Sciencemadness Discussion Board - Asymmetric Etherification of 1,4-dihydroxybenzene

Asymmetric Etherification of 1,4-dihydroxybenzene

PainKilla - 12-5-2008 at 16:25

I've been trying to synthesize 1,4-dimethoxybenzene via 1,4-dihydroxybenzene (hydroquinone). Now before any say that this can easily be achieved using other methods - of them I am aware.

My concern is moreso that it seems theoretically possible to synthesize 1,4-dimethoxybenzene using much more accessible and safe reagents - namely methanol and sulfuric acid.

So, I figured that as a protonated phenol is a species that is less prevalent than a protonated alcohol, a simple etherification would work, in which the CH3OH2+ intermediate is generated, which hydroquinone would then attack, ultimately yielding the phenol methyl ether:

H2SO4 + CH3OH --> CH3OH2+ + HSO4-
CH3OH2+ + HO-Ph-OH --> CH3O(+H)-Ph-OH --> CH3-O-Ph-OH
CH3-O-Ph-OH + CH3OH2+ --> --> CH3-O-Ph-O-CH3

I have run a number of reactions which seem to imply that the reaction works, but I cannot seem to isolate the product:

"Sn2 type alkylation via methyl sulfuric acid and phenoxide"

.09mol HQ (10g)
.18mol CH3HSO4 (~23g - 7.2ml (.18mol) CH3OH + 10.3ml (.18mol) 93% H2SO4)
.2mol KOH (11g)
30ml water, 30ml methanol

HQ was dissolved in methanol and KOH dissolved in water was added. The solution was heated to a light reflux and methyl sulfuric acid slowly dripped in. The water/methanol/DMB? was steam distilled into a brine solution. Only methanol distilled, and upon acidification a dark red/brown solution was obtained that did not extract with toluene.

Note: I found a report which said that 1,4-DMB may be produced in a similar manner, but clearly one must follow that procedure exactly for it to work.
-----
"Sn2 type alkylation via methyl sulfuric acid and phenol" or "Acid catalyzed asymmetric etherification" Run 0

.09mol HQ (10g)
.18mol CH3HSO4 (~23g - 7.2ml (.18mol) CH3OH + 10.3ml (.18mol) 93% H2SO4)
1mol CH3OH (40ml)

HQ was dissolved in 40ml methanol and slowly dripped to a heated solution of methyl sulfuric acid (~110*C), and the mixture distilled slowly. *LOTS* of dimethyl ether was generated. The distilled fraction was diluted with water to yield ~.5ml of a yellowish oil that smelled like DMB. The reaction mixture was diluted with water and yielded ~2.5g visually (spilled into oil bath and not isolated

) of crude, brown/red DMB.

Note: This is basically when I decided that a "regular" etherification is actually occurring and not any sort of strange mechanism via methyl sulfuric acid (although, it might be an intermediate). These are also the conditions in which I may have gotten and isolated (if I didn't spill into an oilbath) a workable amount of 1,4-dimethoxybenzene.
-----

"Acid catalyzed asymmetric etherification" Run 1

.09mol HQ (10g)
.09mol H2SO4 (5ml 93% H2SO4)
1.54mol CH3OH (62ml)

HQ was dissolved in 40ml of methanol and added slowly to a solution of 5ml sulfuric acid and 22ml of methanol held on an oil
bath whose temperature was 150*C. The rate of addition was kept so that the volume of the solution was stable throughout.

The obtained distillate was diluted in water... nothing happened. Upon cooling the reaction mixture separated into two layers. This was diluted with water, still forming two layers. In an attempt to extract the DMB immediately, KOH in water was added, but the solution very quickly turned black (seemingly very rapid polymerization or oxidation) and soon a layer was impossible to obtain. But the yield seemed to be very good (of DMB), and the solution smelled very strongly like DMB. In short the reaction probably worked but the DMB must be isolated without basification, and then purified via water/distillation.

"Acid catalyzed asymmetric etherification" Run 2

.18mol HQ (20g)
.18mol H2SO4 (10ml 93% H2SO4)
3.08mol CH3OH (124ml)

HQ was dissolved in 80ml of methanol and added slowly to a solution of 10ml sulfuric acid and 44ml of methanol held on an oil bath whose temperature was 150*C. The rate of addition was kept so that the volume of the solution was stable throughout.

This was diluted with water, but no layers formed (reaction was not cooled.... hydrolysis?). The solution was basified and extracted - a very small amount of DMB was obtained.

"Acid catalyzed asymmetric etherification" Run 3

.18mol HQ (20g)
.36mol H2SO4 (21ml 93% H2SO4)
6.60mol CH3OH (264ml) (44ml (1.1mol) + 100ml (2.5mol) + 120ml)

21ml sulfuric acid and 44ml of methanol was held on an oilbath whose temperature was 170*C until evolution of dimethyl ether
was seen (the methanol/water formed was distilled off). HQ was dissolved in 100ml of methanol, and added slowly to the
methanol-sulfuric acid such that DME was evolved (1-2 bubbles/second) and the volume slightly increased through the addition. Once the addition of the HQ was completed, an additional 120ml of methanol was dripped into the solution, the excess water and methanol distilled off and DME continued to be evolved. The additions were done at such a rate so as to keep the volume of the solution increasing a slight amount. As soon as addition was complete, the flask was removed from the oil bath and cooled to room temperature at which point a 150ml of cool water was added to the solution.

