd avoid methanol. I've read somewhere that it isolates an intermediate (Yes, Wikipedia, but there was a Journal of Organic Chemistry note that used TCCA/MeOH to isolate some isocyanate in order to make a carboxylate... yes very vague, I have to retrieve the actual article and read it. I did not really understand very much from the abstract). NEED MOAR ACS ACCESS

It should be only like 642 ml of 10 % w/w hypochlorite solution for a 1 mole scale reaction. That's quite a bit of volume, but not that bad. Besides, dilution probably limits side reactions. For instance, the formation of biurets by nucleophilic addition to the isocyanate intermediate with the amine product. First order reaction, it's rate will drop by half when diluted to twice the original volume. Hydrolysis will be kinetically favored by dilution. The only issue would be halogenation of the amine, which seems to be rapid enough to be proceed at a considerable rate under dilute conditions anyway.

[Aperson444]

It should be only like 642 ml of 10 % w/w hypochlorite solution for a 1 mole scale reaction. That's quite a bit of volume, but not that bad. Besides, dilution probably limits side reactions. For instance, the formation of biurets by nucleophilic addition to the isocyanate intermediate with the amine product. First order reaction, it's rate will drop by half when diluted to twice the original volume. Hydrolysis will be kinetically favored by dilution. The only issue would be halogenation of the amine, which seems to be rapid enough to be proceed at a considerable rate under dilute conditions anyway.

Damn good reassurance, man! I'm wondering how yields can be optimized for the Hofmann. Do you know where I could get more info on the kinetics of this particular reaction? Also, my mystical friend only has the proper labware for <500 ml volume reactions and does not want to invest in larger glassware right away. However, I assume only ~200 ml of 10% (excess bleach) should be fine. My friend is also worried that with larger volumes the separation of the amine (in the organic layer) would be difficult. Would decantation of said layer into say a small sep funnel work as well?

[BungHole]

Originally Posted by Aperson444

Damn good reassurance, man! I'm wondering how yields can be optimized for the Hofmann. Do you know where I could get more info on the kinetics of this particular reaction? Also, my mystical friend only has the proper labware for <500 ml volume reactions and does not want to invest in larger glassware right away. However, I assume only ~200 ml of 10% (excess bleach) should be fine. My friend is also worried that with larger volumes the separation of the amine (in the organic layer) would be difficult. Would decantation of said layer into say a small sep funnel work as well?

This document is pretty informative, although there really isn't that much on the kinetics.http://www.sciencemadness.org/librar...actions_v3.pdf Go to page 267 for the Hofmann. Lot's of info on the use of methanol to isolate the carbomate though, as you previously mentioned.

I'm still not sure exactly how the reaction proceeds as far as product formation. Seems that it darkens as the amide is halogenated, then lightens as the isocyanate/carboxylate intermediate forms, and an organic layer should be present upon completion of the reaction. If you really can't hold that much in the glassware, scale down. Having more liquid than can fit in a sep. funnel is a major pain.

I think a good work up would be; once the reaction is considered complete, acidify to pH ~4, wash with halogenated organic solvent (eg. chloroform), add charcoal and heat until just when it begins to boil, filter, bring pH up to ~11, extract with ether, and isolate whichever form from there.

[Aperson444]

This document is pretty informative, although there really isn't that much on the kinetics

Quite interesting actually. Seems that the reaction really sucks up hydroxide (almost every step from formation of the unstable N-haloamide to the hydrolysis of the isocyanate involves some OH-). After reading that, I suppose the Hofmann looks less daunting than I thought. I think that TCCA should be a secondary halogenating agent if NaOCl gives poor yields.

I think a good work up would be; once the reaction is considered complete, acidify to pH ~4, wash with halogenated organic solvent (eg. chloroform), add charcoal and heat until just when it begins to boil, filter, bring pH up to ~11, extract with ether, and isolate whichever form from there.

Is the pH reduction in order to neutralize the leftover NaOH and protonate the amine such that it dissolves in the aq. layer? This serves the purpose of purifying the amine, right? If the organic layer forms by itself, couldn't it be washed with a nonpolar then transferred to a new vessel with fresh water (acidified to a low pH)?

[BungHole]

Originally Posted by Aperson444

Is the pH reduction in order to neutralize the leftover NaOH and protonate the amine such that it dissolves in the aq. layer? This serves the purpose of purifying the amine, right? If the organic layer forms by itself, couldn't it be washed with a nonpolar then transferred to a new vessel with fresh water (acidified to a low pH)?

Two reasons:

Yes, the acidic pH allows the amine to dissolve in the water, allowing the solution to be washed with a nonpolar and filtered over charcoal. I might have seen the step in a Hofmann rearrangement procedure. I'll have to check.

For the most part though, it was based on the speculation that acidic conditions will favor hydrolysis of urea/biuret byproducts to the corresponding amine(ammonium, technically) and carbamic acid.

This inference is based on a 1941 paper discussing the influence of pH on the kinetics of urea hydrolysis, which shows that urea is hydrolyzed to ammonia and carbon dioxide via an equilibrium reaction from urea to ammonium and cyanate ions. Protonation of the cyanate anion to isocyanic acid and it's subsequent hydrolysis pushes the equilibrium of the prior reaction away from urea. Hence, the rate at which ureas and biurets without carbon substitutions are hydrolyzed is enhanced by acids.

In the case of the organic isocyanate, there is no cyanate anion to form isocyanic acid. But, increase in pH does increase the extent to which the nucleophilic freebase amine forms the non-nucleophilic primary ammonium cation. This pushes equilibrium away from the substituted urea toward amine and isocyanate/carbamic acid. Hydrolysis of isocyanate and subsequent decarboxylation of the carbamic acid formed should proceed rapidly as it does in previous steps. Hence, some byproduct is retroactively converted to desired product. A desperate attempt at increasing yield. I figured organic reagents are more valuable than inorganic, sacrifice your mineral acids and alkali hydroxides first.

The problem is that unlike the hydrolysis of unsubstituted urea, the reaction would not depend on elimination of ammonium from urea, but the primary amine. I don't really have much of an understanding of this topic, hence, this whole argument is unfounded and my time would be better spent directly studying hydrolysis of N-substituted ureas. I will not do this now though, as I've spent more than enough time on this post. Oh well, atleast I had fun.

[baffler]

Originally Posted by Aperson444

The only thing I don't like about bleach is that it is only found in rather dilute solutions. I prefer concentrated reagents myself. Maybe 10% NaOCl.

