Sciencemadness Discussion Board

CCl3Br -> CCl4 or CHCl3

Sauron - 16-10-2008 at 06:52

I have just received a liter of trichlorobromomethane that I ordered some months ago

In this country carbon tetrachloride is verboten, and so is chloroform.

But they have overlooked CCl3Br which is perfectly importable without any special permit.

So what I am seeking is a way to replace the -Br with -Cl to obtain carbon tetrachloride, and/or replace the -Br with -H to obtain chloroform.

So far in the lit. I have found only studies of the ClBr interhalogen compound and really nothing that looks preparatively useful to me.

So I am soliciting help with this project. It seems to be that the -Br ought to be more labile, so perhaps refluxing with N-chlorosuccinimide might replace the -Br with -Cl and trap the bromine as NBS.

Simply bubbling in Cl2 sets up an equilibrium with ClBr and CCl4 if I recall, and bubbling in HCl similarly makes an equilibrium with chloroform and Br2. Anyway neither is very satisfactory preperatively.

Photochemical chlorination with Cl2 needs special filtering of the UV to preclude side reaction forming hexachloroethane. Kopp Glass makes such filters, not cheap!

I am tempted to try the wet iron filings routine, this gets chloroform from CCl4 - I am hoping it would selectively reduce the -Br leaving chloroform and not CHCl2Br.

Any ideas anyone?

[Edited on 16-10-2008 by Sauron]

Slimz - 16-10-2008 at 07:15

Chloroform is way easier to make than all that..

NaClO + dimethyl ketone (Acetone) you get a layer of chloroform.
thats 500ml of bleach (normal strength) and 5ml of acetone.

a stronger solution of bleaching powder and water can be used but you should keep the reaction cooled in a bin of ice if doing that

Sauron - 16-10-2008 at 07:19

Go teach your grandmother to suck eggs, slimer.

I do not want to muck around with haloform reaction.

Back to the topic:

The Ph3P reaction with CCl4 or CBr4 to halogenate alcohols or carboxylic acids, ought to work with CCl3Br ought it not? I wonder if it might leave CHCl3 abd an alkyl bromide (or acyl bromide) in this case?

Also, the recently discussed NaBH4 reduction of polyhalomethane, I wonder whether it might be selective in a case like this? Would the product be CHCl3 or CHCl2Br? or a mixture of both?

[Edited on 16-10-2008 by Sauron]

Klute - 16-10-2008 at 07:48

Not too familiar with such compounds, maybe zinc dust would cause selective dehalogenation?

How could you differentiate CCl3Br from CCl4? IR? Or is there a major difference in bp?

Maybe CClBr is interchangeable with CCl4 is certain applications (what do you plan on using the tetrachloride for?), and if it is much more reactive, this is surely du to the Br, so you could play on that to selectively remove/exchange it...

Sauron - 16-10-2008 at 08:05

Significant difference in MW, BP, density, refractive index. Give me a moment to collect the data and I will post it here.

Synonyms: Tetrachloromethane
Molecular Formula: CCl4
Formula Weight: 153.82
Registry number: 56-23-5
MDL number: MFCD00000785
Density: 1.594
Melting point: -23 °C (lit.)
Boiling point: 76 °C (lit.)
nD20: 1.459-1.461

Synonyms: -
Molecular Formula: CBrCl3
Formula Weight: 198.27
Registry number: 75-62-7
MDL number: MFCD00000783
Density: 1.997
Melting point: -6 °C (lit.)
Boiling point: 105 °C (lit.)
nD20: 1.5055-1.5075

See what I mean?

No troule to fractionate. Can probably fractionally crystallize as well.

[Edited on 16-10-2008 by Sauron]

Klute - 16-10-2008 at 08:51

Indeed, quite convenient. i was rather thinking of following the reactiosn though that direct workup, to determine the best tempa nd reaction times etc. I guess the refractive index can come in handy if you have the necessary equipement.

Sauron - 16-10-2008 at 09:08

An Abbe refractometer is on my list of things to buy.

But seems to me that given a spread from 1.59 to 1.99 in density, that a set of hydrometers (which I have) will also quickly and easily determine any mixture quantitatively to decent accuracy.The hydrometers read to 3 or 4 decimel places.

The way that CCl3Br is made is to treat CCl4 with AlBr3. Maybe treating the mixed tetrahalide with AlCl3 might reverse that?

Any mechanism that proceeds via the trichloromethyl radical needs to be shunned or hexachloroethane will result.

Sauron - 17-10-2008 at 02:26

The Ph3P reaction appears not to be selective, or at best partially selective. The famous "One-Pot Conversion of Alcohols to Amines" which is on all the notorious druggie sites has the system Ph3P-CBrCl3 producing mixed alkyl chlorides and bromides. They prefer the bromides for higher reactivity with NaN3.

I have found a totally selective reducing agent that takes bromotrichloromethane to chloroform. But it remains to be seen if this has any practical preperative utility.