The solution smelled strongly of DMB but no layers formed, and extraction with toluene and evaporation of the solvent yielded no appreciable amount of DMB.

-----

The general idea behind the proportions used was to "selectively" protonate all the methanol (thereby having unprotonated HQ and CH3OH2+) and then distill off the extra methanol and formed water, which should drive the reaction to completion. It certainly *appears* to work (and makes everything smell very nice) but again, no isolation of product can occur.

In short, the dark products seem to occur whenever the phenoxide of hydroquinone forms (I assume this is oxidation of the hydroquinone to the benzoquinone). 1,4-dimethoxybenzene also seems to be formed, based on the smell at least, but then actually isolating any is problematic. There is also 4-methoxyphenol formed, but it's easy to separate from the 1,4-DMB.

Also, these conditions may form a small amount of dimethyl sulfate in situ although I am unsure of whether or not it does in reality. In any event, I would appreciate any advice which could help perfect these conditions as they would prove to be very useful for alkylation of simple phenols.

I will be retrying something along the lines of "Run 0", as it seems that having the conditions which generate *LOTS* of DME are more important than removing water from the reaction (as per Runs 1, 2 and 3).

[Edited on 12-5-2008 by PainKilla]

Klute - 13-5-2008 at 02:34

Thank you for sharing your experiments!
I was under the impression that MeOH/H2SO4 would mainly form p-MeO-phenol under acidic conditions? The black oil seperating on cooling corresponds pretty well to what happens with the same conditions but a little benzoquinone added. I know the added benzoquinone surely implies a different mechanisms (maybe at those high temps some BQ is formed from atmospheric/dissolved oxygen).

Why not try to make the mono-methyl ether with the conventional conditions, and then try to furhter methylate it with methyl sulfuric acid, or one of it's salt, as a first experiment? You would see if it is even possible to methylate the phenol with only MeOH/H2SO4. If it works an dyou can isolate a reasonable amount of the dimehtyl ether, you could go back and try a one-pot reaction (excluding the BQ, as it seems to supress formation of DMB pretty effectively).

Have you tried directly using a salt of MeHSO4? I guess it's lenghty preparation is best avoided, and that's why you try using in-situ MeHSO4...

Good luck and keep us updated!

Ullmann - 13-5-2008 at 07:02

I agree with klute the methylated compound you get must be p-Meo-phenol through the presence of some benzoquinone that catalyse the transformation as it is well know from various patents on the process.

You cannot dimethylate the HQ to the DMB this way. It works only with naphthohydroquinone and with phloroglucinol (this one only for one or two etherification, never three)....

BTW DMB is a dead end unless you want to do a gatterman reaction, a chloromethylation/sommelet or maybe a modified duff but the yields will be poor in that last reaction unless you halogenate para first (in fact i dont know that is a wild guess it may still give 50%)... And the other two are quite toxic and no fun... nonetheless it is a bad intermediate IMHO. p-Meo-phenol is much more versatile as you can use CHCl3/NaOH or HCHO/Mg to place the formyl then methylation of the phenol should be easy with KMeSO4 or Methyl-tosylate or CH3I. Methyl tosylate of course OTC from Boric acid/MeOH reflux on tosic acid itself readily avaiable from toluene and - i think - that reagent (methyl tosylate) is particularly more suited. You will have better luck with that route through p-Meo-phenol nonetheless i am convinced.

[Edited on by Ullmann]

Klute - 13-5-2008 at 08:48

Sorry for the off-topic, but Ullman, have you tried the methyl tosylate synth from trimethylborate/TsOH yourself? How good were your yields? Or do you assume it works?

PainKilla - 13-5-2008 at 11:48

All of the reactions I have seen that selectively produce p-methoxyphenol use benzoquinone - that reaction is entirely different from this one because it involves acetals as intermediates. This is just a simple etherification, so I see no reason why the reaction would not go to completion.

In fact, if you look at the production of p-methoxyphenol, you can see that certain conditions (favorable for etherification as earlier described) actually produce a fairly substantial amount of 1,4-dimethoxybenzene in addition to p-methoxyphenol. Thus I see no reason for this reaction to not proceed to completion - and it certainly does seem to work... I will retry run 0 in a few minutes and see if I can avoid spilling stuff into an oil bath.

The black "oil" is not quite what I mean. I do know what you mean as I've done the 4-methoxyphenol synthesis a few times, but the oil obtained from this etherification is actually quite clear - it is only upon basification and exposure to air that a solution turns black. This is just unreacted hydroquinone oxidising, as a pure sample dissolved in base does the exact same thing.

I do have a bunch of very pure 4-methoxyphenol, I just don't feel like using methylating agents for the reasons stated. However this etherification does appear to work, and using methyl sulfuric acid I think will not matter, because the reaction will still proceed through the same general pathway/conditions. It's just a matter of optimizing them.