Originally Posted by BungHole

It should be only like 642 ml of 10 % w/w hypochlorite solution for a 1 mole scale reaction. That's quite a bit of volume, but not that bad. Besides, dilution probably limits side reactions. For instance, the formation of biurets by nucleophilic addition to the isocyanate intermediate with the amine product. First order reaction, it's rate will drop by half when diluted to twice the original volume. Hydrolysis will be kinetically favored by dilution. The only issue would be halogenation of the amine, which seems to be rapid enough to be proceed at a considerable rate under dilute conditions anyway.

Ya, like I remember making DMDO with a quasi-elaborate setup w/cold finger and dropping funnel, distillation setup etc with a 4 L 3-neck and shit the yield was like 20-30 mL 0.08 M DMDO from ~ half pound of oxone... This is gonna be alright haha. Plus, may increase yields as BungHole has deduced and in addition, wouldnt it be kick ass to get a procedure that you could just go down to the closest HEB or whatever and buy some fucking bleach without having to alter it or anythin??

Originally Posted by Aperson444

Stasis has the right journal article for the copper sulfate + aldehyde + NH2OH + NaOAc to amide. The reason the amide should be washed is more because there may be side-reactions during the Hofmann due to impurities in the amide. Could just be paranoid thinking

Yes, your paranoia is well-founded!! It is known that impurities in the amide can lead to poor yields in the Hoffman.

Originally Posted by Aperson444

but hey, there's nothing like freshly isolated amides.

My thoughts, precisely

Originally Posted by Aperson444

I'd avoid methanol. I've read somewhere that it isolates an intermediate (Yes, Wikipedia, but there was a Journal of Organic Chemistry note that used TCCA/MeOH to isolate some isocyanate in order to make a carboxylate

Ya actually I looked at http://www.sciencemadness.org/talk/v....php?tid=16010 and realized that Ephoton always had trouble rearranging the haloamide in MeOH/H2O mix and distilling off MeOH after formation to afford the haloamide pure is a bad idea (explosive perhaps). Probably you can't very well Hofmann it up in the mixture of MeOH+H2O because like you sorta mentioned, the isocyanate will be somewhat extracted so that not only are you getting less (or no) product but you also could get trimerization to the biuret...

Originally Posted by Aperson444

However, I assume only ~200 ml of 10% (excess bleach) should be fine.

I don't know, I mean that sounds like quite a bit of excess--I'm betting just 100 mL excess will do the trick. Less excess means less amine halogenation, though maybe very slightly less amide halogenation. There's a balance, but I'd say 100 mL or even less is bueno. Mostly because of what I read on erowid (will post below)

Originally Posted by BungHole

This document is pretty informative, although there really isn't that much on the kinetics.http://www.sciencemadness.org/librar...actions_v3.pdf Go to page 267 for the Hofmann. Lot's of info on the use of methanol to isolate the carbomate though, as you previously mentioned.

I'm still not sure exactly how the reaction proceeds as far as product formation. Seems that it darkens as the amide is halogenated, then lightens as the isocyanate/carboxylate intermediate forms, and an organic layer should be present upon completion of the reaction. If you really can't hold that much in the glassware, scale down. Having more liquid than can fit in a sep. funnel is a major pain.

I think a good work up would be; once the reaction is considered complete, acidify to pH ~4, wash with halogenated organic solvent (eg. chloroform), add charcoal and heat until just when it begins to boil, filter, bring pH up to ~11, extract with ether, and isolate whichever form from there.

Originally Posted by BungHole

Yes, the acidic pH allows the amine to dissolve in the water, allowing the solution to be washed with a nonpolar and filtered over charcoal. I might have seen the step in a Hofmann rearrangement procedure. I'll have to check.

For the most part though, it was based on the speculation that acidic conditions will favor hydrolysis of urea/biuret byproducts to the corresponding amine(ammonium, technically) and carbamic acid.

This inference is based on a 1941 paper discussing the influence of pH on the kinetics of urea hydrolysis, which shows that urea is hydrolyzed to ammonia and carbon dioxide via an equilibrium reaction from urea to ammonium and cyanate ions. Protonation of the cyanate anion to isocyanic acid and it's subsequent hydrolysis pushes the equilibrium of the prior reaction away from urea. Hence, the rate at which ureas and biurets without carbon substitutions are hydrolyzed is enhanced by acids.

In the case of the organic isocyanate, there is no cyanate anion to form isocyanic acid. But, increase in pH does increase the extent to which the nucleophilic freebase amine forms the non-nucleophilic primary ammonium cation. This pushes equilibrium away from the substituted urea toward amine and isocyanate/carbamic acid. Hydrolysis of isocyanate and subsequent decarboxylation of the carbamic acid formed should proceed rapidly as it does in previous steps. Hence, some byproduct is retroactively converted to desired product. A desperate attempt at increasing yield. I figured organic reagents are more valuable than inorganic, sacrifice your mineral acids and alkali hydroxides first.

The problem is that unlike the hydrolysis of unsubstituted urea, the reaction would not depend on elimination of ammonium from urea, but the primary amine. I don't really have much of an understanding of this topic, hence, this whole argument is unfounded and my time would be better spent directly studying hydrolysis of N-substituted ureas. I will not do this now though, as I've spent more than enough time on this post. Oh well, atleast I had fun.

Thanks for the input!! It's excellent to have a bit of qualitative data and kinetics and theory info and we're happy to have you contribute

Also, I should mention that there's a synth--in case ya'll haven't seen it--using the traditional Hofmann (i.e. Br2 which is not hard to make, but is hard to store) that is on erowid with a 75% yield of the amine (PMA in this case), not shabby!!:

" 2-Amino-1-(4-methoxyphenyl)-propane (II)
To a stirred solution of sodium hypobromite [Br2 (4.6 mL, 0.09 mol), NaOH (18.72 g, 0.48 mol) in 150 mL water] was added a finely divided amide 5 (15 g, 0.078 mol) at 0°C during 10 min. The reaction mixture was heated to 70°C for 2 h. The progress of the reaction was monitored by TLC (BuOH:EtOH:NH3, 7:2.6:0.3 mL). After completion of the reaction, the reaction mixture was extracted into CH2Cl2 (75 mL). Organic layer was separated, washed with water (2×75 mL), dried (Na2SO4) and concentrated to obtain the title compound II as a syrup (9.6 g, 75%) that exhibited comparable 1H-NMR spectrum with that reported in literature4f,11a. For the purpose of characterisation II was also converted to the corresponding hydrochloride11b [10.5g, 65%, mp 208–210°C (lit.4a 208°C)] by treating with 5% HCl in MeOH."

from http://www.erowid.org/archive/rhodiu...a.hwe-rxn.html

Note that they use "finely divided" which probably aids dissolution, the main problem associated with decreased yields for that method.