2,6-dimethyl-3,5-dicarbomethoxy-1,4-dihydropyridine, a derivative of 2,6-lutidine, is the reducing agent, and is oxidized to the corresponding pyridinium bromide. This is a free radical reaction and was first observed with CCl4 while trying to obtain NMR spectra. The reaction is slow, but later that with bromotrichloromethane was found to proceed more rapidly.

The prep of this compound is in a 1914 paper in Monatsh. by Hans Meyer and Hans Tropsch. I have requested it. So more to follow later.

[Edited on 17-10-2008 by Sauron]

DH.jpg - 37kB

Sauron - 17-10-2008 at 04:00

The compound shown above is also the parent structure for the potent coronary vasodilator and hypotensive agent nifedipine, which differes from it only by having a 2'-nitrophenyl group at the 4-position.

OK now I have Bayer's patent, the 1914 Monatsh.article, and at first glance this looks fine. Condensation of two mols acetoacetic ester with 1 mol formaldehyde and 1 mold ammonia. However the devil is always in the details so let me digest these before commenting further. I also found a nice Chem.Rev piece on the 1,4-dihydropyridines.

I will post these after perusing.

By the way the condensation of acetoacetic ester (2 mols), an aldehyde and an amine to form 1,4-dihydropyridines is the Hantzsch reaction and these compounds are often reffered to as Hantzsch-type structures,

[Edited on 17-10-2008 by Sauron]

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Sauron - 17-10-2008 at 19:36

Actually the Hantzsch Dihydropyridine Synthesis is better stated to be the condensation of an active methylene compound (two mols) with ammonia or a primary amine, and an aldehyde.

There's also the Knoevenagel-Fries modification which allows for prep of unsymmetrical dihydropyridines.

But this target of ours is simple classical methyl acetoacetate, formaldehyde, and ammonia. I suspect paraformaldehyde etc works. Hexamethylenetetramine has been used. The reaction is sone in methanol and yields are good to excellent.

In the case of that anti-angina drug, 2-nitrobenzaldehyde replaces the formaldehyde. Simple as that. The Bayer US patent is attached, the examples give a good idea of the ease of preparation of this class of compounds.

When used to reduce CCl3Br to chloroform, the dihydropyridine is oxidized to the aromatic pyridinium bromide quaternary salt. Fortunately this can be reduced and reused. Whether it is easier to just make more, remains to be seen. The usual reducing agent is sodium dithionite.

Org Syn website was down for a couple days but is now up again. A Hantzsch synthesis of shown for 2,6-lutidine (2,6-dimethylpyridine) in which the initial product is the ethyl ester form of our target. (2,6-dimethyl-3,5-dicarbomethoxy-1,4-dihydropyridine.) Their prep employs ethyl acetoacetate and aqueous formaldehyde soln (formaline) and anhydrous ammonia.

They then oxidize and decarboxylate the Hantzsch compound to obtain the dimethylpyridine.

Looks good to me.

[Edited on 18-10-2008 by Sauron]

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Sauron - 18-10-2008 at 17:00

Here is the Org Syn prep of 2,6-lutidine, or dimethylpyridine. This is a pretty typical Hantzsch reaction although the authors did not even tip their hats to his pre 1890 work.

I am not so sanguine about the 10 drops of Et2NH, or the delay before introducing NH3. There are alternatives to admitting ammonia as anhydrous gas, notably ammonium acetate.

You can ignore the second half of the prep, unless you want to use the Hantzsch as they did to prepare pyridines instead of dihydropyridines.

[Edited on 19-10-2008 by Sauron]

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Klute - 18-10-2008 at 17:22

Are you sure NH3 can be replaced by ammonium acetate here? I guess it simialr to some kind of mannich reaction, but you might want to check if there is a simialr procedure using an ammonium salt in the particular variant.

Sauron - 18-10-2008 at 17:34

Go a few posts up and download the Chem Rev monograph.

There's more than one way to add formaldehyde, and more than one way to add ammonia.

And alternatives to acetoacetic ester(s) albeit not for this particular product.

The Chem Rev paper also references other reviews. There's a Wiki page on the Hantzsch reaction, and it has some refs as well.

The Hantzsch is like the Mannich reaction in having three components, but is a lot more facile than the Mannich which requires very fiddly control of pH. There's absolutely no indication of such requirement here. It seems to be, chill mix, stir, let sit for 2 days. seperate, dilute, chill again,saturate with NH3, let sit again for 2 days. Filter and dry. The hardest thing about this prep is waiting 48 hrs x 2.

While I can buy anhydrous NH3, the SS regulator is expensive, hence my interest in an alternative.

Also see the patent I posted which replaces formaldehyde with benzaldehyde to prepare nifedipine, it may contain some variants on how to get the N in the ring as well.

One of the Pyridine volumes in the Chemistry of Heterocyclic Compounds series (which most of are now available for download from References) covers this material although it is organized from the pyridine not dihydropyridine standpoint.

I believe ammonium acetate is introduced along with NaOH and forms NH3 in situ. NaOAc salts out.