Nicodem - 13-5-2008 at 21:51

This can not be a normal etherification since then you would obtain only dimethyl ether (ArOH is nearly not as nucleophilic as MeOH which, being a solvent, predominates anyway). Alcohols with phenols in highly acidic media rather give C-alkylation products since at the acidic conditions required these are the products of the less reversible reaction. Though it is possible that in run 0 where you used methyl sulfuric acid (I assume from MeOH/Na2SO4/H2SO4?) some 1,4-dimethoxybenzene could have formed I find it hard to imagine this could be made into the main product. The other runs where you used MeOH/H2SO4 should, in my opinion, not produce any detectable 1,4-dimethoxybenzene. The smell means little to nothing. It would be best if you could follow with TLC instead. Why not trying in basic media to cleanly get the product using methyl sulfuric acid? This way you could use water as solvent.

PainKilla - 14-5-2008 at 13:34

I realize that ArOH is not nucleophilic enough to compete with MeOH, but I am playing around with the conditions to hopefully make it so. By only using enough methanol to have it all protonated (1mol H2SO4 - ~1.5mol CH3OH), with enough methanol constantly added as the ether and methanol are removed, all of the hydroquinone should be converted to dimethoxybenzene with a long enough reaction time. As just about all of the reactants can be recycled, it makes this procedure particularly attractive, even if the yields aren't superb.

In fact, I did redo run 0, and seem to have isolated a small amount of 1,4-dimethoxybenzene (~3-4g) from 10g of hydroquinone (am currently working it up, will have more details soon). I also generated a very large amount of 4-methoxyphenol (~5g), and there was a small amount of hydroquinone left unreacted. In short, I think with a long enough addition time of methanol it is entirely possible to forcefully shift the equilibrium towards the right.

I will try the methylsulfate alkylation if this does not work, but this truly seems promising. I did find a patent that suggested something like this could work (but I don't have it with me), and it does appear to be...

"Acid catalyzed asymmetric etherification" Run 4

.09mol HQ (10g)
.18mol 93% H2SO4 (10ml)
120ml methanol

Hydroquinone was dissolved in 40ml methanol and 10ml sulfuric acid and slowly heated on an oil bath whose temperature was ~170*C until dimethyl ether was evolved. 80ml methanol was then slowly dripped in so as to keep the rate of ether formation relatively constant (1-2 bubbles/second). Once the addition was complete, the reaction mixture was cooled to room temperature, quenched with ice water (resulting in a large amount of tan precipitate), basified and extracted with toluene.

I'll update as soon as I remove all the toluene.

Note: This reaction seems to work best when it's sulfuric acid and methanol (~1:~1) and a dilute HQ solution in methanol is slowly added to this heated solution. But I will see for sure soon...

Edit: After evaporation of the solvent I got 1.2g of a dark yellow oil that melted at about 54-56*C. It looks like there is a small bit of impurities but one should vacuum distill the dimethoxybenzene anyway.

So thus yield was not as good as originally estimated, but still significant considering these conditions appeared to be less than ideal and there is much room for improvement. I will try next time to start using a small amount of 4-methoxyphenol, for it will then be absolutely clear just how long the reaction needs to be run (and if it can be tuned to work well at all).

Edit 2: Good news! I just recycled the methanol and upon diluting the last bit I got a bunch of very pure, white crystals of DMB! I figured that the steam (well, steam/methanol) distillation would be pretty slow and that a significant amount would not carry over but it appears that it does and it looks VERY pure... I will take a weight in just a moment, but this makes this reaction extremely promising!

Edit 3: The distilled 1,4-DMB weighed .5g. This isn't significant, but given the high amount of 4-methoxyphenol that also formed, it appears that a longer reaction time will afford very pure 1,4-dimethoxybenzene using conditions similar to those in runs 0 and 4. The ideal system for maximum efficiency would be as in the picture:

[Edited on 14-5-2008 by PainKilla]

worst picture ever.JPG - 29kB

Victory! A Methylation Using Methyl Bromide

PainKilla - 15-5-2008 at 19:37

I saw on another forum that methyl bromide was used to methylate hydroquinone, so I decided to try this out myself. Unlike DMS or MeI, MeBr is cheap to make (DMS costing time, and MeI costing money). While I had hoped to not use a traditional methylating agent, it turns out methyl bromide is actually not very toxic!

So anyway on to the good stuff:

110g hydroquinone (1mol)
450ml methanol
150g KOH (2.7 mol)

412g NaBr (4mol)
300ml water

250ml methanol (5mol)
230ml H2SO4 (4mol)

In a 1L RBF flask equipped with a dropping funnel and set up for distillation, methanol and sulfuric acid were slowly mixed together with cooling, and dropped onto a boiling (saturated) solution of sodium bromide over the course of two hours. The water/methanol/HBr (very little formed) vapors were condensed into a sealed flask, and the methyl bromide was collected with a plastic tube connected to the vacuum adapter, which led directly into a solution of hydroquinone in methanol. The methyl bromide was first slowly released to displace the oxygen in the flask, and potassium hydroxide (flake) then quickly added with *good* stirring while cooling the flask on ice bath. Methyl bromide was then generated (controlled by rate of MeOH/H2SO4 addition) more rapidly and driven through the solution until the supply was exhausted (2 hours), with vigorous stirring.