Also, taking a closer look at the 1958 paper reviewing the limitations of the Hofmann I realized it states that as long as the amide is dissolved well before the temperature reaches 40 C (at which temp the hypohalite decomposes) then it's all good to raise the temp like to 70 C as you mentioned. Dilution seems to be implied as a good idea also to prevent side reactions with larger molecules. Also, adding amide to the solution is important to reduce or eliminate the halogen+amine being present at the same time.

Also to note: the slight excess (.09 mol Br2 with .078 mol amide)

EDIT: Also, the erowid site has links to interesting articles; from http://www.erowid.org/archive/rhodiu...alkylation.pdf :

"Preparation of 1 -p-methoxyphenyl-f?-propanone oxime. An alcoholic solution containing
1-p-methoxyphenyl-2-propanone (21 g., 0.1 28 mole) was mixed wi t h a n aqueous solution
containing hydroxylammonium chloride (2,l g., 0.30 mole). After adding sufficient sodium
hydroxide (20y0 solution) t o render t h e mixture j u s t basic, i t was refluxed five minutes, pre-
cipitated b y adding water a n d cooling. T h e oxime (20 g., yield 870j0) was a mixture of s y n -
and a n t i - isomers, m.p. 56-61'."

[Aperson444]

Ya, like I remember making DMDO with a quasi-elaborate setup w/cold finger and dropping funnel, distillation setup etc with a 4 L 3-neck and shit the yield was like 20-30 mL 0.08 M DMDO from ~ half pound of oxone...

Damn, I'm thankful that my friend avoided the DMDO method. Was gonna oxidize the aldehyde to the COOH then form the amide.

I don't know, I mean that sounds like quite a bit of excess--I'm betting just 100 mL excess will do the trick. Less excess means less amine halogenation, though maybe very slightly less amide halogenation. There's a balance, but I'd say 100 mL or even less is bueno. Mostly because of what I read on erowid (will post below)

Yep, I re-read Bunghole's reference and found that they call for only slight excess of the halogenating agent.

Also, taking a closer look at the 1958 paper reviewing the limitations of the Hofmann I realized it states that as long as the amide is dissolved well before the temperature reaches 40 C (at which temp the hypohalite decomposes)

Yep. I suppose one could dissolve the amide in the NaOH/NaOCl solution and wait a few minutes at 0-10oC then proceed to jack up the temperature as fast as possible the result should be fine.

I should mention that the amide-->amine Hofmann of the very amide we speak of is mentioned here: http://www.erowid.org/archive/rhodiu....dalcason.html

There's no info on the actual reaction, but there's some very nice references down at the end. Not sure if those will help a whole lot, bit literature is literature (the scheme I speak of is Scheme no. 9).

Yes, the acidic pH allows the amine to dissolve in the water, allowing the solution to be washed with a nonpolar and filtered over charcoal. I might have seen the step in a Hofmann rearrangement procedure. I'll have to check.

For the most part though, it was based on the speculation that acidic conditions will favor hydrolysis of urea/biuret byproducts to the corresponding amine(ammonium, technically) and carbamic acid.

Ah, that's good thinking. All this talk of ureas, carbamates and biurets has got me worried a bit. So basically you want to acidify --> heat --> wash --> filter --> basify --> isolate amine? Sounds like a good way to flush out the nasty shit anyways.

[baffler]

Originally Posted by Aperson444

Damn, I'm thankful that my friend avoided the DMDO method. Was gonna oxidize the aldehyde to the COOH then form the amide.

Oh hell ya. I think this method will give better results anyways from what I've been reading. Unless you happen to have gotten you some thionyl chloride:-P

Originally Posted by Aperson444

Yep, I re-read Bunghole's reference and found that they call for only slight excess of the halogenating agent.

Originally Posted by Aperson444

I suppose one could dissolve the amide in the NaOH/NaOCl solution and wait a few minutes at 0-10oC then proceed to jack up the temperature as fast as possible the result should be fine.

Yeah I think this is a good idea.

Originally Posted by Aperson444

I should mention that the amide-->amine Hofmann of the very amide we speak of is mentioned here: http://www.erowid.org/archive/rhodiu....dalcason.html

There's no info on the actual reaction, but there's some very nice references down at the end. Not sure if those will help a whole lot, bit literature is literature (the scheme I speak of is Scheme no. 9).

Am checking this and other shit now...

Originally Posted by Aperson444

Ah, that's good thinking. All this talk of ureas, carbamates and biurets has got me worried a bit. So basically you want to acidify --> heat --> wash --> filter --> basify --> isolate amine? Sounds like a good way to flush out the nasty shit anyways.

Absolutely, A/B all the way

Aw dude and I just edited my post so you should check that.

Also EXACT REACTION:

in which it states that the pure amide of interest (alpha-methyl-3,4-methylenedioxypropanamide) forms white flakes when crystallized with benzene. Melting point 120 C -- It's so nice to have data on this!!

When the Hofmann was performed (meh only 40% yield for them... after two distillations though) there was used 1.1 mol hypochlorite to 1 mol substrate. Now they say that they use dioxane as the solvent (actually cosolvent) which might have pulled yields up from totally shitty for them due to its help in preventing the intermediates from extracting each other.

EDIT: BTW that was from
"3-Methyl-3,4-dihydroisoquinolines and 3-Methyl-1,2,3,4-tetrahydroisoquinolines" by Walter S. Ide, Johannes S. Buck
J. Am. Chem. Soc., 1940, 62 (2), pp 425–428
DOI: 10.1021/ja01859a050
Publication Date: February 1940

and this procedure was followed for helionamide as well as B-(3,4-Dimethoxyphenyl)-isopropylamine: The Hofmann reaction on the corresponding amide was carried
out as usual, with 1.1 mol of sodium hypochlorite. The
amide may be added dissolved in dioxane. After two
distillations the amine forms a colorless, refractile liquid,
with a sweet, musty odor.

That's all that was given on that paper, essentially

[Aperson444]

When the Hofmann was performed (meh only 40% yield for them... after two distillations though) there was used 1.1 mol hypochlorite to 1 mol substrate. Now they say that they use dioxane as the solvent (actually cosolvent) which might have pulled yields up from totally shitty for them due to its help in preventing the intermediates from extracting each other.