[Edited on 19-10-2008 by Sauron]

Sauron - 19-10-2008 at 04:31

Here is the original, 1881, two page short and sweet paper on what became known as the Hantzsch Pyridine (Dihydropyridine) Synthesis.

Ber., 14, 1637-1638 (1881) cortesy of FREE BnF Gallica, and nuts to Wiley!

[Edited on 19-10-2008 by Sauron]

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Klute - 19-10-2008 at 04:42

Ok, perfect then. I was thinking you were planning on using the ammonium salt directly to the acetoacetic ester. This really does look like a evry handy reaction, and I'm wondering what other uses we could find for the dehydropyridine, as a mild and selective reducing agent.. The fact that it can be recyle easily seems very promising, and perhasp it could be used in catalytic amounts, adding dithionite gradually to the compound to be reduced/dehalogenated and the dehydropyridine, reducing the pyridine bromide as it is formed..

EDIT: I've just realized I've read about this reaction last night in the "Chemistry of Enamines", from the FTP, jump to page 543 (on the DejaVu menu), and you will see that enaminones can be used in the reaction, so the ammonia can be added tot he acetoacetic ester before the formaldehdye.

Apparently, heating the enaminone with benzaldehdye, benzoic acid and ammonium acetate gives a tetrahydropyridium acetate, which could be either reduced and decarboxylated to a 4-amino piperidine, or maybe dehydrogenated to the pyridine, and decarboxylated (route to DMAP?):

Ref to the enaminone variant:
- F. Micheel, H. Dralle, Justus Liebig's Ann. Chem.; 670, 57 (1963)
-A. H. Cook, I. M. Heilbron, L. Steger, J. Chem. Soc.; 413 (1943)
-U. Kuckländer, P. Ulmer, G. Zerta, Arch. Pharm. (Weinheim); 322, 437 (1989)

[Edited on 19-10-2008 by Klute]

Sauron - 19-10-2008 at 05:13

It gets better. Apparently the reduction is a free radical one and only a tiny amount of the dihydropyridine is required to reduce a much larger amount of the CBrCl3.

The reaction can be initiated photochemically or thermally and while they were doin this in methanol for kinetics studies, the paper states that the reaction also works in nest bromotrichloromethane, but the ppt of pyridinium bromide made rate measurements difficult. Well, we don't care about kinetics so methanol be damned.

I'd better post the paper I am paraphrasing so you can suss it out yourself. You just ignore all the deuterated stuff and the pchem malarky. Bottom line is that this is not a stoichiometric reaction and not much dihydropyridine is needed at all. Fine with me.

[Edited on 19-10-2008 by Sauron]

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jarynth - 19-10-2008 at 05:21

Originally posted by Sauron
Here is the Org Syn prep of 2,6-lutidine, or dimethylpyridine.

You can ignore the second half of the prep, unless you want to use the Hantzsch as they did to prepare pyridines instead of dihydropyridines.

From the last step it appears that the decarboxylation of pyridinecarboxylic acids can be effected in good yields without the use of copper chromite catalysts. Klute, this might be something for your pyridine from niacin experiments.

Klute - 19-10-2008 at 05:52

Sorry to say this Jarynth, I'm not the one that was trying to prepare pyridine by decarboxylation :) I beleive it was Ordenblitz.

But I have been pretty interested in preparing dimethylaminopyridine from cheap starting materials, although for the moment it's been nothing but a paper distraction..

In any case, forming a piperidine ring from acetoacetic ester seems like a very good option. Possibly benzaldheyde could be replaced by formaldehyde in the recation I described above.

Sauron - 19-10-2008 at 05:59

In one of the papers I have, 2,6-dimethylpyridine-3,5-dicarboxylic acid is oxidized to 2,3,5,6-pyridinetetracarboxylic acid, and the 2 and 6 positions decarboxylated. The product is dinicotinic acid. I think you will find that the 3 and 5 positions, beta to the ring N are very hard to decarboxylate. Maybe better to degrade nicotinamide to 3-aminopyridine and get rid of the amino group via diazotization, is what you want is pyridine. Seems like a lot of work just to make pyridine.

You might consider making citrazinic acid from citric acid, haloginating the 2,6-hydroxyls and then getting rid of the halogen by reduction. Voila, pyridine from citric acid. See my thread on citrazinic acid from last year.

Well, nicotinamide (niacin) is cheap, I have a Kg of Roche pharm grade sitting here.

Klute - 19-10-2008 at 06:11

No, no, no! I don't want to make pyridine :) I just buy the stuff. I was more interested in things like 4-aminopyridine, although the nitration of pyridine-N-oxide and subsequent reduction look much more pratical after all. It would ahev been nice to have a reaction starting from something else than pyridine as the stuff reeks..