The solution first turns brownish (oxidation of hydroquinone) with a yellow tint (phenoxide of 4-methoxyphenol) and eventually a large mass of whitish crystals form (potassium bromide).

The potassium bromide was filtered (the solution is completely neutral at the end), washed with methanol and dried. 250g was recovered (79% recovery).

About half the methanol was then evaporated (~200ml) and the remains were quenched with 1.5L water and cooled to 5*C. The precipitated clear/white crystals were then filtered, washed a few times with warm water, vacuum filtered and dried.

Yield: 114g (83% yield)

The obtained DMB melts at 54-56*C.

In short, this methylation is very easy to perform, non-toxic and high yielding. It reportedly works for other substrates also, and I would be interested to see if it can work on deactivated substrates. In any case, this is definitely the way to methylate simple phenols!

Edit: Just to clarify, the reactions previously mentioned (the H+ catalyzed etherifications) are still seem promising, although they still need some more optimization. If anyone else wants to pick up where I left off, I would recommend redoing run 4 using more methanol, perhaps in a setup as shown so as to allow recycling of the materials (as per the picture). However, given the ease of the methylation with methyl bromide, I will close my lab book in regard to the synthesis of this specific ether using that method.

[Edited on 15-5-2008 by PainKilla]

Nicodem - 16-5-2008 at 00:38

Excellent job!

For years I was wondering why nobody reports using this method for methylating phenols while it is the most obvious choice for those who don't have any dimethyl sulfate or methyl iodide. I often considered trying it myself, but then picking up the bottle of dimethyl sulfate off the shelve is so much easier, so I never bothered. I'm glad someone else finally did it. You really should write down a full report for the Prepublication section!

PainKilla - 16-5-2008 at 00:59

I'll try and get some pictures if I have time, although I really don't need more dimethoxybenzene. Maybe I can try using this type of methylation on another sort of phenol(ic aldehyde) as that would certainly show its potential as a methylating agent.

In any event, I'll definitely try again and document this method as soon as time permits.

[Edited on 16-5-2008 by PainKilla]

not_important - 16-5-2008 at 01:28

Quote:

Originally posted by PainKilla
...
In short, this methylation is very easy to perform, non-toxic and high yielding.
...

While it is an effective and simple proceedure, I must disagree on the non-toxic part, MeBr and MeI are similar in their toxicity:

Quote:

Methyl bromide, labeled with a DANGER signal word, is an extremely toxic vapor. In humans, methyl bromide is readily absorbed through the lungs. Most problems occur as a result of inhalation. About 1,000 human poisoning incidents caused by methyl bromide exposure have been documented, with effects ranging from skin and eye irritation to death. Most fatalities and injuries occurred when methyl bromide was used as a fumigant.

Inhalation of 1,600 ppm for 10-20 hours, or 7,900 ppm for 1.5 hours is lethal to humans (8). The lowest inhalation level found to cause toxicity in humans is 35 ppm in air.

Methyl bromide is a dangerous cumulative poison. First symptoms often are due to damage to the nervous system, and may be delayed from 48 hours to as long as several months after exposure. This delay, combined with methyl bromide's lack of odor, means that the victim may not realize that exposure is occurring until much time has passed.

Symptoms of poisoning vary widely. Soon after inhalation of large doses, symptoms may include headache, dizziness, nausea, chest and abdominal pain, and a dry throat. Three to 12 hours after vapor inhalation, symptoms include slurred speech, blurred vision, temporary blindness, mental confusion, and sweating. More severe symptoms may include lung swelling; congestion; hemorrhaging of the brain, heart, and spleen; severe kidney damage; and numbness. Death may occur within 1-30 hours, usually from respiratory failure.

Although skin absorption is not an important route for methyl bromide intoxication, the skin is affected by contact with this chemical. Methyl bromide can cause enormous blisters that are rarely deep enough to destroy the entire skin layer. Small amounts of skin or eye contact brings on shortness of breath and itching. If absorbed through the skin, nausea and vomiting may result. Clothing that can not "breathe" may delay the evaporation of the pesticide from the skin. Continued contact with skin can cause death. Ingestion of methyl bromide may cause hand tremors, and convulsions.

The inhalation LC50 for rats is 3,120 ppm/15 minutes (7), 2,700 ppm/30 minutes, and 1,164 ppm/60 minutes. For guinea pigs, it is 300 ppm/9 hours and it is 2,000 ppm/11 hours in the rabbit (7). The rat LD50 administered in liquid is 20 mg/L (11). The dermal LD50 for rabbits is 15 ppm.

Quote:

In DNA-binding studies performed in rats and mice, 14C-labeled methyl chloride was given by inhalation, and methylation of DNA bases was examined. The compound did not lead to specific DNA adducts. In particular, methylation of DNA bases was not observed. In contrast, methyl bromide and methyl iodide, upon oral and inhalation administration to rats and mice, caused systemic DNA methylation.
http://www.ncbi.nlm.nih.gov/pubmed/8260067

Klute - 16-5-2008 at 04:27

First of all, a big Bravo to Painkilla! You are the firt person I hear using MeBr in amateur settings, and getting it to work! Indded the preparation looks simple enough!

