DMF purfication question and vilsmeyer formylation

[little_princess]

I know two ways for purifying DMF:
 stir with KOH and then distill in vacuo over CaO
or distill in vacuo over CaH

My previous attempts at formylating 1,4 dmb with methods found on rhod site (vilsmeyer) failed all. I know the purity of the 1,4 and of the oxychloride and they are over 99%. I don't know the purity of DMF and since it is hygroscopic and it stayed on conctact with air some time I think it is too damp for this reaction (has water a big influence in this formylation?). All that I get is some white solid that distill at 100°C at water pump and melt at the same time that 1,4 dmb, so I think that is starting material. with 35g starting 1,4 I get 30g of this product and the remaining in the RBF is a black oil, too few a oil for distilling it at 145 (bp of 2,5 dmb)! But the complex is yellow and the reaction turn black. The only variations i've done is put the dark mixture in hot (65°) basic water (and then basify the remaining acid) instead of ice/water and then basify and extract with chloroform instead of DCM.

my questions are:
-has anyone have success with similar reaction and would like to help
-can CaCl2 be substituted in the purification of DMF for CaO or CaH2? ie stir DMF over KOH and then distill over CaCl2
(my DMF utilised in the above reaction was dryed with MgSO4 and distilled under reduced presure) can MgSO4 be used insted of CaH2 or CaO?
-is the absence of water really that important?
-when I extract an appreciable amount of brown solid form in the aqueous black layer, is this normal? When Dr S do his formylation he never extract nor basify: he filter the formed crystals. maybe these crystals are product? (but i don't think so)

[Osmium]

The vilsmeyer formylation used on that molecule produces only 16% yield according to the literature.
I'm not fat just horizontally disproportionate.

[Antoncho]

"... to 85 g DMF there is added 10 g benzene, 4 g water and the mixtr is distilled. 1st a mixture of benzene, water and some other impurities distills off, then pure DMF is distilled under reduced pressure, bp 153 C / 60 mmHg"


I can't say for sure that "purification" in this case is equivalent to drying, but i still suppose so, beecause in this way even ethanol can bee dehydrated with ease. You can always use a little more benzene to remove any additional water present.

Further on.... There was a report on HyperLab of this experiment with identical results - 1st a total failure, due to wet DMF (the author said that appearance of a white crust, phosphoric acid, on the flask's walls was a true sign that formylation would fail). Another run w/ a thoroughly dried DMF resulted in circa 10% yield.

But, yet further, i suggest everyone interested will look at

Post 70528

(karel: "Synth of 2,5-dimethoxybenzaldehyde", Serious Chemistry) by Karel. It at least _looks_ "real"!

Now, bees, it's all very funny , since Karel has made only 11 posts thus far at these boards, but he's still around!

Karel, what do you say? (i'll PM him right away).



Antoncho

[little_princess]

Osmium : the procedure for karel tell about 70% Rdt, and in pihkal not much formylation totally fail, there are at least 40% rdt for most of them. I don't think it will only do 16% max, at least i hope. I think that the people who have done it with good yield had just not published because that's not what they were doing.

Antoncho: the procedure of karel was the one I used more often. (i tried a modified procedure based on the 2ct2 synthesis in pihkal, shorter reaction time, filtration and not extraction, warm water, at least this reaction worked more than this one ie in the EDDA stage my soltn became orange and not yellow like when i used karel's method (but my crystals were not bright orange like a nitrostyrene, but glassy white with faint teint of orange in them).

A more detailed write up:

The Vilsmeyer complex was prepared by 30 min addition of 92 ml phosphoryl chloride
(freshly opened ampoule) to 150 ml anhydrous DMF with stirring and cooling in ice.
idem but scaled down 3.5 times, solnt yellow, slighty viscous, put it in 15min not 30.
Light orange solution was then added dropwise during 2 hrs to a stirred solution
of 116 g 1,4-dimethoxybenzene (prepared from hydroquinone and dimethyl sulphate
in water, not purified, well dried) in 150 ml dry DMF at 100 - 110 deg C (bath),
a calcium chloride guard tube was used.
idem but put in 1h30
Heating was continued for 3 hrs. idem Resulting black mixture THAT IS REAL BLACK!
was poured onto 1 liter of ice-water, neutralized with 20% NaOH
(pH = 7-8) and extracted with CH2Cl2 (3 x 150 ml).
put it in 65° basic water, rebasify for neutralising, on coolings crystals formed (these crystals that shulgin filter). Here I don't filter but extract four times with CHCL3, some more crystals formed (a lot!)(these crystals are insoluble in CHCl3! what's this?
Combined extracts were washed
with 100 ml water, dried over Na2SO4 and distilled at atmospheric pressure (bath
temp. lower than 80 deg C).
100 water then 100 brine, not dried, distill chloro then vacuumed the rest of the chloro, warmed it to 125°C, some white solid evap at 95°C (with high vacuum), and then climb to 98-100°C and a lot of off white-very pale brown evap. Stop it, weigh the flask 40g (from 35g of 1,4)(recrystalised 36g not so dry solid, white, mp same as 1,4 dmb (but I tested these mp on thehot plate, so not very precise, bp same as well (but i didn't compare the bp with my little pure 2,5 dmb sample), this fraction contained some liquid as well, but all the mass crystalised off white color. In the RBF there was still a black oil, not so much to contain my product. Change flask, reput vacuum and at 110°C some yellow solid passed, these solid became orange 1 hour or so after, not like the brown of 2,5 dmb too! got 2g of this, put it with the other fraction.
Crude black product was crystallized from a mixture of
120 ml ethanol and 80 ml water. Crystallization was finished in freezer. I recrystalised the distilled sample and got two phase! but it became one at 95°C, then two on cooling, let it cool, seeded it and they became full of crystal. Put in freezer, filter, 36g wet crystal, white, pure by eyes, 1,4 dmb i bet!
Yield 106 g
pure, light brown 2,5-dimethoxybenzaldehyde (76%, m.p. 52-53 deg C). Isolation
of product by distillation under diminished pressure (b.p. 146 deg C / 10 mm.) should
provide somewhat higher yield, of course.
Not for me ! but distillation is the easiest way to remove the black color from your crystals I think


Antoncho, I think toluene could be substituted for benzene, right? But after distilling the azeotrope tolu/h2o, and vacuum distilling the remaining tolu/DMF, must I decant? because i do not think I will effectively separe them by vacuum distillation. I would prefer one method in this style: stir DMF with KOH, filter, put CaCl2 in DMF, let it stay for one day, distill in vacuo (or the same with MgSO4) it will be ok nop? what do you think?

Oh and i never saw any white crust: the mixture is black and the solids come only when I hydrolise it in water (on cooling or directly if cold water/ice is used.)

rem:
-there was a typo in your last post: the bp of DMF is 41-43 at 10mmHG and 153 at 760mm.
-The same reaction was attempted with thionyl chloride: same result, complex yellow, soltn black/brown (not so black than with POCl3), precipitate in H2O, same colour of crystals if filtered, but this reaction with SOCl2 STINK! deadly corpse odor...

I am sure that there are some people here that have a better experience than me on this reaction, It is one obvious pathway for the loved 2,5 DMNS and i know that a lot of people dreamed of it. On UTFSE notso much info is avaiable on the vilsmeyer formylation, but pihkal contain a lot of them (but not this one), and most give decent yield. I know someone have the answer... can he share?

[karel]

Dear bees,
the product I obtained by Vilsmeier formylation of 1,4-dimetoxybenzene was subjected to NMR analysis last week -
it is the starting material 1,4-dimethoxybenzene. It was my fatal error - the only identification of product I did previously was melting point, so I shouldn´t post that procedure. That was something what serious researcher had to never do. I am very sorry for misinformating of other bees. Anyway, recently I tried the procedure from post 70528 with 1,3-benzodioxole and the result was unreacted benzodioxole, so the conclusion is 1,4-dimethoxybenzene and 1,3-benzodioxole are not formylable with DMF/POCl3.
But something promising at the end - according to Chemical Abstracts it is possible to formylate 1,3-benzodioxole with N-methylformanilide (NMF) to give piperonal in 82% yield (Hung. Teljes, 60708, 28 Oct 1992) - maybe Vilsmeier formylation is not dead for us. If somebody can search and translate hungarian patents, it could be helpful to find it. It would be also useful to try general Vilsmeier formylation procedure with NMF/POCl3 as is e.g. in Organikum (there is also preparation of NMF from N-methylaniline and formic acid) with 1,3-benzodioxole and 1,4-dimethoxybenzene.
Sincerely

Karel

[Antoncho]

there are actually some patents in english about methylformanilide formylation of benzodioxole at espacenet - i've read them, but don't have time to find them now. Just type 'piperonal' into the query.

Yes, they mentioned that benzodioxole wasn't DMF/POCl3-formylatable, but never p-DMB.

Sad



Antoncho

[little_princess]

but Karel what's this ref then : Ref: J.C.S. Perkin 1, 1974, 1353-1354??? is it a general procedure? or is it a true procedure for 2,5 dmb??