The 3 and 5 position are decarboxylated with Ca(OH)2 when preparing 2,6-dimethylpyridine, in the OrgSyn pre you posted. Are you not confusing with the 2 and 6 carboxyl?

panziandi - 19-10-2008 at 06:12

I was looking into making fluorine compounds myself and found that reaction of tri-iodomethane with silver fluoride (can also be mercury fluoride and several others too) gives various fluoro-iodomethanes along with trifluoromethane sometimes explosively! Now further research revealed the use of antimony trifluoride. Exchanges of I and Br for F worked. Perhaps Cl3C-Br could be converted to CCl4 by the use of silver chloride or antimony trichloride. Now I don't know if this would work, there wouldn't be much literature (I haven't found any) on this proposed reaction mainly because CCl4 and CHCl3 are produced by far more economical routes industrially. But perhaps Sauron, if you could spare a little Cl3C-Br for experimenting, you could try reacting it with silver chloride, mercury chloride or perhaps antimony trichloride? Perhaps it would require reflux or perhaps heating in an autoclave?

Sauron - 19-10-2008 at 06:31

CBrCl3. Anyway I have a folder on fluoform somewhere. If memory serves isn't it a gas?

Klute, I just buy pyridine too.

Are you sure you want to prepare DMAP? It is a very very toxic Ca-channel blocker, the LD50 is quite appalingly low. That's why they sell it in prills, to make handling safer.

panziandi - 19-10-2008 at 06:40

Cl3C-Br makes it clearer to some of the people potentially reading this that what bond im talking about.

Indeed many of the fluoromethanes are gases. The reactions are done in steel setups and the products cool in dry ice traps I had diagrams in one paper I found. But I don't see any real reason why an analogous reaction with chlorine compounds couldn't work. The driving force is the lattice energy of the AgI vs AgF I believe. Antimony trifluoride was used to replace the first two fluorines as using heavy metal fluorides was too vigorous, then silver or mercury fluoride was used to replace the last iodine. If you used silver chloride and fractionated/refluxed at the same time you could remove the CCl4 as it was formed. Perhaps it is worth a small scale experiment to see if it is feasible?

Sauron - 19-10-2008 at 06:59

Antmony trichloride difluoride is often used in lieu of the uoride or the pentafluoride. See Brauer for preparation.

triflAgF and HgF are very old (19th century) reagents. CoF3 is more contemporary and the above mentioned SB compounds intermediate in vogue.

You can write it as you see fit but I desribed the substance as bromotrichloromethane throughout so I do not think alongside that, CCl3Br or CBrCl3 are at all ambiguous. C-C-I3-Br makes no sense at all. So a tetrahalomethane is all it can be, especially when reduced to chloroform, or chlorinated to CCl4.

[Edited on 19-10-2008 by Sauron]

Klute - 19-10-2008 at 08:02

Well, Panreac and Acros sell DMAP in small format (20-25g) at a reasonable price, but I was more interested in trying to prepare a polymer-supported version (like I love to do with any catalyst I hear about), the commercial poly-DMAP is incredibly expensive. A supported version would have several advantages, like being very easy to seperate and re-use, as most heterogenous catalysts, but also making it must less easily absorbed by skin and thus much easier to handle and supposebly less toxic. But I'm already scattering myself over several projects, so I'll keep this for a distant period. Sorry if I'm diverting the topic, I'll stop there.

panziandi - 19-10-2008 at 08:08

CoF3 is indeed a very useful and powerful fluorinating agent but is likely out of reach of most people doing chemistry as a hobby unless they can order from Aldrich.

AgF and HgF2 and perhaps to some extent SbF3 and SbF5 are far more likely to be obtainable (allbeit hard) and would be feasible to prepare some of these from HF etc. In fact they would be cheaper, easier to obtain and easier to handle than CoF3 even for a professional. CoF3 AFAIK requires F2 to generate it which is probably out of most peoples hands.

Indeed C-C-l3-Br makes no sense but that is not what I wrote.

I merely see that this reaction for halogen exchange in tribromo and tri-iodomethanes to F could perhaps be adapted for exchange to Cl using your starting material CCl3Br to generate CCl4. And I think, if CCl3Br is easy to obtain compared to CCl4 then why the hell not try a reaction that uses readily obtainable chemicals like AgF and HgF2?

Sauron - 19-10-2008 at 08:19

I gleaned two refs from the Chem Rev monograph that are very interesting. The text says that while the source of nitrogen in the Hantzsch is usuallu ammonia or ammonium acetate, hexamethylene tetramine and aldehyde-ammonia have occasionally been used. Of the four references, one is an early Hantzsch paper from Annalen, two are from Ber., and the fourth is not accessible online (Bull.Soc.Chim.Fr.) Well, 3 out of 4 ain't bad. So the Ann. one I will request in Refs, and the two from Ber. I will pull up in BnF.

It is unclear to me whether or not hexamine is the source of only the NH3 or all or part of the H2C=O as well. I guess we will find out in the full texts. I will post them here.

Another variation is that ethyl 3-aminocrotonate replaces ethyl acetoacetate and this improves yields. I guess because the N is built in.

[Edited on 19-10-2008 by Sauron]

panziandi - 19-10-2008 at 13:04

I will move my halogen exchange posts to a new thread anyone interested in fluoromethanes or polyhalogentated methanes especially can look there.