I totally agree with Nicodem's suggestion of posting this in prepublication, if you can make a somewhat detailed write-up. It would be evry interesting to see if it works with phenolic aldehydes, I see no reason why it wouldn't, considering that MeI works perfectly, and TMP also gives very good yields while been much less reactive. You might need to find a way or keeping the MeBr into solution a bit longer though (dissolving it into a solvent? Sealed apparatus?) or use a healthy excess, which isn't a problem considering the price of KBr and the 80% recovery you achieved! I think this is a breakthrough (the whole use of MeBr, not the KBr recovery

)

Hum, indeed, I don't think you can use the word "non-toxic"... On the other hand, With a little more precautions, this can be safer than using/making MeI.

I would use a conc. NaOH wash bottle, or NH4OH, flush the system with argon or nitrogen, add the KOH to the phenol as an alcoholic solution, in the cold (to avoid quinone/side-reactions) and with good stirring, then start generating MeBr. The fact that it is formed in-situ can mean 0 exposure if done correctly! Just add NH4OH to the NaBR/H2SO4 solution at the end, purge the system with a slow flow of air (sending all the MeBR vapors in the washbottle), and you are fit for work up!
And if your compound isn't a aldehdye, such as DMBenzene, you can basify with ammonia to destroy any dissolved alkyl halide, a dilute hydroxide solution should work too if done in the cold and not left for long.

I'm very impressed by your work. Keep up the good stuff, and can't wait to see how this goes with phenolic aldehdyes!

not_important - 16-5-2008 at 05:38

Quote:

The fact that it is formed in-situ can mean 0 exposure if done correctly!

Yes, quite true, a little caution and you can avoid exposure; plus there's no storage concerns beforehand.

Klute's suggestions sound worthwhile, even if you can't do the inert gas flush adding the base in solution should help.

PainKilla - 16-5-2008 at 11:28

Thanks for the comments everyone!

As far as the rate of reaction... it actually goes quite fast (as it is *quite* exothermic) - I think in reality one doesn't really need to generate MeBr for two hours, rather 30-45 minutes would suffice. In addition, one can also run the reaction in the cold (0*C) and the methyl bromide would stay in solution , though the reaction would probably be pretty slow then.

But as far as recycling is concerned, maybe the MeBr would be used for some other application? How about driving it into a solution of methanol and NaCH3SO4? No one can complain about easy DMS if it works.

Otherwise I don't really know what can be done to improve the reaction, I think it's important to evaluate how effective it is for less activated substrates as we currently aren't aware at how well it methylates such things...

not_important, when I say that the compound is effectively non-toxic, I mean in comparison to the carcinogenicity of methylating agents... Otherwise it's just like any chemical.

I don't have a hood but what I did was just run another vacuum adapter tube from the MeOH/HQ flask to the window... It was thus effectively a closed setup anyway.

http://ntp.niehs.nih.gov/index.cfm?objectid=070917F9-D058-F1...

It's definitely not something you want to use as a fragrance, but it's also not as toxic as methyl iodide or dimethyl sulfate (cancer).

[Edited on 16-5-2008 by PainKilla]

Klute - 18-5-2008 at 02:58

Fleaker and I were discussing your brilliant experiment, when he suggested using the MeBr to make some MeI with iodides in acetone..
Knwoing that alkyl iodides are more reactive than bromides, wouldn't a catalytic amount of I- be helpfull for the more delicate substartes, such as phenolic aldehydes? IIRC, this trick is often used in alkylations using alkyl bromides... I also think alkali iodides are more soluble in acetone than alkali bromides, so this difference could help displacing the equilibrium.

The MeBr could also be used to make methyl tosylate, by passing a slow stream into a suspension of a salt of tosic acid in a adequate solvent, filtering the bromide salt, and adding the obtained solution to the substrate. This would mean diminsihed toxicity, and the possibility of reflux without loosing the product through the condenser, though it's another step added. IIRC methyl tosylate and methyl bromide are of similar reactivity, if not more for the ester, so it could be avantageous.

Nicodem - 18-5-2008 at 03:13

Methyl bromide is not much less electrophilic than methyl iodide. They are more or less similarly reactive. Only methyl chloride is way less electrophilic. For every methylation where MeI works, MeBr can surely be used as well. (Coincidentally, MeBr is used as a standard electrophile in the measurement of relative nucleophilicty of test nucleophiles.)
Just think about the alkylations with EtBr or PrBr which work perfectly well on phenols even in refluxing ethanol (not even DMF is needed!). And the reactivity of alkyl bromides follows the general SN2 direction: MeBr > EtBr > PrBr >> i-PrBr...

You can not prepare MeOTs from MeBr and a metal tosylate since the bromide ion is much more nucleophilic than the tosylate ion. Such a reaction would require the use of silver tosylate to push it in the direction of MeOTs, but other metal tosylates can't work.

