Sommelet reaction on ortho-subst'd BzX's ?

[bottleneck]

I have been hearing that maybe the Sommelet reaction of benzyl halides to benzaldehydes by reaction with hexamethylenetetramine does not work well on ortho-substituted benzyl halides.

Antoncho also mentions this in a previous posting.

Does anyone have any reference to the use of the Sommelet reaction on an ortho-substituted benzyl halide, or know some more about these restrictions on using ortho-substituted substrates?

Thanks!

[Bandil]

Hi!

Swib read that the sommelet will give somewhat lower yeilds when ortho substitued and nothing at all, if both ortho positions are taken. Could steric hinderance explain this? HMTA is a pretty large molecule, that needs to attack the halogen somehow. Is it a possibility that the 2,5-diOH compound would giver better/faster yeilds than the corresponding 2,5-diMeO ether?

Any thoughts?

Regards
Bandil

[hermanroempp]

Yes, steric hinderance is the explanation. Hexamethylenetetramine - as already stated by you - is a bulky molecule, due to its adamantane structure. So if both ortho-positions of the aromatic ring are blocked by (bulky) substituents, the it is very difficult for the HMTA to add to the benzylic carbon in the side chain. If only one ortho-position is blocked and the substituent is not too bulky, addition of HMTA and the subsequent formation of the quaternary ammonium compound  will still occur, but the yield of product can be diminished.
For bulky substituents the Hass-Bender reaction which involves the use of the sodium salt of nitropropane (or nitrocyclohexane) (instead of HMTA) should offer better yields...theoretically. Another option is the Kröhnke reaction which employs pyridine as a base and p-nitroso-dimethylaniline as reactant. At least the Kröhnke works for sure with o-nitro-benzylbromide, yielding o-nitro-benzaldehyde, yield about 60% or more if my memory serves me right.
Back to the Sommelet...if both ortho positions are blocked you can expect yields in the 0-70 % range, depending on the substituents. For example 2,4,6-trimethyl-benzylchloride will yield no aldehyde at all, the reaction takes another path, you will get the corresponding 2,4,6-trimethylamine and its N-methylation products. The same thing happens with o-xylylenechloride. But...2,5-dimethoxy-terephthaldehyde in 63 % yield is gotten from the corresponding benzylhalide, according to "I.H. Wood et al., Am. Soc. 72, 2992 (1950)".
So I would simply give it a try and work with the 2,5-diMeO compound. The 2,5-diOH compound should not be chosen, as with phenoles Duff reaction (similar to Sommelet) will occur with mediocre yields.
Quidquid agis, prudenter agas et respice finem!

[Antoncho]

a) The rxn works fine w/salicylaldehyde

b) accordcing to Hest's xperience, it works well with methoxylated ald's (i think)


c) UTSE



Antoncho

[hermanroempp]

Octanal:
To a solution of 5.47g (119 mmol) of anhydrous formic acid in 150 ml anhydrous THF under an atmosphere of nitrogen a solution of ethylmagnesium bromide, prepared from 14.6 g (134 mmol) ethyl bromide and 3.26g (134 mmol) magnesium turnings in 160 ml THF, is added during the course of 2h with constant stirring at 0-2 °C. At the same temperature then a solution of n-heptylmagnesium bromide, prepared from 14.9g (82.2 mmol) and 2.02g (83.2 mmol) magnesium turnings in 110 ml THF, is added with stirring during the course of 1h. The solution is stirred for another 2h at room temperature.
The batch is then hydrolysed by adding 100 ml of 2M HCl and extracted by shaking with 400 ml Ether (in a sep funnel). The organic phase is washed with saturated NaCl solution and then dried over sodium sulfate. The solvent is removed under a weak vacuum and the remaining oil is purified by fractional distillation.
Yield 7.45g (70 % of the theory) of octanal, b.p.(13 Torr) = 62-65 °C, n_D²⁰= 1.4207

Note: Anhydrous formic acid is obtained by drying over anhydrous copper sulfate and distillation of the pre-dried acid, b.p.(760 Torr)= 100-101 °C.