I would have thought that tetrachloromethane would be more useful as a solvent than trichloromethane. I certainly prefer the tetrachloromethane and so handy with it's azeotropes, I have an ample supply but before I got that I looked into chlorinating trichloromethane.

Sauron are you more interested in trichloromethane than tetrachloromethane? Solvent wise, I expect that bromotrichloromethane itself would be fairly useable, wouldn't it? I doubt it would interfer in many reactions / crystalisations.

I suppose if the dihydropyridine method reports good yields of trichloromethane then it's worth persuing!

Sauron - 19-10-2008 at 18:34

Bromotrichloromethane is available to me, and CCl4 and CHCl3 are not. Period full stop. 99% of my interest in this mixed tetrahalomethane lies in its being convertible into solvents I need, and I need both of the higher chloromethanes. (DCM is not yet a problem here.)

CBrCl3 costs me, delivered, $500 a Liter. Making it into chloroform will lose some mass, making it into CCl4 will still lose some, but not as much.

Tyros will pop up and say "CHCl3 is easy to make." They know how to make 50 ml or so via haloform. Scaling up the haloform rxn is not very simple and not very safe. Cooling become an issue. Runaways are common. Phosgene can be released. Making 1000 ml via haloform rxn is simply a lot of work and I'd sooner throw money and chemistry at the problem, this way.

CCl4 is best made by chlorinatng CS2. CS2 is costly and flammable. The product is a mixture of CCl4 and SCl2 and S2Cl2 difficult to seperate. It can be done via a trick. The sulfur chlorides are nasty, but can be utilized to make Ac2). The other route is chlorination of MeSCN. Again starting material is costly. This gets you TCT but I can buy that and do. Continuing the chlorination after filtering off the TCT eventually produces a mixture of CCl4 and sulfur chlorides just like from CS2.

Doable but again, if I can buy and convert a liter at a time, why not?

My only reaction of CBrCl3 per se (apart from its reduction) is reaction with MeCN and sodium dithionite to produce Cl3CNO, trichloronitrosomethane, a blue liquid related to chloropicrin. This is a model Novichok binary CW component. Now if if one Cl was exchanged with F, i.e.., CFBrCl2, the product would be a binary Novichok component proper, very nasty and not something I will ever make. I have reasons you see for NOT wanting F-exchange reagents around my lab.

Sauron - 19-10-2008 at 18:49


I am awaiting the seminal 82-pqge paper by Aurthus Hantzsch.

The later paper by him involved acetaldehyde-ammonia adduct to make the 4-Me variant (2,64.6=trimethyl-3,5-dicarboethoxy-1,4-dihydropyridine, a collidine derivative,. The Griess and Harrow paper using hexamethylenetetramine as source of nitrogen and formaldehyde, produced the correct structure but the results were a little off analytically so maybe this was not such a great idea.

A 1944 J.Pharm Soc Japan reference suggests formamide can be used in lieu of NH3, but apart from a CA abstract, the full text is likely useless and in any case in Japanese.

So far the Org Syn prep of 2,6-lutidine has clearest details and so I will go dig through its references in hope that similar clear instructions can be found for use of a 1:1 adduct of formaldehyde-ammonia, or ammonium acetate, etc. Anything but gaseous NH3.

[Edited on 20-10-2008 by Sauron]

Sauron - 20-10-2008 at 02:26

Not a terribly productive day so far.

The 82 page Hantzzsch paper turned out to concern dihydrocollidine-dicarboxylic acid and derivatives rather than my target. That is, it employed acetaldehyde-ammonia rather than formaldehyde-ammonia. So the 4-position bears a Me group.

So I dug out Volume 14 Part 1 of the Chemistry of Hetrocyclic Compounds series, Pyridine and Derivatives. This includes a review through 1957 as cited in the Chem Rev paper posted above. Disappointingly, most of the entries on 2,6-dimethyl-3,5-dicarbethoxy-1,4-dihydropyridine preps were from papers I already have.

I still have a few stones unturned but it appears the Org Syn prep is probably the best one for this specific target to be found. It is also posted above. Just a matter of using methyl acetoacetate rather than ethyl.

I looked up ethyl (and methyl) 3-aminocrotonate. Available, not too expensive but 7X more costly than methyl acetoacetate. The latter is $70/2.5 L and the crotonate is $100/500 g. I'll stick with the acetoacetic ester.

Incidentally the mysterious 20 drops of ethylamine added to the formalin soln and acetoacetic ester in the Org Syn prep, without any explanation or obvious purpose. Nothing in the notes or discussion or text and the the references were rather mingey.

Apparently this is just a pH adjustment, optimum pH is said (elsewhere) to be 8.5, mildly basic.

Here's a 1902 paper by Knoevenagel and cowoker, prep details are on p 1791.