Klute - 18-5-2008 at 03:25

I'm surprised of this, I could have sworn I had seen a preparation of tosylate from alkyl halides... I beleive you, but I will need to go through some articles to see what made me think this works..

It's true alkyl bromides are often used when it comes to 2 carbon chain and more, I'm guessing the difference of prices comapred to the small difference of reactivity isn't worth the change. I guess with MeBr the iodides could help keeping some alkyl halide in the time it reacts.

EDIT:
Hum, I think I inversed the reaction in my head... The article I had in mind was the one I'm attaching, but indeed it deals with the preparation of alkyl iodide from alkyl tosylates and NaI.. The other way around...
On the other hand, alkali sulfinates can dispalce halides, maybe that got me confused to, by analogy. (Note 2 from this OrgSyn prep ). Too bad for the idea then...

Article attached:

"The action of sodium iodide on some esters of p-toluenesulfonic acid"
R.S. TIPSON, M.A. CLAPP, L.H. CRETCHER

[Edited on 18-5-2008 by Klute]

Attachment: jo01165a017.pdf (363kB)
This file has been downloaded 1493 times

Nicodem - 18-5-2008 at 03:42

Quote:

Originally posted by Klute
I'm surprised of this, I could have sworn I had seen a preparation of tosylate from alkyl halides... I beleive you, but I will need to go through some articles to see what made me think this works..

I think you found the paper here: http://sciencemadness.org/talk/viewthread.php?tid=10275&...
But silver tosylate is used which makes the reaction toward the ROTs irreversible due to the insolubility and the formation of covalent bond in AgBr.

Methyl bromide is never used for preparative methylations in organic labs simply because it is a gas at room temperature while methyl iodide is a liquid. So you can be sure everybody would prefer MeI due to practical reasons and not that much because MeBr is somewhat less reactive. After all, in many solvents dimethyl sulfate is also somewhat more electrophilic than methyl iodide and still both are often used.

stoichiometric_steve - 19-5-2008 at 13:46

a bit off topic, but i think it fits here since the use of MeBr is discussed:

during the ether cleavage of methyl phenyl ethers using AlCl3/Pyridine, MeCl is formed. is there any efficient way of making this react to something harmless?

EDIT: I'm stupid. what was i thinking...the MeCl reacts with Pyridine to N-Methylpyridinium chloride.

[Edited on 19-5-2008 by stoichiometric_steve]

ShadowWarrior4444 - 19-5-2008 at 14:14

Quote:

Originally posted by stoichiometric_steve
a bit off topic, but i think it fits here since the use of MeBr is discussed:

during the ether cleavage of methyl phenyl ethers using AlCl3/Pyridine, MeCl is formed. is there any efficient way of making this react to something harmless?

Inhalation is an efficient way to accomplish that.

On a serious note, you can likely react it with chlorine gas at 400-500C to produce progressively more chlorinated versions. A mixture of methyl chloride, DCM, chloroform, and CCl4 should result, which would then be separated by distillation. You may also want to run it though a gas liquefier, bottle it, and use it as a refrigerant.

garage chemist - 19-5-2008 at 14:39

MeCl is much less toxic than MeBr.
Anyway, a good way to render alkyl halides and alkylating agents in general harmless is to add them to ammonia.
Ammonia and amines are rapidly and easily alkylated, consuming the alkylating agent.

PainKilla - 19-5-2008 at 21:41

Another interesting modification may be to perform the reaction at a low temperature (<3*C) so as to keep all of the methyl bromide in solution. While the reaction rate will be slower, the concentration of MeBr should be quite high, thereby promoting the reaction... I would think that MeBr is also fully miscible with methanol (or basically any Sn2 solvent) so this would also make removal of the gas non-problematic (as it would just be a liquid in solution).

The only potential problem with this is that the reaction (in the case of hydroquinone) is quite exothermic, enough to keep the methanol at 50-60*C (estimated). Granted, this could be fixed by using very efficient cooling but I think the easiest thing to do would be to just to use a longer reaction time, letting MeBr enter the reaction flask at a slower rate.

I think next time I will also add hydroquinone to KOH in methanol (instead of the other way around), as this should help to prevent oxidation (although this problem is pretty much unique to hydroquinone).

Klute - 19-5-2008 at 22:26

Quote:

I think next time I will also add hydroquinone to KOH in methanol (instead of the other way around), as this should help to prevent oxidation (although this problem is pretty much unique to hydroquinone).

Hum, I don't totally agree. I've witnessed that nearly all phenolates are readibly oxidized by atmospheric oxygene even at RT. This can be seen by the difference in colour of the medium if the formation is done under argon or not, all other conditions been equal.
With salicylaldehdye, the phenolate is orange/yellow under argon, but quickly turns dark brown/black when done under atmospheric conditions. This also happens with phenol to a lesser extent, aswell as other non-aldehydic phenols.
That's why i always prefer adding the base to the phenol, or the other way around, at cold temperatures (0-5°C), under argon, and over 10min, leaving it to stir for another 10-15min.

PainKilla - 19-5-2008 at 22:42

I think salicylaldehyde is a bad example to use though, I mean orthohydroxy aldehydes tend to polymerize fairly easily from what I've seen in the literature, and I haven't seen so rapid a change with any plain phenols. Even hydroquinone oxidises pretty slowly.