Fuck, 40% is pretty damn low. I gotta check out the full article once I get back to a place I can access from.... Hopefully BungHole's proposal and the omission of distillation will bring the yield back up. It's also possible that the dioxane actually contributed to lower yields... Possibly by isolating some intermediates from the reaction mixture (methanol is often used to isolate the isocyanate intermediate, I believe, dioxane has different properties, but might serve a similar purpose). That low yield really does worry me. Hopefully my mystical friend will receive some aldehyde in order to do small scale reactions.

[baffler]

Here is my accumulation of data!!!

Okay so I've been looking around and the oxime is greenish-white (prolly white when pure) apparently while the amide is typically white (as described above).

So an MDA synth is in:
" 1-Pyridylisoquinolines
D. H. Hey and J. M. Williams
J. Chem. Soc., 1951, 1527-1532
DOI: 10.1039/JR9510001527 "
There is a procedure: A cold solution of alkaline sodium hypochlorite was prepared by absorbing chlorine ( 5 . 5 g.) in a solution of sodium hydroxide (20 g.) in water (50 c.c.) and crushed ice (100 g.). To this mechanically stirred solution was added the above powdered crude amide (25.5 g.). After 10 minutes the temperature was slowly raised t o 50 C and a solution of potassium hydroxide (36 g.) in water (200 c.c.) was slowly added. When all the amide had dissolved the mixture was again heated to 70 C and kept a t 70-80 C for half an hour, during which an oil commenced to separate from the solution.
The mixture was cooled and extracted with benzene. After removal of benzene from the dried (K2CO3) extract, the residue was distilled under reduced pressure to give 1-3' : 4'-methylenedioxyphenyl-2-propylamine [[[i.e MDA!!]]] (9.5 g . ; b. p. 149-150 C/14 mm.).

Yields were about the same ~40% for this MDA synth though they do start from a crude product (they make the amide from acyl chloride then ammonia and just rotovap the ether off and grind into powder). This yield could be improved I believe by cleaning up the amide, chemically like we talked about (who knows what leftover acyl halides and whatnot could do to the Hofmann...).



Also, from http://www.erowid.org/archive/rhodiu...myristicin.pdf
A very similar compound was made (with quite a bit of excess NaOH+a little extra Cl2; aka a little extra bleach and a fuckload more lye). Now they didn't specify what amount of this "solution" they used... so idk about that. But damn:

3-Methoxy-4,5-methylenedioxyphenethylamine Hydrochloride.--The finely powdered amide (12.5 g . ) was added with stirring to an aqueous solution containing 1.1 moles of chlorine and 6 moles of sodium hydroxide. The mixture was heated to 70 C over a period of thirty minutes and kept at this temperature for an additional thirty minutes. Eighty milliliters of potassium hydroxide was added and the temperature was kept at 80 C for one hour. After cooling, the reaction mixture was extracted with ether (total of 370 ml.) and the combined extracts dried over solid potassium hydroxide.
Ten milliliters of ether was treated with alcoholic hydrogen chloride to yield 0.3 g of hydrochloride, m . p . 161-162 C with softening at 150 C. It was recrystallized twice from a mixture of ethyl alcohol, ethyl acetate, and ether, m . p . 167.2-168.1 C;

In this, the yields looked like it was 0.3 g of the hydrochloride from each 10 mL ether and there was 370 mL total so 37 aliquots of 10 mL would mean 0.3 x 37 = 11.1 g of the crude hydrochloride salt of the amine from 12.5 g of the (finely divided) amide!! Pretty damn good yield for this I'd say, although that's crude, and quite a bit excess of the reactants (hypochlorite soln) were used. You know, I bet that SUFFICIENT AGITATION would be helpful for yields (dissolution yeh).



Also, Probably not even worth mentioning but here it is anyways from http://www.erowid.org/archive/rhodiu...y/tma.hey.html

dl-1-(3,4,5-trimethoxyphenyl-2-aminopropane hydrochloride (second method)
The above amide (5.06g) was dissolved in dry methyl alcohol (100 mL) and sodium (46 g) dissolved in dry methyl alcohol (25 ml.) was added and the mixture cooled to 0?C. Bromine (3.2 g), diluted with twice its volume of dry methyl alcohol, was added all at once, with rapid stirring. A further amount of sodium 0.46g) was then added in the same way as the first and the reaction mixture heated at 60?C for two hours. The methyl alcohol was partly removed by distillation and the residue diluted with water. A brown oil separated out and slowly solidified at room temperature and which was presumably the crude urethane (VII). The solid was filtered off and boiled for eight hours with 20 percent. (constant boiling) hydrochloric acid. After cooling the reaction mixture was extracted several times with chloroform to remove non basic impurities. Basification of the residual aqueous liquid precipitated the base which was extracted and converted to the hydrochloride as in the previous preparation; mp and mixed mp with the material from reduction of the nitrostyrene, 219?C. Yield 0.81g (15% of theory).



And, just to look at and see, here is from

"Physiologically Active Phenethylamines. I. Hydroxy- and Methoxy-α-methyl-β-Phenethylamines (β-Phenylisopropylamines)"

J. Am. Chem. Soc., 1938, 60 (2), pp 465–467
DOI: 10.1021/ja01269a065
Publication Date: February 1938

alpha - Methyl - beta - methoxyphenethyamines.--The amines were prepared by dissolving 0.1 mole amide in a solution composed of 0.106 mole bromine dissolved in 4.0 moles of 10% potassium hydroxide solution cooled below 15 C. The solution was shaken until no more amide went into solution, whereupon the cold solution was filtered and the filtrate heated under reflux at 70-80 C for one and one-half hours. Sixteen grams of solid sodium hydroxide was added and the temperature kept at 80 C for two hours. The amine which separated as a brown oil, upon cooling the solution, was extracted twice with ether. The ether solution was dried quickly with anhydrous magnesium sulfate, filtered, the magnesium sulfate washed with a little ether, and after removal of the solvent distilled in vacuo. The hydrochlorides were prepared by passing dry hydrogen chloride gas into an absolute ether solution of the amine. Recrystallization was from an absolute ethyl alcohol-
ether mixture.
In a trial run using alpha-methyl-p-methoxycinnamamide
with sodium hypochlorite a much larger amount of material
failed to go into solution. Since it was thought desirable
t o have a s much material in solution as possible the use
of sodium hypochlorite was discontinued.