What i will do with all my 1,4 then!! and my butanamines for my exams! bwahahahahah  

But I got some orange soltn with EDDA anc nitromethane one week ago, so there is some aldehyde at least, maybe different reaction condition like add the substrate in the complex ala shulgin (and not the reverse) then warm it to 100° a short time then experimenting with long or short reaction time. It is a general reaction that work with different formamide, so DMF must do it too!

[karel]

Yes, JCS Perkin 1, 1974, 1353-1354 is general procedure for formylation of activated arenes such is 2-methyl-1,4-dimethoxybenzene.
And yes, you are right, there is some aldehyde in the reaction mixture, but only a few percents I think.
So what to do with 1,4-dimethoxybenzene? I recommend bromination to 2-bromo-1,4-dimethoxybenzene with Br2/AcOH, then chloromethylation with HCHO/HCl to 4-bromo-2,5-dimethoxybenzylchloride, reaction with NaCN/DMF or DMSO to form 4-bromo-2,5-dimethoxybenzylcyanide and finally reduction with AlH3/THF to 2CB. If you are interested in, I will submit the procedures.

Karel

[Antoncho]

Yes, please, submit the procedures - in particular, the 1st two steps - bromination (well, this is sorta trivial, but still might bee some useful details there. One thing that truly intrigues me is the posible usage of dioxane*Br2 as a more selective and high-yielding bromination agent) and, particularly, chloromethylation of 2-bromo-1,4-diMeO-B, as a procedure of chloromethylating this particular comp'd was never posted to the Hive (although mentioned).

Please, do (the rest is well-known, AFAIK).



Antoncho

[hest]

1: The DMF for an wil´smeyer hack must bee dry and clean (destilation)
2: The wilsmeyer hack on 1,4-dimethoxybenzen works greath. disolve 1,4-DMB in some clean dry DMF, coll the solution. then add the POCl₃, let it reach room temp, then heat it to 80°C for 3-4 houers. Works nice (I'm sure the synth is at rhodiums site)
Karl, ad the bromine after the reduction, else you are just reducing it off again.

[Rhodium]

Hest: Are you really sure about that? The highest recorded yield using standard vilsmeyer conditions on 1,4-DMB is as little as 23% as far as I have seen - therefore most preparations of it are using the Gattermabn synthesis... Do you have references, or a detailed reproducible variaety nobody have thought of?

[little_princess]

1: The DMF for an wil´smeyer hack must bee dry and clean (destilation)

So does stir w/ KOH then dist over MgSO4 or CaCl2 is enough for dry it or have I to use CaO or CaH2, is it obligatory? Why different solvent have different purification procedure?

2: The wilsmeyer hack on 1,4-dimethoxybenzen works greath. disolve 1,4-DMB in some clean dry DMF, coll the solution. then add the POCl3, let it reach room temp, then heat it to 80°C for 3-4 houers. Works nice (I'm sure the synth is at rhodiums site)

Are you SURE that it work for 1,4 dmb? No there isn't any synthesis at Rhodium's site, there is one from karel wich does not work and one with pyrophosphoryl chloride which is not the same as phosphoryl chloride.

Is this write up ok?

All glass washed with MeOH and dried for 30 min at 150°C in the oven.

To 50 ml dry DMF in a 250ml RBF was added dropwise 28ml POCl3 (0.25mol) in 15 min with stirring and cooling in cold water.
The yellow solution was then put in the addition funnel and the calcium chloride tube reattached.

in a dry beaker 35g of melted 1,4 dimethoxy benzene (0.25 mol) was dissolved in 50 ml dry DMF, the mixture is added in the previous RBF w/ a stirbar and cooled in an ice water bath.

Ten minutes after the 1,4 soltn is cold and the POCl3 soltn is at RT. The dropwise addition of POCl3 sol to 1,4 sol start and go for 1h30 at 80°C  (or have I to directly put it in one portion to the cold 1,4 dmb and let stir, take the ice bath away, warm to RT and then heat it?) (Shulgin add his POCL3 in once portion but the ref at Rhod all speak of dropwise addition)

When the black mixture has stirred for 4h at 80°C (Is 110°C too much?) it was poured in 500 ml 65°C (or ice?) stirred water, let it stir one night, cooled, filtered (and not basified nor exctracted), the remaining crystals (with black impurites on them) (these impurities does not go away when recrystallising with MeOH and I haven't got hexane) are then distilled with vacuum at 100°C, the remaining 1,4 DMB recolted and recycled, the next fraction at hopefully 145°C (bath temp 180°C) is recolted, and recrystallised from the same weight of methanol, recrystalisation finished in freezer.