180 g ethyl acetoacetate
60 g 40% aqueous formaldehyde
180 g 10% NH3 in EtOH

90% yield (>150 g)

[Edited on 21-10-2008 by Sauron]

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Sauron - 20-10-2008 at 21:00

The way the mechanism of the Hantzsch Dihydropyridine Synthesis is almost always represented is that 1 mol of acetoacetic ester reacts with NH3 to form ethyl 3-aminocrotonate while formaldehyde reacts with a second mol of acetoacetic ester to form methyleneacetoacetic ester. These two then reach in a Michael condensation and cyclicization.

That the substitution of ethyl 3-aminocrotonate for one of the equivalents of acetoacetic ester, not only works buts ups yield, supports this mechanism. However, according to "Pyridines and Derivatives" Part 1, in the Chem.Het.Compounds servies (Vol 14) the mechanism has not been rigirously proven.

Good old Alan Katritzsky at U Fl did a mechanistic study that may well be more recent than those remarks. I will see if I can get my paws on it.

[Edited on 21-10-2008 by Sauron]

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CBrCl3 + Toluene -> Benzyl Bromide + CHCl3 !

Sauron - 21-10-2008 at 08:24

We have a whole new ballgame:

It turns out that bromotrichloromethane is a brominating reagent.

Under the action of UV, arenes such as toluene are brominated and the hydrogen abstracted forms chloroform from the trichloromethyl radical. JACS and JOC call this preparatively useful.

I am chasing the papers.

Here's one of the key papers from JACS attached.

The author worked on a half molar scale in Pyrex using a G.E. 275 W sun lamp for illumination place 6" under the flask and kept the flask cooled with air at 60 C. Time 6 hours. With various substrates he obtained conversions from 34% (toluene) to 72% (ethylbenzene). In every instance there was a very close agreement between the molar amounts of chloroform and a-brominated arene recovered. Unconverted CBrCl3 and substrate were also recovered quantitatively.

Bromination and H-abstraction occured exclusively at benzylic positions. Dibromination was observed only in the pase of p-xylene where a small amount of p-methylbenzal bromide formed.

The author's photochemical setup was far from optimum. A quartz immersion well and 400-450 W Hg arc medium pressure lamp would be more efficient and this is the equipment I have operable on a multi-liter basis.

It appears that this can be optimized easily ans scaled up conveniently to 10-20 molar basis (1-2 Kg CBrCl3) - after all the stuff is 2 Kg to the liter!

[Edited on 22-10-2008 by Sauron]

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Sauron - 21-10-2008 at 19:51

If the photolytic bromination of the arene can be driven to completion or nearly so then we are left with only chloroform and benzyl brmide, > 100 C delta in bp's.

Else, we have a mix of the arene, BrCCCl3, chloroform and the a-bromoarene. For the simplest example, toluene, bp's are as follows

chloroform 62 C
toluene 105 C
bromotrichloromethane 111 C
benzyl bromide 198-199 C

Since we do not have to seperate the toluene and CBrCl3, which will still be in equimolar amounts, the workup is easy.

Strip chloroform.
Fractionate the cut boiling between 80 and 115, that is the mixed starting materials to be recycled

Pot residue is benzyl bromide with a trace of hexachloroethane.

Chloroform, remember, is not allowed to be imported where I am. Well, neither is benzyl bromide! Probably because it was long ago used briefly as tear gas. (See Sartori.) Acros lists it for $300/liter.

I need CHCl3. Getting the benzyl bromide as a byproduct is great and toluene costs almost nothing.

I can exploit the bromide to make phenylacetonitrile (I have a Kg or two already but hey.) I can exploit that to make BOC-On. (Sorry, I do not need PAA.)

Arenes that a-brominate in this fashion more raspidly than toluene include p-xylene, ethylbenzene, n-propylbenzene, and sec-butyl benzene. All are costlier than toluene and I have no need whatsoever for the resulting a-bromo compounds. So I will stick with toluene.

This looks like fun.

Sauron - 22-10-2008 at 19:39

I am looking at various Hantzsch intermediates.

-- Ethyl 3-aminocrotonate - prepared by bubbling a rapid stream of anhydr NH3 into neat acetoacetic ester for 5 hours w/stirring. In first hour temp rises to 40 C, and is held to 35-40 with cooling. The product is taken up in ether and water of reaction seperated and discarded. The ether is stripped off and the product distilled in vacuo. Paper posted below

-- ethyl acetopyruvate - this one has a Org Syn prep. Will post shortly. Prepared from diethyl oxalate and acetone via sodium ethoxide.

-- The Knoevenagel condensation product of formaldehyde and acetoacetic ester, I have not decided as to the best name. Most likely from anhydrous formaldehyde and acetoacetic ester in a manner analogous to the prep of the enamine above. Possibly from paraformaldehyde or trioxane and acetoacetic ester. No refs yet.

[Edited on 23-10-2008 by Sauron]

[Edited on 23-10-2008 by Sauron]

Attachment: baminoenester.pdf (426kB)
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Klute - 23-10-2008 at 03:23

Nice find! Obtaining equimolar amounts of toluene and BrCCl3 is indeed very practical, and you could make large batch-type reactions, or even consider a semi-continous operations (distilling the chloroform as it forms, and introducing trecycled toluene/BrCCl3 fractions gradaully). I'm sure removing the chloroform as it forms with help the reaction proceed, although with higher temps you might get a little more tarry residu..