In this I thought it was important to note that they extracted with ether like right after cooling, then just crystallized the hydrochloride out w/ HCl (g). No extra workup necessary. Also, I copied the part regarding the more similar molecule to ours that they mentioned didn't dissolve well in hypochlorite solution... No yield was reported at all but this compound is a bit different (it's a beta-methoxyphenethylamine) so I'm not sure it would be that reliable with respect to helionamide degradation to MDA.
And I would suggest (if this method or really in any extraction) that the organic solvent--ether in this case--be used to extract three times, not two. Trust me

EDIT: btw I spent a while trying to clean up the shitty copy pasta because alot of it was weirdly spaced etc (probably cus some of these papers are so damn old). Hopefully it's readable!!

[baffler]

Originally Posted by Aperson444

Fuck, 40% is pretty damn low. I gotta check out the full article once I get back to a place I can access from.... Hopefully BungHole's proposal and the omission of distillation will bring the yield back up.

Hopefully, hopefully...

Originally Posted by Aperson444

It's also possible that the dioxane actually contributed to lower yields... Possibly by isolating some intermediates from the reaction mixture (methanol is often used to isolate the isocyanate intermediate, I believe, dioxane has different properties, but might serve a similar purpose). That low yield really does worry me. Hopefully my mystical friend will receive some aldehyde in order to do small scale reactions.

From what I read in that (now notorious) 1958 paper I keep referencing, dioxane actually should increase yields, at least for longer chain aliphatic amides in the Hofmann. Dioxane acts as a cosolvent which prevents this intermediate isolation/extraction from the solution from happening. Essentially (as the theory goes), without dioxane, a mostly nonpolar amide and its intermediates can actually extract each other and prevent each other from being in the hypochlorite solution, and thus reacting, from what I understand. Now, it doesn't seem that dioxane is always necessary for this type of thing, but I'm not sure; what I do know is experiment is king. Also, I would bet a nice OTC procedure could be discovered, without the use of this little solvent.

And yay for small scale reactions at first!!!

[Aperson444]

An imaginary friend has just informed me that he has perhaps 28 grams of a desirable aldehyde on the way as a free sample from a fragrance company (hopefully it is not a scam or something). Unfortunately, it has proven difficult to find an affordable hydroxylamine source. Hopefully he can complete the rxn and pass on some data to me for you guys. He is interested in the Cu(II) idea for amide formation that was suggested.

Also, I would bet a nice OTC procedure could be discovered, without the use of this little solvent.

I wonder if THF (not really quite so OTC, but moreso than dioxane... I suppose) or diethyl ether would work. At this point, any sort of yield booster would be great. This Hofmann rearrangement rings as sort of tricky to me, not unlike the Kochi reaction I was theorizing before for the helional-COOH. Lots of places where shit could go wrong.

[baffler]

Originally Posted by Aperson444

An imaginary friend has just informed me that he has perhaps 28 grams of a desirable aldehyde on the way as a free sample from a fragrance company (hopefully it is not a scam or something). Unfortunately, it has proven difficult to find an affordable hydroxylamine source. Hopefully he can complete the rxn and pass on some data to me for you guys. He is interested in the Cu(II) idea for amide formation that was suggested.

Noice goin

Originally Posted by Aperson444

I wonder if THF (not really quite so OTC, but moreso than dioxane... I suppose) or diethyl ether would work. At this point, any sort of yield booster would be great. This Hofmann rearrangement rings as sort of tricky to me, not unlike the Kochi reaction I was theorizing before for the helional-COOH. Lots of places where shit could go wrong.

Well they are both miscible with pure water, but THF is more polar... but Idk, I'll see if I can find out. And yeh like if that oxone article is good for makin the acid and then you did a Kochi on that to get halosafrole, then perhaps oxidize with NaIO4 if you have DMF to MDP2P (if you don't feel like sealin pipes )

Also a couple things to bring up:
Industrial bleach seams to be a little bit more concentrated so that could be a backup. I think (did in head, could be off) that there is about 3 mols so ~200 g of NaOCl in a gallon of household bleach.

Also, I've been trying to look into like a Double Baeyer Villiger for aldehydes (or just the normal but inserting the oxygen between the two carbons to make a formate) which could then be hydrolyzed to MDP2P-ol + CO2 and then oxidized to MDP2P. I just got back from a short Reunion so now I can look more...

Oh and it'd be good to read through:

Facile Oxidation of Aldehydes to Acids and Esters with Oxone
Benjamin R. Travis, Meenakshi Sivakumar, G. Olatunji Hollist, and Babak Borhan
Org. Lett., 2003, 5 (7), pp 1031–1034
DOI: 10.1021/ol0340078

(which I plan on taking a look at also now that I'm back) just for shits and giggles


Here is an interesting web archive quoted on SM for producing dioxane just from that blue car ethylene glycol shit you can buy by the gallon: http://web.archive.org/web/200710110...s/dioxane.html

Also, I wouldn't think much of it would be needed to dissolve the amide and introduce that to solution. I bet it would increase yields if there was the right amount of it in there as a cosolvent!!


EDIT: and it's worth bringing up that if you got gallons of this not-illegal-to-own substance, helional, then a 40% yield on the Hofmann--as long as the oxime forming and Beckmann rxn's go smoothly--is nothing to be particularly worried about, although I would also fancy it bein higher haha.

Aw shit!! Also, just looked up and the yield (granted it's for 2,5-dimethoxyphenyl-isopropylamine) gave a 70% yield of distilled amine when with dioxane. They note that they dissolve the amide in about 1/3 the Vol. of the hypchlorite solution of dioxane and add that to solution, probably optimizing surface area by dissolution--they note, it's good for insoluble amides in general:
Richard Baltzly and Johannes S. Buck
J. Am. Chem. Soc., 62, 161-164 (1940)

here: http://www.designer-drug.com/pte/12....h.analogs1.pdf

[baffler]

Originally Posted by Indigo

70% from the Hoffman? That seems a bit high. One should expect yields closer to half of that (unless everyone knows something that I don't), anything over 45% is high.

Few tips:

1. It is easier to get solid aldoxime by adding the base DRY. It is not necessary though because if it doesn't solidify you can just extract with Xylene and move onto the Beckman.

2. You can squeeze out another 5-10% yield from the Beckman if you use more Ni. (2.7g per 100gr of aldoxime), but it does yield a dirtier product.

3. The cleaner your amide is the better your yield will be. It is possible to get snow white amide, it is a pain in the ass though...

4. Do not try to run the Hoffman at room temp, chill everything to just above freezing and use a CaCl2 ice bath.

5. Let hypo/amide/base stir in an ice bath for 2 hours or so before bringing up to degradation temp.

6. During the Hoffman, adding your amide to your hypo solution and letting it stir for 15-20mins before addition of the base will increase yields, but I have also heard of good results the other way around (adding amide to base solution first and letting that stir before hypo is added).