Is it OK? Correct me if I'm wrong, please..

Thank you hest, you brought me some hope in this reaction 

[terbium]

So does stir w/ KOH then dist over MgSO4 or CaCl2 is enough for dry it or have I to use CaO or CaH2
Distilling from MgSO4 or CaCl2 is not a good way to dry something. These two drying agents remove water by forming hydrates. Heating these hydrates reverses the process. You will need to use a drying agent like CaO which chemically reacts with water.

[karel]

For Antoncho: Here is it   :

2-Bromo-1,4-dimethoxybenzene

Method A - bromine and hydrogen peroxide in acetic acid

2 ArH + Br2 + H2O2 ---> 2 ArBr + 2 H2O

To ice-cooled and stirred mixture of 138 g 1,4-dimethoxybenzene (DMB) and 600 ml acetic acid was carefully added a solution of 26 ml bromine in 50 ml acetic acid during 20 min. Then 52 ml of 30% hydrogen peroxide were dropwise added during 30 min. Ice bath was then removed and stirring was continued for 30 min. Then the mixture was poured into 3 l water and dark red liquid product was extracted with CH2Cl2. Work-up and yield - see Method B.

Method B - hydrobromic acid and hydrogen peroxide in dichloromethane/water

ArH + HBr + H2O2 ---> ArBr + 2 H2O

To water-cooled and stirred mixture of 138 g 1,4-DMB, 200 ml CH2Cl2, 150 ml water and 115 ml 48% hydrobromic acid were dropwise added 110 ml of 30% hydrogen peroxide during 1 h. The reaction mixture was stirred for 1 day (TLC control) and then filtered through Celite to allow separation of layers. Water layer was extracted with 50 ml CH2Cl2, organic extracts were dried over Na2SO4 and evaporated in vacuo to give 193 g of dark red liquid (1).
Crude product was distilled at 0.2 kPa with aid of 15 cm Vigreux column - 30 g of forerun were collected at 55-90 deg.C (2) and then 144 g (66% yield) of pure product at 90-100 deg.C (3).

1.  Method A and B gives similar crude products consisting of 82% 2-Br-1,4-DMB, 12% unreacted 1,4-DMB and 6% 2,5-diBr-1,4-DMB (molar % estimated from NMR).
2.  It is mixture containing cca 15 g of 1,4-DMB and 15 g 2-Br-1,4-DMB, from which part of 1,4-DMB crystallizes on standing; and can be reused in another bromination of 1,4-DMB.
3.  From brown distillation residue, which often spontaneously crystallizes on standing, 2,5-diBr-1,4-DMB can be isolated by dissolving it in warm CH2Cl2 and slow evaporation of majority CH2Cl2 on air to afford 10 g of yellowish crystals of 2,5-diBr-1,4-DMB.

4-Bromo-2,5-dimethoxybenzylchloride

ArH + CH2O + HCl ---> ArCH2Cl + H2O

To vigorously stirred mixture of 130 g 2-Br-1,4-DMB, 58 ml 35% HCl, 24 g 1,3,5-trioxane (1) and 130 mg cetyltrimethylamoniumbromide (2) in 500 ml RBF was introduced gaseous HCl (about 17 g was necessary) at 80 deg.C (oil bath) during 2 h (3). Hot mixture was then poured into 1 l water containing crushed ice with stirring (glass rod) to avoid formation of big pieces of crude product. Filtration, several washings with cold water and drying over KOH pellets in vacuum dessicator provided 156 g of light yellow crude product (4). One crystallization from minimum amount of dry acetone gave 81 g (51% yield) of white crystals (5).

1.  This is modification from Bull.Soc.Chim.Fr. 1953, C46. Author used 325 g 2-Br-1,4-DMB and 175 g 35% CH2O and bubbled gaseous HCl during 2 h. My "38% CH2O" gave only 40% yield of chloromethylated product in that reaction (probably due to partial decomposition and polymerization of old formalin solution), so I chose stable and water soluble 1,3,5-trioxane as formaldehyde source.
2.  Tetradecyltrimethylamonium bromide as PTC was used in bromomethylation reaction of arenes with 1,3,5-trioxane and 48% HBr/acetic acid; see Synlett 1989, 55.
3.  Crude product often started to crystallize from reaction mixture. If not, continue heating for another hour.
4.  This is a mixture of 68% 4-Br-2,5-diMeO-BnCl, 30% 6-Br-2,5-diMeO-BnCl and trace probably 3-Br-2,5-diMeO-BnCl as indicated NMR spectrum.
4-Br-2,5-diMeO-BnCl:
1H NMR (CDCl3,400MHz) 7.10 (s,1H), 6.95 (s,1H), 4.61 (s,2H), 3.87 (s,3H), 3.84 (s,3H).
13C NMR (CDCl3,100MHz) 151.4 (s), 149.9 (s), 125.6 (s), 116.4 (d), 114.1 (d), 112.0 (s), 56.9 (q), 56.4 (q), 41.1 (t).
6-Br-2,5-diMeO-BnCl:
1H NMR (CDCl3,400MHz) 6.86 (s,1H), 6.84 (s,1H), 5.47 (s,2H), 3.86 (s,6H).
5.  From NMR. Purification of crude product at benzylchloride stage is much easier than at next benzylcyanide stage. Even chromatographical separation of 4-Br-2,5-diMeO-BnCN and 6-Br-2,5-diMeO-BnCN was fruitless.