Aldehyd synthesis by addition of a Grignard compound R-MgX to the magnesium bromide salt of formic acid (generated from formic acid + ethylmagnesium bromide) and subsequent hydrolysis. The use of THF as solvent is essential for this kind of synthesis.

[Translated from:
Tietze-Eicher: "Reaktionen und Synthesen im organisch-chemischen Praktikum", p. 93, 1981, Thieme-Verlag, Stuttgart; New York]
Italics mine

This looks very interesting, to say the least. Someone might give it a try for benzaldehydes...
Quidquid agis, prudenter agas et respice finem!

[Rhodium]

That was a novel reaction I haven't seen before. Is there another way of preparing the MgBr salt of formic acid that doesn't require wasting grignard reagent? Any other equivalent salt?

What about reacting equimolar amounts of HCOOH : MgO : HBr followed by drying, or maybe HCOOH : Mg : HBr?

[hermanroempp]

this method is no so novel as it seems. It was briefly mentioned by GC_MS in his post [No 354361], route no.5, where he cites several routes for benzaldehyde syntheses from "Meyer: Synthese der Kohlenstoffverbindungen", but gives no direct "cooking" directions. I found it out right now as I was looking for "Meyer" in the search engine.
The method in my previous post is some kind of successor to the Meyers aldehyde synthesis, which originally involves reacting 4,4-dimethyl-2-oxazoline (prepared from formic acid and 2-amino-2-methylpropanole) with methyliodide, thus yielding the 3,4,4-trimethyl-2-oxazolium iodide, which in turn is reacted with the Grignard compound of an aryl halide to yield the corresponding aromatic aldehyde. The yield reported for p-methoxy benzaldehyde from p-bromoanisole is good, 85 % of the raw product.
Your idea of preparation for the HCOOMgBr salt is very interesting...and so easy   . But I have several concerns on this. Maybe the salt is not that stable or if it has water of crystallization in it, it may decompose on drying. Perhaps I'm wrong (I have no more data available about this synthesis and the HCOOMgBr salt), but I have the strong feeling that it is absolute essential to prepare the salt solution in THF, maintaining absolute anhydrous conditions. I don't even know if the HCOOMgBr stays in solution or precipitates out (it is not mentioned in the procedure from the book). If so (concerning precipitation), the THF could very well be needed to replace water in the lattice of the salt.

For those bees with access to databases and journals:
- the Meyers method is detailed in "A.I. Meyers, E.W. Collington, J. Am. Chem. Soc. 92,6676 (1970)"
- the successor method from the aforementioned post is detailed in "F. Sato, K. Oguro, H. Watanabe, M. Sato, Tetrahedron Lett. 1980, 2869"

Hopefully someone in here can come up with more info, because this synthetic route is really fascinating me. It seems to be easy, gives good yields...and it could work where the Sommelet fails. Btw., not a benzyl halide should be chosen, an aryl halide (e.g. bromobenzene) must be used as starting material. With a benzyl halide as starting material, the result will be phenylacetaldehyde  

Quidquid agis, prudenter agas et respice finem!

[GC_MS]

We're not talking about the same Meyer though. Check out references 7, 8 and 9 in that post if you are looking for more information. You'll need an antique library though   .
Ave Hive, synthetisandi te salutant!

[hermanroempp]

I have already checked this out in the ZVAB   , but the "Meyer" is only in parts available. But I don't have access to chemical databases like Beilstein etc. nor to chemistry journals like Tetrahedron, all I have is the small chemical library (partially antique)    in my study. And I'm aware that "Meyer" and "Meyers" are quite different, but the thing I'm really interested in is the route of F. Sato et al....of course more information concerning the Meyers aldehyde synthesis would be also appreciated  
Quidquid agis, prudenter agas et respice finem!

[Rhodium]

herman: I have uploaded the JACS article you mentioned, see the following PDF:

https://www.thevespiary.org/rhodium/Rhodium/pdf/formylation.grignard.2-oxazoline.pdf

The actual article starts on page 2, I took the liberty of including the preceding article in case someone wanted to read that one too.