Concerning the ethylamine: my interpretation is that the ethylamine forms the enaminone more easily than NH3, whcih then condenses with a mole of the crotonate, forming the cylcisation product and expelling ethylamine, which would be a better leaving group than NH3. I guess the pH issu could also come into play.

BTW, I have lawys found ethyl and methyl acetoacetate perfectly exchangeable in most reaction, including aminolysis etc (reactions involving departure of the alcohol moeity)

Looking forward to see how this goes.

Sauron - 23-10-2008 at 08:39

Thanks. I think it will be very practical.

Regarding the Hantzsch, I had a look at the ACS monograph on formaldehyde from forum library. Knoevenagel was first to condense acetoacetic ester and formaldehyde (as formalin) in 1894 and he used pyridine or diethylamine as catalyst. The product was methylenebis(acetoacetic ester), a 1,5-diketone, which is immiscible with water and seperates out as lower layer, and can be seperated and dried but not distilled.

Treating the preformed methylenebis(acetoacetic ester) with anhydrous NH3 is what closes the ring.

If you read the Org.Syn. prep of 2,6-lutidine posted above this is exactly what they did in first step.

So the mechanism of the Hantzsch as elucidated by Alan Katritzky (also posted above) and described in your Patai-series book on enamines, certainly holds for the three component reaction where formaldehyde (or other aldehyde) and acetoacetic ester (or other active methylene) and ammonia (or other PRIMARY amine) are mixed simultaneously. And in a ratio of 1:2:1.

But if the reaction is conducted as a sequence of two 2-component reactions, for example above in absence of ammonia, there's no enamine formation, or if an enamine forms from the catalytic (a few mol%) secondaty or tertiary amine, it is solely as intermediate to the methylenebis diketone which is isolable.

A secondary amine can form an enamine but not an imine, and I am a little fuzzy about whether or not a tertiary amine can form a (quaternary) enamine at all, I'd guess not.

The authory in Org.Syn waited 48 hrs after condensing the formalin soln and 2 mols of acetoacetic ester, and the hydrophobic lower later formed just as described in the ACS monograph, and only after isolation and dilution with ether did they introduce dry NH3 and obtain the dihydropyridine.

The methylene bridge forms at the active methylene carbon C3 of each of the two mols of acetoacetic ester. If we draw this you can readily see what will occur with introduction of NH3 and I do not have to put in a bunch of curved arrows, do I?

We already know (as I spent a couple days digging up the refs) that the enamine can also be preformed (ethyl-3-aminocrotoante) from acetoacetic ester and dry ammonia, and isolated. It is sold commercially. So one could do that as Step One and then introduce formaldehyde and a second equivalent of acetoacetic ester, and certainly get same product.

But that is not how McElvain did it in Org.Syn. and that procedure appears to be the gold standard, often referenced by later workers as the paradigm.

[Edited on 24-10-2008 by Sauron]

methylenebis.jpg - 40kB

Sauron - 23-10-2008 at 09:30

Here are the pages from the ACS monograph on Formaldehyde (forum library.)

As you will see, Knoevenagel's original reaction of formalin and acetoacetic ester (2 mols) catalyzed by Et2NH or pyridine, produced cyclic condensation products (or so he thought.)

Ref.17, Ann. 1894 which I will post soon.

The isolation of the methylenebis(ethyl acetoacetate) was done a decade later by other workers

Ref 24, Ann. 1904, which I will also post shortly.

[Edited on 24-10-2008 by Sauron]

Attachment: Pages from formaldehyde.pdf (861kB)
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Sauron - 23-10-2008 at 10:42

And here is the Paul Rabe paper from Ann. in 1904.

The original Knoevenagel prep paper from 1894 is 100+ pages and 3.6 Mb so too large to post here. Anyone interested can find it in References if they want to read it, it is in a rar file on RS along with this Rabe paper.

For comparison here is the pertinent paragraph from the Org Syn prep of same compound:

"To 500 g. (3.85 moles) of freshly distilled ethyl acetoacetate in a 1-l. flask, set in ice and well cooled, are added 152 g. (2 moles) of 40 per cent aqueous formaldehyde solution and 20–25 drops of diethylamine. The flask and contents are kept cold for six hours and are then allowed to stand at room temperature for forty to forty-five hours. At the end of this time two layers are present, a lower oily layer and an upper aqueous layer. The layers are separated, and the aqueous layer is extracted with 50 cc. of ether. The ether solution is added to the oily layer, and the resulting solution is dried over 30 g. of calcium chloride. The ether is then removed by distillation on a steam bath. The residue, amounting to approximately 500 g., is diluted with an equal volume of alcohol and is thoroughly cooled in an ice bath. Ammonia is then passed into the mixture until the solution is saturated. This requires from four to eight hours, and during this time the flask is kept packed in ice. The ammoniacal alcoholic solution is allowed to stand at room temperature for forty to forty-five hours. Most of the alcohol is now evaporated; the residue is cooled, and the solid 1,4-dihydro-3,5-dicarbethoxy-2,6-dimethylpyridine is removed from the remaining alcohol on a suction filter. The dried ester melts at 175–180° and weighs 410–435 g. (84–89 per cent of the theoretical amount)."