Anyway, the idea would be to add the hydroquinone to a flask with air displaced by MeBr. You'd lose a bit of MeBr initially but then since you don't lose any later on, you can use a much smaller equivalent of all reagents and on top of that, be able to recover most of the bromide put into the reaction.

Gas management becomes a non-issue then too!

Nicodem - 20-5-2008 at 00:31

In my experience, aqueous solution of sodium phenolate is stable for weeks. It does darken a bit after a couple of days, but the oxidation products are not detectable on HPLC, so they must be only in ppm concentrations.

With hydroquinones (or catechols) the most problematic is not the oxygen in the air above the solution, but the oxygen dissolved in the solvent used. Oxygen need some time to dissolve, so it is mostly the already dissolved oxygen that causes the darkening seen initially. Thus it is best to degas the solvents prior use. This can be easily done by letting it stay for a minute under the aspirator vacuum or to heat the solvent to boil. Another often used trick is to add a pinch of sodium dithionite in the reaction mixture. This small amount does not interfere with the alkylation but it does reduce all dissolved oxygen and all of the quinones formed by oxidation.

Ethanol or isopropanol should absorb MeBr gas more rapidly than methanol even when warm. And both are also better solvents for SN2 reactions since they solvate the phenoxide anions considerably less so than methanol (unsolvated anions are much, much better nucleophiles, since solvation is the main factor in increasing the activation energy of the reaction).

Klute - 20-5-2008 at 08:53

My experience with phenol was with it's magnesium salt, during the formylation with Mg(OMe)2/(H2CO)n. No dissolved oxygen as the magnesium methoxide was generated with magnesium metal, reducing any dissolved oxygen and saturating the suspesion with H2 I suppose, and all the added solvents were degassed under vacuum/argon cycles.
Of course, the conditions were surely a little rougher than RT in water , as it involved distn and several hours reflux in toluene, when the recation was done under atmospheric conditions, the phenolate was definatively darker/browner than when argon was used. The magnesium counter-ion could be responsible in part for easier degradation, i suppose.

For the alkylations, I've always considered 3x vacuum/argon cycles to degass the solvent pretty effectively, especially with DMF which tolerates a higher vacuum before ebullition.
But I guess the oxidation occurs to a very small extent, and that it shouldn't be to detrimental to the yield. Just to perfectionist (or nit-picky

) I guess

It's just that having the vacuum and argon at hand it doesn't cost much to use it, and it's routine at work. I admit it isn't be mandatory here.

PainKilla - 20-5-2008 at 14:06

I don't think the oxidation by-products are a big deal with HQ anyway, although for more sensitive substrates precautionary measures could be taken. Venting the solvent/flask with MeBr should work well too (for those that haven't access to Ar).

Using other solvents definitely is a good idea as well - I just used what I had on hand (my isopropanol is 91%, although that should also work fine).

Isopropanol might provide a neat workup though, as one can make the 2-methoxypropane and extract with it (granted a bit of extra MeBr would then need to be used)! It boils at 32*C, so after diluting the RM and separating the layer, one can just let it sit and evaporate, which after a few minutes should leave very pure and dry product.

[Edited on 20-5-2008 by PainKilla]

Brainiac - 7-6-2008 at 13:45

Hi,

Recently I have been trying to form 1,4 Dimethoxybenzene via methylation of Hydroquinone with Methyl Iodide.

0.1M HQ was dissolved in 75ml Acetone. 0.2M NaOH was added followed by the dropwise addition of 0.2M MeI.

The reaction was kept at reflux for 6 hours. During this time, the entire contents of the reaction mixture turned black.

50ml. of the Acetone was then Vacuum distilled off and the residue was added to ice water. This precipitated out black and white crystals. When vacuum filtered, they took upon an irridescent appearence.

Could anyone suggest what these crystals might be?

I look forward to hearing your views on the subject.

Klute - 7-6-2008 at 15:07

.....1,4-dimethoxybenzene?

Using MeI, especially with such ane xcess, seems wastefull. I would advise preparaing p-methoxyphenol using MeOH/H2SO4/benzoquinone, then alkylating that with MeI, using stoechiometric amount of base, the 100% exces NaOH you used surely degraded half your MeI... Thsi takes more works howeevr.

I would use a salt of methylsulfuric acid as reported previously, very cheap satrting material and no toxic and cancerigenic product....

Brainiac - 7-6-2008 at 16:17

Surely the 0.2M Methyl Iodide is required to methylate both the 1 and the 4 position in the first place? And then the 0.2M Sodium Hydroxide to react with the 0.2M Hydrogen Iodide that would be produced?

Or am I just way off with my thought trends here?

Thanks

Klute - 7-6-2008 at 16:54

Oh! My bad sorry I had the p-methoxyphenol alkylation in head

You a absolutly right, 2 equivalents are needed, sorry for the confusion

Why do you doubt the crystasl are your product? try taking a mp after recrysatllization would confirm, but it seems you obtained the wanted product. What was the yield like?