7. Holding the contents of the flask at degradation temp for 15-20 minutes before allowing it to cool does help yields a bit, but be careful the temperature does not get much hotter than that or else you will end up with alot of tar.

As Distortion said, there is a shit load of information on all of this on that thread, but I am sure already know that...Do let me know if I can be of any assistance.

Hope someone finds this useful.

Sorry for the double post!! But here's a good quote from Indigo a while back that states his thoughts.

feel dumb that like reading through the previous posts I definitely found a few ideas that I brought up, that were already mentioned... oops.. i didn't mean tuh

Anyhow, the oxone method of oxidation implies the use of DMF as it seems you have already mentioned... But looking back through I did a few searches and read over and will repeat what's good and my ideas/thoughts too:

http://pubs.acs.org/doi/abs/10.1021/jo0612574 talks of mere household bleach taking aldehydes to carboxylic acids in high yields, if you're taking one of those routes. And if you are, it's worth mentioning that if you take it to the 2-halohydrosafrole (i.e. 3,4-MDP-2-halopropane) via Kochi or Hunsdiecker then I would suggest taking it to the organobromide. From there, check out: http://www.google.com/url?sa=t&rct=j...OiFciZIAYhQvZw
which (with 30% H2O2 added to EtOH) should take this to MDP2P!!

You also mentioned the brand new (2012) Tetrahedron Letters paper that concerned Copper (II) Sulfate Pentahydrate ($5/lb on ebay!!) catalyzed Beckmann. I never really commented on this so sorry for that, but now I wish to say that this looks very promising. The journal is reputable, the theory makes sense, and most o the yields are ballzgood
Optimized Reaction conditions: aldehyde (1 mmol), NH2OH.HCl (1 mmol), NaOAc (1.1 mmol), CuSO4.5H2O (5 mol %), 110 °C, under air; I would suggest for ~6 hours.

--The only thing is that they decided to purify by column (silica gel)... hrmm... Also, they state that a 66% yield was obtained with these conditions for isobutyraldehyde (and 95% for phenylacetaldehyde, a non-aromatic aldehyde) but my guess is this could be further specifically optimized for our gamma-(3,4-methylenedioxyphenyl)isobutyraldehyde, which is helional (I may have fucked that up but close enough; essentially just stating helional is just a substituted isobutyraldehyde).

So basically the only thing to worry about is separation. I am thinking distillation (fractional??) perhaps under like aspirator vacuum. I started thinking this because of: http://www.google.com/patents/US6706153
and http://www.google.com/patents/US20020005343 and also looking up the BP's of a similar but more used substrate, phenylacetaldehyde at (STP):
BP(phenylacetaldehyde) = 193 C, BP(phenylacetaldoxime) = 272 C, BP(phenylacetamide) = 312 C. This seems to be a general trend and maybe if the leftover aldoxime was hydrolyzed (catalyzed by a lil acid) then just separating aldehyde and amide would be a cinch by distillation. Now, if (as is claimed by some of the reactions in the Cu (II) cat. patent) there is virtually no aldoxime leftover because the Beckmann is so thorough then perhaps just an extraction with organic solvent and then recrystallization is in order. That'd be nice!! Or, as http://www.google.co.il/patents/US5227028 seems to mention sorta, if there happens to be aldoximes, then hydrolyze them, and 'still off the helional. Then probably recrystallize the amide in like toluene (close enough to benzene like in the refs, I would think). Just brainstormin!!

Hohooo and they state: "No demanding or solvent-intensive isolation and purification of product are involved due to almost exclusive amide formation in most cases. The key greener features combined with generality, cost effectiveness, high selectivity, and efficiency make the present protocol synthetically appealing."

And regarding amides, http://www.freepatentsonline.com/7205440.html this seems like it's worth goin though.

In addition, that I2 + H2O2 in NH3 (aq.) would be hellanice if you could get your hands on some iodine (probably recyclable) from http://ntur.lib.ntu.edu.tw/bitstream...1046/1/105.pdf

And here's this:
Hydroxylamine HCl straight from SM's http://www.sciencemadness.org/member...erivatives.pdf :

1) 61 g nitromethane was mixed with 114 g 32% hydrochloric acid in a 300 mL glass bottle (molar ratio CH3NO2:HCl:H2O 1:1:4.3). The top was screwed on the bottle and it was immersed in an oil bath heated to 100°C (Figure 2). The solution was left at this temperature for 24 hours whereby the nitromethane and acid layers formed a homogeneous solution. The solution was then transfered to a wide mouth beaker and left at the same temperature until evaporated to about 1/3 of its initial volume. On cooling the solution to -5°C hydroxylamine hydrochloride precipitated as large white flakes which were filtered and dried. Further concentration and cooling yielded further crystals for a total of 41 g (59%)

2) A similar process to that described above was used but with a molar ratio of 1:1:10. This allowed the solution to be heated in a non-pressurized vessel without significant loss of HCl. Plastic film and a rubber band was used to cover the flask containing the solution. The solution was heated for 40 hours at 100°C and concentrated and precipitated as before; the yield was 32 g (46%). When heated on a spoon the NH2OH.HCl decomposed energetically with release of white smoke but no flame.

[Aperson444]

And regarding amides, http://www.freepatentsonline.com/7205440.html this seems like it's worth goin though.

That patent is actually pretty good. Here's what I think the process should be. Basically the recrystallized amide should be stirred into some alkaline water which has been set to cool in an ice/NaCl bath. One could also do the halogen first and then the alkaline. With the halogenating agent first, one should add it dropwise such that the temp remains at around 0oC. All the amide should be dissolved in solution BEFORE this addition. The reaction should be stirred occasionally and left to sit in the cool bath for 3-4 hours. Afterwards, some bisulfite can be added to neutralize the halogenating agent. The reaction mix should then be transferred to a moderately large volume if water held at 95-100oC. It should decrease due to addition of cold water, but make sure it stays above 70oC. If need be, add the reaction mix slowly, but do not let the mixture get too hot (will destroy the N-chloramide). Let that shit sit for 4-8 hours, with careful observation of course. The patent calls for distillation, but I say that distillation is not absolutely necessary.

I think perhaps, it is necessary to allow the reaction to take its course longer. Also, it's critical to keep the temperatures in the right range.

http://pubs.acs.org/doi/abs/10.1021/jo0612574 talks of mere household bleach taking aldehydes to carboxylic acids in high yields, if you're taking one of those routes. And if you are, it's worth mentioning that if you take it to the 2-halohydrosafrole (i.e. 3,4-MDP-2-halopropane) via Kochi or Hunsdiecker then I would suggest taking it to the organobromide. From there, check out: http://www.google.com/url?sa=t&rct=j...OiFciZIAYhQvZw

A friend of mine had done that reaction on helional. It indeed does work, a white-colored precipitate formed even with a lower than 2.5 mol % of NiCl2.