For Hest: I'm afraid you aren't right. Bromine atom from aryl bromides is difficult to split off without transition metal catalysis. AlH3/THF sure don't do it. Anyway, how do you think SWIM obtained that NMR

Post 298778

(karel: "2CB NMR", Methods Discourse)?

Karel

[hest]

Sorry gues, I was thinking of 1,5-dimethoxytoluene. I look't intp my notes, and yes, a made the aldehyde from the bromde (With BuLi but I'm sure adding DMF(destilated) to the Gringnard reagens works as well.)
Maby AlH3 wont remove a halogen, but why not bee on the safe side and add it as the last step. This also made the cleanup easyer (working with almost unactive material is a lot mure fun than workin with material active at the mg scale)
And for the DMF thing, just destilate the DMF, don't use the first 5-10% of the destilate (thats where the wather are That is cleaning enough.

[hest]

But then again, this is from the aldhydefaq at rhodium
-------------------------------
2,5-dimethoxybenzaldehyde
The Vilsmeyer complex was prepared by 30 min addition of 92 ml phosphoryl chloride (freshly opened ampoule) to 150 ml anhydrous DMF with stirring and cooling in ice. Light orange solution was then added dropwise during 2 hrs to a stirred solution of 116 g 1,4-dimethoxybenzene (prepared from hydroquinone and dimethyl sulphate in water, not purified, well dried) in 150 ml dry DMF at 100 - 110 deg C (bath), a calcium chloride guard tube was used. Heating was continued for 3 hrs. Resulting black mixture was poured onto 1 liter of ice-water, neutralized with 20% NaOH (pH = 7-8) and extracted with CH2Cl2 (3x150 ml). Combined extracts were washed with 100 ml water, dried over Na2SO4 and distilled at atmospheric pressure (bath temp. lower than 80 deg C). Crude black product was crystallized from a mixture of 120 ml ethanol and 80 ml water. Crystallization was finished in freezer. Yield 106 g pure, light brown 2,5-dimethoxybenzaldehyde (76%, m.p. 52-53 deg C). Isolation of product by distillation under diminished pressure (bp 146C/10 mm.) should provide somewhat higher yield, of course.
Edit, this synthesis might not work, read the whole thread

Ref: J.C.S. Perkin 1, 1974, 1353-1354
----------------------
Sounds ok to mee.

[Rhodium]

That was posted by Karel in

Post 70528

(karel: "Synth of 2,5-dimethoxybenzaldehyde", Serious Chemistry), right. Perhaps I should remove his procedure from my page?

[hest]

And I guess that karl sayes it dosen't work in this thread.
Ok, god to know.

I will look the ref op this week, I'm not sure I have the time to doo the synth.

Rhodium, I think you shuld doo that

[karel]

Yes Rhodium, please delete this procedure

Post 70528

(karel: "Synth of 2,5-dimethoxybenzaldehyde", Serious Chemistry) from your pages.
Thanks

Karel

[Antoncho]

^{Originally posted by Little_Princess:}
Please Antoncho and Hest can you continue your discussion about these other way to make 2,5 dmb in the DMF purfication question and vilsmeyer formylation thread? I'm really interested by your exchange of thoughts. And maybe we can rename the thread 'Other way than vilsmeyer to 2,5 dmb from 1,4 dmb'?

Now that Karel's procedure turned out to bee misleading, i really think there is not such a way at all

The thing is, Antoncho really broke his head trying to figure one for 6 months and he just hasn't been able to.

So....

It is either a chloro/bromomethylation of 2-bromo-diMeO-benzene, or Vilsmeier formylation of the same...

But i have no clue if Vilsmeier will work on that compound. Can anyone please, help us with that?


Antoncho