[hermanroempp]

Thanks Rhodium, your effort is really appreciated by me. The article is interesting, especially the yields of aldehydes they obtained with this ingenious synthesis. The only drawback I see is the use of HMPA, it is toxic and I bet it is not so easy to buy for private use. I will have to talk to my friendly pharmacist soon...
The other "ingredient", 4,4-dimethyl-2-oxazoline is easily prepared as already mentioned in the JACS article.

For those interested in in this synthesis, here is the detailed preparation of 4,4-dimethyl-2-oxazoline:

To 89.1g (1 mol) of 2-amino-2-methylpropanol 49.05g (1.02 mol) of 96 % formic acid are added with constant stirring during the course of an hour. During the addition the batch is cooled in an ice-bath. When the addition of the acid is finished, the mixture is distilled at 240 °C. The distillate, which consists of an oxazoline-water mix, is collected in a receiving flask which is filled with 100 ml of diethyl ether and which is cooled in an ice-bath.
After the distillation (of the oxazoline/water mixture) the phases are separated, the aqueous phase is saturated with NaCl and extracted with 3x 50 ml diethyl ether. The original ether layer and the extracts are pooled, dried over anhydrous potassium carbonate and are then fractionated under normal pressure by using a 20 cm Vigreux column. After the solvent is distilled off, the 4,4-dimethyl-2-oxazoline distills in the range of 99-100 °C (760 Torr). Yield after distillation is 63.4 g of the oxazoline (64 % of the theory), a colourless liquid.

[Translated from..you guess it..
"Tietze-Eicher: Reaktionen und Synthesen im organisch-chemischen Praktikum", p. 338, 1981, Thieme Verlag, Stuttgart; New York]
Italics mine
Quidquid agis, prudenter agas et respice finem!

[bottleneck]

Concerning steric hindrance, why not use the DMSO-oxidation?

Nitropropane is smaller than hexamethylenetetramine, but DMSO is even smaller, right?

[moo]

I had come across the Tetrahedron Letters article last year while going through interesting papers referenced in March's 5th edition, a goldmine. The procedure is a 1/10 scale version of the one posted by hermanroempp. Several substrates are tested and the yields reported are 81% for benzaldehyde, 61% for phenylacetaldehyde and 67% for cinnamaldehyde. What they tell about the HCOOMgBr intermediate is that it "seemed stable under the reaction conditions and was converted to aldehyde only by hydrolysis" which was verified with proton NMR.

These were also found in the March's 5th : In Tet. Lett., 24(11), 1143-1146 (1983) different N-formyl-N-alkyl amines are reacted with grignard reagents, 85% yield of benzaldehyde with 2-(N-formyl-N-methyl)-aminopyrimidine. In Synthesis, 1978, 403-404 the same Meyers applied 2-(N-methyl-N-formyl)-aminopyridine in similar fashion, giving 72% benzaldehyde and 70% cinnamaldehyde. They also tried benzyl chloride (not the grignard that is), yield 80%. The amine which the formylation reagents were prepared from was recycled in both articles. I can type the preparations and procedures if requested.

[hermanroempp]

bottleneck:

b) accordcing to Hest's xperience, it works well with methoxylated ald's (i think)

I haven't looked myself in TSE for the post of Hest about conducting the Sommelet with 2,5-dimethyl-benzyhalides, but I think Antoncho is trustable and I would simply give it a try - first a test reaction on a small scale (I always do this before working with larger batches) with about 0.05 - 0.1 mol of reactant and if this test reaction (including cleanup of product) performs well and the yield of product satifies me, the reaction is scaled up to 0.25 - 1 mol, depending on amount of reactant available. Methoxy groups are not that bulky and the Sommelet should work.

moo:
I'm very interested in the Tetrahedron Letters article mentioning the HCOOMgBr intermediate (I'll call it the "Sato synthesis" from now on) and I'm sure other bees are too...
Please, could you upload the article to the hive or send it via mail to Rhodium, I think it would make a very nice addition to his page  

For those bees interested in more of Meyers' work, here's a link to a publication list I found today:
 

http://franklin.chm.colostate.edu/aim/pubs.html

Quidquid agis, prudenter agas et respice finem!