The Kochi or Hunsdiecker to Halosafrole route is a bit tricky, even the original Kochi paper describes iffy yields ranging from 50-60something%.

1) 61 g nitromethane was mixed with 114 g 32% hydrochloric acid in a 300 mL glass bottle (molar ratio CH3NO2:HCl:H2O 1:1:4.3). The top was screwed on the bottle and it was immersed in an oil bath heated to 100°C (Figure 2). The solution was left at this temperature for 24 hours whereby the nitromethane and acid layers formed a homogeneous solution. The solution was then transfered to a wide mouth beaker and left at the same temperature until evaporated to about 1/3 of its initial volume. On cooling the solution to -5°C hydroxylamine hydrochloride precipitated as large white flakes which were filtered and dried. Further concentration and cooling yielded further crystals for a total of 41 g (59%)

2) A similar process to that described above was used but with a molar ratio of 1:1:10. This allowed the solution to be heated in a non-pressurized vessel without significant loss of HCl. Plastic film and a rubber band was used to cover the flask containing the solution. The solution was heated for 40 hours at 100°C and concentrated and precipitated as before; the yield was 32 g (46%). When heated on a spoon the NH2OH.HCl decomposed energetically with release of white smoke but no flame.

This reaction is really handy, but be careful, as it releases carbon monoxide, I believe.

Aw shit!! Also, just looked up and the yield (granted it's for 2,5-dimethoxyphenyl-isopropylamine) gave a 70% yield of distilled amine when with dioxane. They note that they dissolve the amide in about 1/3 the Vol. of the hypchlorite solution of dioxane and add that to solution, probably optimizing surface area by dissolution--they note, it's good for insoluble amides in general:
Richard Baltzly and Johannes S. Buck
J. Am. Chem. Soc., 62, 161-164 (1940)

Woah

I suppose then the amide could be added to the alkaline halogenation solution dissolved in dioxane or THF. I wonder if a PTC would help.

Optimized Reaction conditions: aldehyde (1 mmol), NH2OH.HCl (1 mmol), NaOAc (1.1 mmol), CuSO4.5H2O (5 mol %), 110 °C, under air; I would suggest for ~6 hours.

--The only thing is that they decided to purify by column (silica gel)... hrmm... Also, they state that a 66% yield was obtained with these conditions for isobutyraldehyde (and 95% for phenylacetaldehyde, a non-aromatic aldehyde) but my guess is this could be further specifically optimized for our gamma-(3,4-methylenedioxyphenyl)isobutyraldehyde, which is helional (I may have fucked that up but close enough; essentially just stating helional is just a substituted isobutyraldehyde).

I was thinking something like just extract the crude amide with EtOAc. There might by a very minute amount of water (formation of the oxime liberates water), but the rest of the shit is amide, salts and unreacted helional. Ethyl acetate or even toluene might pull out the goodies nicely. These can then be recrystallized to purify the amide. Repeated recrystallizations should yield the described whitish crystals.

I'm not sure how much of a problem unreacted helional would be. Helional has a rather high BP (280-285oC) compared to the 120oC (I believe?) for the amide. That really is sort of odd, considering that most aldehydes boil at relatively low temperatures. I'm no O Chemist though.

Hohooo and they state: "No demanding or solvent-intensive isolation and purification of product are involved due to almost exclusive amide formation in most cases. The key greener features combined with generality, cost effectiveness, high selectivity, and efficiency make the present protocol synthetically appealing."

There are a couple of other ones using other catalysts. I mentioned one for ZnCl2 earlier in this thread, but there's another Cu(II) one in which they use Cu(OAc)2 and reflux at 100oC for a long time. They reported 93% yields from piperonal to pperonamide. I suspect that addition of aldehyde using dioxane or THF as a solvent may help as well (since many larger aldehydes are hydrophobic).

Here's the reference for that paper: Tetrahedron 68 (2012) 3948e3951; "Copper(II) acetate-catalyzed one-pot conversion of aldehydes into primary
amides through a Beckmann-type rearrangement"

On Scribd: http://www.scribd.com/doc/96247782

[baffler]

Okay now yay for another long ass post with more copy pasta

Originally Posted by Aperson444

That patent is actually pretty good. Here's what I think the process should be. Basically the recrystallized amide should be stirred into some alkaline water which has been set to cool in an ice/NaCl bath. One could also do the halogen first and then the alkaline. With the halogenating agent first, one should add it dropwise such that the temp remains at around 0oC. All the amide should be dissolved in solution BEFORE this addition. The reaction should be stirred occasionally and left to sit in the cool bath for 3-4 hours. Afterwards, some bisulfite can be added to neutralize the halogenating agent. The reaction mix should then be transferred to a moderately large volume if water held at 95-100oC. It should decrease due to addition of cold water, but make sure it stays above 70oC. If need be, add the reaction mix slowly, but do not let the mixture get too hot (will destroy the N-chloramide). Let that shit sit for 4-8 hours, with careful observation of course. The patent calls for distillation, but I say that distillation is not absolutely necessary.

I think perhaps, it is necessary to allow the reaction to take its course longer. Also, it's critical to keep the temperatures in the right range.

Intersting Ideas!! I'm curious about a couple things and below, I have gone through that 1958 paper again and posted some shit it had of importance. Anyhow, so I'm concerned with the long reaction times and perhaps the addition of the bisulfite. It seems the noteworthy reactions above only take 30-90 minutes, and there is typically much vigorous agitation prior to heating to aid amide dissolution. But maybe (it can be tried at least) a longer period of cooling prior to heating is a good idea, but still heating for an hour or an hour and a half tops should be sufficient. And Us And Our Friends Should Take Note: typically the temperature is increased to 45-50 C first and then raised to 70-80 C shortly after.

There are a couple things to note about the Hofmann (the examples I posted) that most of the Hofmann degradations I posted used a combination of NaOH and KOH (usually making a solution of K or Na hypohalite and then adding the hydroxide of the other usu. in the form of a solution like half-way through the reaction).