Brainiac - 8-6-2008 at 02:31

Well, I have yet to weigh the yeild because I havent had a chance to get back to the lab. However from what I have collected through filtration (the black pearlescent solid) the crystals seem distinctivly not white (as most MSDS for 1,4 Dimethoxybenzene state).

There is, however a very pleasent smell that I believe could be attributed to the reaction product. It certanly is not similar to Methyl Iodide- or infact Benzoquinone.

Will take a melting point test and quantify the yeild later today and report back.

Regards,

Klute - 8-6-2008 at 08:54

The black colour is du to quinonic impurities trapped in the product, that black colour your reaction medium had when the abse was added. A simple recrystallization should get rid of it.
Indeed, dimethoxybenzene has a pleasant smell, so I guess that's what you've obtained.

But again I would suggest using somethign else than MeI which is a very noxious compound, and when you say the product doesn't smell like MeI, I hope you didn't take a sniff from your bottle!

I would go by the methyl sulfuric salt method, even commercial dimethoxybenzne is much cheaper than MeI.

Brainiac - 8-6-2008 at 11:28

MeI, while normally is expensive, I only pay £5 for 100ml. so cost is not exactly an issue.

Though I do see your point, 1,4 Dimethoxybenzene is rather cheap- though the lab skills have been invaluble.

MeI is not that awfully noxious- I wouldnt reccomend drinking it, but in comparison to some things (cyanide etc) it really isn't that bad.

Thanks. I'll water wash the product and quantify yields.

Regards,

PainKilla - 8-6-2008 at 12:01

I'd work with cyanides any day over working with methyl iodide. It's carcinogenic, toxic - both acute and as a mutagen, and on top all that: volatile!

If I were you, I'd reconsider your position on methyl iodide toxicity, as carcinogens are among the few chemicals that will come back to bite you after an unknown period of time.

Try dissolving your solid in a bunch of NaOH/methanol, and then dump that mess into 10x the volume of water, the dimethoxybenzene will crystallize out.

Brainiac - 8-6-2008 at 13:23

Not to get picky... Methyl Iodide is Cat 3 carc. And just because I said that its relatively not too toxic- doesnt mean to say that I use it haphazardly!

Fume Cupboard, nitrile gloves, lab coat and face sheild/respirator, after having refridgerated the bottle for several weeks to reduce volitility!

Thanks very much however for the concern and for your advice with regards the NaOH MeOH. Its very much appreciated.

Ritter - 6-8-2008 at 09:49

Quote:

Originally posted by Brainiac
Well, I have yet to weigh the yeild because I havent had a chance to get back to the lab. However from what I have collected through filtration (the black pearlescent solid) the crystals seem distinctivly not white (as most MSDS for 1,4 Dimethoxybenzene state).

There is, however a very pleasent smell that I believe could be attributed to the reaction product. It certanly is not similar to Methyl Iodide- or infact Benzoquinone.

Will take a melting point test and quantify the yeild later today and report back.

Regards,

I own 2 500 gm bottles of HQ dimethyl ether. The product is white & the smell is pleasant. See http://en.wikipedia.org/wiki/1,4-Dimethoxybenzene

[Edited on 6-8-2008 by Ritter]

benzylchloride1 - 18-3-2009 at 19:50

1,4-dimethoxybenzene can be alkylated with tert-butyl alcohol in acetic acid using sulfuric acid as a catalyst. The product forms nice crystals. The procedure can be found in newer editions of the Williamson textbook in the Friedel-Crafts reaction section. I ran this synthesis in o-chem lab last year. I am interseted in preparing some 1,4-dimethoxybenzene using the bromomethane method as I have 250g of hydroquinone. I prepared 1,4-diethoxybenzene once using bromoethane, but the product was dark in color and was obtained in low yield.

IPN - 24-6-2011 at 09:00

I'm currently running a veratraldehyde synthesis using the MeBr method that PainKilla described in one of his posts in this thread. It's on smaller scale though (70 mmol vanillin) but I'm hopeful that it will be a success.

I'll post a writeup when I finish the reaction and work it up, it's currently in the MeOH/H2SO4 addition phase.
A picture of the general setup is found in the attachment. Washing bottle was filled with 10% ammonia in water (just to the inlet tube).

A quick note: Be careful on the addition rate of the MeOH/H2SO4 solution (in this and all gas generation reactions ofc.)! I succeeded in testing the gas tightness of my apparatus by being sloppy on the addition funnel tap and managed to blow open the receiver I'm using as the overpressure "valve".

No harm done though (using a proper full face gasmask with ABEK filter when working, no fumehood

) , just scared my self a little.

[Edited on 24.6.2011 by IPN]

Finished the addition few hours ago, started N2 flow and increased the heating on the MeBr flask for few minutes. Picture of TLC attached (1:5 EtOAc:hexane; product left, vanillin right; developed with 20% H2SO4)
I think I lost some MeBr through leaks as the inlet tube was clogged with KBr.

Might need to run more MeBr through it tomorrow.

[Edited on 24.6.2011 by IPN]

[Edited on 24.6.2011 by IPN]

jzhhua - 27-6-2011 at 23:04

I think the methyl iodide is an good methyl reagent