It will be interesting to compare that to the procedures of Knoevenagel (1894) and Rabe (1904) while noting that the Org.Syn prep was authorored in the mid 1930s.

And while the rest of that prep is a good read it is entirely concerned with oxidizing the dihydropyridine to pyridine, saponifying the ester groups, and decarboxylating the compound to obtain lutidine. Not my target. I will be following the procedure in paragraph above, merely substituting methyl acetoacetate for ethyl, which, Klute reminds us, is a piece of cake.

[Edited on 24-10-2008 by Sauron]

Attachment: PRabeAnn1904.pdf (802kB)
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Sauron - 23-10-2008 at 21:05

I guess I ought to have a closer look at the Knoevenagel reaction, and reread the Katritzky paper on the mechanism of the Hantzsch dihydropyridine synthesis. I would like to know whether the 1:1 condensation product of acetoacetic ester and formaldehyde that he spotted by NMR is isolable.

I am pretty sure that the ARK mechanism applies only to the formal, 3-component Hantzsch. In fact it is pretty clear that procedures like the one in Org Syn are not precisely Hantzsch reactions at all, although they involve the same reagents and arrive at the same products, simply because they aren't 3-component reactions. I don't think this is splitting hairs.

I did have another go at ARK's mechanism paper and he does include the methylenebis-ethylacetoacetate in his master reaction scheme and obviously recognizes the complexities. Well, I really would not expect any less from Katritzky.

His experiments were using benzaldehyde not formaldehyde.

Below is theethyl 2-methyleneacetoacetate resulting from condensation of one equivalent acetoacetic ester and one equiv. formaldehyde. Just as clearly, we could call this ethyl 2-acetylacrylate.and expect it to be highly reactive and readily polymerizing. I am a little dubious about whether or not this can be isolated, except maybe in a cold trap. where the self-condensation can be retarded. But ARK's spectral evidence for in situ formation and role in reaction with ethyl 3-aminocrotonate is pretty compelling.

The ACS Formaldehyde monograph described methylenemalonic esters and methylenebis(malonic esters) and as anticipated these do polymerize on standing but not instantly, and are isolable and distillable. However, no mention is made of a methyleneacetoacetic ester, just the methylenebis compound. I will have to dig deeper.

[Edited on 24-10-2008 by Sauron]

2-methyleneAcAcOEt.jpg - 13kB

Sauron - 24-10-2008 at 17:08

The Katritzky paper posted above concludes from NMR experimental evidence that the main pathway of the three-component Hantzsch is (by reference to his Sceme 1 diagram) enamine 5 + Knoevenagel product 6 -> Michael addn product 10 -> ring closure product 15 ->dehydration product 14.

The enamine (in case of our target, this is methyl 3-aminocrotonate) forms within minutes of addition of ammonia, while clalcone 6 takes a few hours. The dienamine and the 1,5-diketone were not observed. - that is, were not detectable by NMR under these experimental conditions.

Did Katritzsky load the dice by using benzaldehyde rather than formaldehyde? I wish I had a NMR so I could find out. In the meantime I guess his mechanism is the best game in town.

[Edited on 25-10-2008 by Sauron]

ARKMech.jpg - 59kB

Sauron - 24-10-2008 at 21:54

In my sketch above, 10 is the Michael addition product of enamine 5 (methyl 3-aminocrotonate, formed from ethylacetoacetate and NH3) and 6 the Knoevenagel chalcone formed from a second equivalent of methyl acetoacetic ester and formaldehyde. The enamine forms faster than the chalcone.

15 is the ring closure product with loss of H2) from 10

14 is the final dihydropyridine from loss of H2O forming the second pi bond.


Sauron - 18-2-2009 at 07:17

I have found what appears to be the solution of this problem.

According to the attached US patent to Dow Chemical, antimony, tin, zinc or vanadium chloride catalyzes the elemental chlorination of alkanes with at least one substitutable bromine.

In their first example, Br2CCl2 is chlorinated to BrCCl3 using Cl2 and SbCl3. No photolysis, no pressure, just reflux.

So CCl4 can be prepared this way.

Most likely the chlorine adds to SbCl3 in situ forming SbCl3, the released bromine also adds to the antimony catalyst forming SbCl3Br2 or SbCl2Br3, so the catalyst accelerates the chlorination and retards bromination reverse reaction. This is similat to antimony chlorofluorides in fluorine exchange reactions. The patent makes it clear that SbCl3 is the preferred catalyst along with SbCl5 and mixtures of the two.

[Edited on 19-2-2009 by Sauron]

Attachment: US4197262.pdf (154kB)
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