And (yet again) from that 1958 paper, it states that: "It also seemed likely that formation of nitrile, observed by Hofmann with amides of intermediate chain length, was due to his technique of adding bromine to a solution or mixture of the other reactants. Where the amide is added to an initially cold alkaline solution of hypohalite, conversion to a halogenoamide should be a smooth reaction and no amine would be present along with free halogen. For this as for most other purposes we considered hypochlorite to be preferable to hypobromite since the dismutation to halide and halate is more facile with increasing size of the halogen."

Now also, they describe the reaction temperature increasing on its own pretty well (perhaps halogenation is exothermic) and then that increase can just take the temp up to degradation temperature;
So to sum up: amide should be introduced to hypochlorite solution, quick dissolution is important because reaction temp will increase, it seems that the reaction temp will climb high enough on its own for degradation to take place (and they even state, like we sorta mentioned, that they suggest--at least for long aliphatic amides-- that "external heating once the reaction has commenced may be undesirable"), and continued stirring is advantageous.

Interestingly enough, here's some succesful reactions they specify with quite hydrophobic amides (like helionamide):
---Standnrd hypochlorite solution. I n a distilling flask equipped with a dropping funnel was placed 6.7 g. of potassium permanganate. The side arm of the flask was joined by a glass-to-glass connection to a tube dipping below the surface of a solution containing 16 g. ( 0.4 mole) of sodium hydroxide dissolved in 110 cc. of water and cracked ice contained in a graduated cylinder. The cylinder in turn was surrounded by an ice bath. Fifty cc. of concentrated hydrochloric acid was admitted slowly through the dropping funnel so as to produce a slow stream of chlorine. When all the acid had been added, the contents of the flask were heated with a small flame until the reflux point was a little below the junction with the side arm. A Pyrex wool plug below the side arm served to prevent acid splashings from being carried over. The hypochlorite solution mas then made up to 160
cc. Such solutions contain slightly over 0.1 mole of sodium hypochlorite and 0.2 mole of excess sodium hydroxide. For the Hofmann reactions, the standard hypochlorite solutions were added to the amides contained in round-bottom flasks equipped with reflux condensers, magnetic stirrers, and thermometers. In runs I-III, and VII, the amides were present as solids; in the other runs (using 33% dioxane as solvent) the amides were dissolved in 80 cc. of dioxane (purified by 24-hour reflux over sodium followed by distillation.
---Amylamine (Run I). The suspension of caproamide (11.5 g.) in hypochlorite solution was warmed with stirring to 45 C when the heat of reaction sufficed to maintain the temperature. When the exothermic reaction had ceased, the solution was warmed to 75 C and kept at that temperature for 1 hr. The flask was then equipped for steam distillation and the reaction mixture was steam distilled into an excess of hydrochloric acid until no more base was coming over. The distillate was then evaporated to dryness in vacuo giving 11.7 g. (95% yield) of amylamine hydrochloride. A portion was
converted to the picrate which melted at 137-139 C as did a specimen prepared from commercial n-amylamine.
---Nonylamine (Run X ) . To the capramide (17.1 g.) in 80 cc. of purified dioxane was added the hypochlorite solution and the mixture was warmed to 45 C with stirring. The temperature then rose spontaneously to 65 C in two minutes. Stirring was continued without external heating for 2 hr at which time the temperature was 42 C. On cooling an oil layer separated. This was removed and the aqueous layer was extracted with benzene. The first amine layer and the benzene extract were combined, water was drawn off, and the base was extracted into 100 cc. of N hydrochloric acid. The acid layer was basified with concentrated alkali and the liberated base was taken into benzene. The benzene extract was dried over sodium hydroxide pellets, filtered, and saturated with hydrogen chloride gas. The mixture was
then concentrated to 50 cc. volume with an air stream and 50 cc. of dry ether was added. The amine hydrochloride when collected weighed 11.9 g. (66.4%), m.p. 185-186'.1


Weird... they do Externally Heat at first to 45 C.

Originally Posted by Aperson444

A friend of mine had done that reaction on helional. It indeed does work, a white-colored precipitate formed even with a lower than 2.5 mol % of NiCl2.

Ahh so, which reaction was performed--the Ni-catalyzed Beckmann??

Originally Posted by Aperson444

This reaction is really handy, but be careful, as it releases carbon monoxide, I believe.

That's right--that shit can kill, no smell!!

Originally Posted by Aperson444

Woah

I suppose then the amide could be added to the alkaline halogenation solution dissolved in dioxane or THF. I wonder if a PTC would help.

Ya in a couple papers I was reading there was mention of perhaps a PTC (benzyltrimethylammonium chloride I think) but I didn't really look into it for whatever reason. And I would suggest a non-dioxane trial and a dioxane trial similar to compare!!

Originally Posted by Aperson444

I was thinking something like just extract the crude amide with EtOAc. There might by a very minute amount of water (formation of the oxime liberates water), but the rest of the shit is amide, salts and unreacted helional. Ethyl acetate or even toluene might pull out the goodies nicely. These can then be recrystallized to purify the amide. Repeated recrystallizations should yield the described whitish crystals.

I'm not sure how much of a problem unreacted helional would be. Helional has a rather high BP (280-285oC) compared to the 120oC (I believe?) for the amide. That really is sort of odd, considering that most aldehydes boil at relatively low temperatures.

Yeah like the EtOAc can just be dumped into the cooled reaction mix, then filter, vap off and see what you're left with (recrystallized most likely, if needed--maybe toluene). And I'm not thinking helional leftover will be an issue because most of the Beckmanns that we've discussed tend to have almost quantitative conversions and also high yields. And that 120 C is actually just the melting point of the amide, and I imagine helional+friends follows the trend of the boiling points decreasing in this order: amide>aldoxime>aldehyde

Originally Posted by Aperson444

I'm no O Chemist though.

Coulda fooled me

Originally Posted by Aperson444

There are a couple of other ones using other catalysts. I mentioned one for ZnCl2 earlier in this thread, but there's another Cu(II) one in which they use Cu(OAc)2 and reflux at 100oC for a long time. They reported 93% yields from piperonal to pperonamide. I suspect that addition of aldehyde using dioxane or THF as a solvent may help as well (since many larger aldehydes are hydrophobic).

Here's the reference for that paper: Tetrahedron 68 (2012) 3948e3951; "Copper(II) acetate-catalyzed one-pot conversion of aldehydes into primary
amides through a Beckmann-type rearrangement"

On Scribd: http://www.scribd.com/doc/96247782

I'll have to take a closer look!! It seemed (when I looked before at the relevant Beckmann procedures) that the copper sulfate pentahydrate solvent free one was quite impressive!!! For a few compounds like no aldehyde was left, and yields as high as 98% and I bet that could be optimized for helional--score.