Sciencemadness Discussion Board - Methylation of phenols with Methyl Nitrate

Methylation of phenols with Methyl Nitrate

smuv - 18-3-2009 at 15:21

Methyl nitrate is easy to prepare in high purity and on a large scale. According to a brief toxicity search it is less toxic than other di and trinitrate esters. Unfortunately no data related to its carcinogenic potential was uncovered. According to a table of reaction rates (forget source) methyl nitrate is a bit slower to react with sodium methoxide than methyl chloride; in some reactions though the nitrate ester had a faster reaction rate than the chloride. All experiments related to O-alkylations with methyl nitrate will be dumped here...

Nitric Acid
803g NaNO3 (finely ground)
656mL ca. 80% Sulfuric acid

Cut two fractions, the first below 100c the second above 100c. The higher bp fraction came out to be 20M, the lower bp fraction came out to be 26M (obviously incorrect) by crude titration of a 1mL sample with neat CaCO3 (method worked accurately in a test on HCl); endpoint when fizzing stopped/precipitate were noticed.

(what's left of nitric acid after proceeding reactions; first fraction is in flask, second in bottle)

Methyl Nitrate
solution 1
50mL Nitric acid (40mL 20M acid + 10mL water containing ~1g of urea)
60mL Sulfuric acid (assumed to be 80%)

solution 2
25mL (.52mol) MeOH
10mL H2SO4

The orgsyn procedure was followed (basically solution 2 was added to 1) although a slower addition was employed and the temp was only ever allowed to reach ca. 30c. After addition only very little ester was noted, but upon standing a good quantity of a clear organic phase seperated. Workup as the orgsyn procedure; although during workup it can be confusing because with the first wash with brine, the organic phase is the UPPER layer; after this wash the organic phase is the LOWER layer. After drying over CaCl2 (dry twice as in orgsyn procedure, this IS necessary) 31.3g of ester were obtained (77% yield). A paper towel soaked in MeONO2 could not be detonated by hitting vigorously w/ a hammer. It burned with a white/grey flame similar to ethyl nitrite.

(what's left of ester after 2, 5mmol alkylations. Ester strongly discolors septum stopper, turning it black)

p-methoxyanisol
5.5g Hydroquinone (.05mol)
9.6g MeONO2 (.15mol)
18.2g K2CO3 (.13mol)
60mL Acetone

The carbonate was added to acetone and brought to reflux. The phenol was added, causing immediate darkening from yellow to tan/maroon. After refluxing for a few minutes, the MeONO2 was added in one portion. The stuff was allowed to reflux gently with slow stirring for 24h. About 30mL of 30% NaOH was added to the flask as it cooled (to destroy ester). After cooled the reaction mix was poured into a beaker and 50mL of 30% NaOH and ca. 350mL water were added. Crystallization was latent, requiring lots of scratching and ice cooling. After crystallization finally occurred, the solution was vac filtered (SLOW!). The filter cake was washed a few times with water yielding 2.0g (29% yield) of tan flakes, which, qualitatively, had a relatively low melting point and a pleasantly intoxicating, although somewhat overwhelming to work with, floralish smell. The crude product was recrystallized from aqueous isopropanol (which was tricky, as the right ratio of IPA to water had to be found so the product didn't first separate as an oil and then recrystalize upon further cooling). The mp of a somewhat damp product was 54-55c (consider this mp rough as controlling the heatup rate at low temps was difficult). The final yield has yet to be determined (waiting on a second crystal crop) although the workup had significant loss.

(crude product)

(less crude, recrystallized product...unhappy with this)

Discussion
The workup for the alkylation is sub-optimal and probably lossy. With the filter paper used (coffee filters) some product passed through the filter. In the future the reaction solvent will be distilled off and the flasks contents will be partitioned between DCM/aq. NaOH. A better way of cleaning the p-methoxyanisol needs to be found as well; suggestions are welcome.

A similar reaction in Methyl ethyl ketone is running currently; maybe higher temps will squeeze out a slightly higher yield. An alkylation of paracetamol is planned if/when the kinks get worked out.

Ebao-lu - 18-3-2009 at 15:52

Quote:

After cooled the reaction mix was poured into a beaker and 50mL of 30% NaOH and ca. 350mL water were added. Crystallization was latent, requiring lots of scratching and ice cooling. After crystallization finally occurred, the solution was vac filtered (SLOW!).

That is not purification. You'd better should have separated the product in a separating funnel, and wash the organic layer with NaOH as many times, as it is required for aqueous layer to remain transparent(colourless) (it would be coloured if the free phenol OH's , so the transparency would indicate there is no p-methoxyphenol left).
In your case, NaOH can convert unreacted p-methoxyphenol into water-soluble phenoxide, but after its air-oxidaion, it would bacome like a dye, and that is the reason of your product is not whitish. Try to dissolve it in a byphasal system and wash with alkaline several times, maybe this could help. If not, try to distill in vacuo or steam distillation

[Edited on 19-3-2009 by Ebao-lu]

PainKilla - 18-3-2009 at 16:03

I would recommend a workup in which you just dump your reaction mixture into cold water, make it alkaline, stir for some time to destroy the alkylating agent, and then heat the solution so that the dimethoxybenzene melts. Your hydroquinone and 4-methoxyphenol phenoxides will dissolve in water leaving dimethoxybenzene, which will solidify after the solution is cooled. Repeat the process with a NaHSO3 solution to reduce the benzoquinone (which is by and large the dark impurity); this allows for a cleaner product (white).

Alternatively you could just recrystallize or distill... But why use MeNO3? It seems like a far more dangerous approach than using methyl bromide, and yields are far worse than with MeBr too.

But thanks for taking the time to do this, I've always been curious as to how well MeNO3 works!

[Edited on 18-3-2009 by PainKilla]

smuv - 18-3-2009 at 17:08

I pretty much did that without the bisulfite; thanks for the tip. Did you find the product very slow to filter? What was the crystaline form of your product? very thin flakes?

The MeONO2 alkylation was tried because (from nitric acid) it can be prepared quickly and easily, it is a liquid at rt and its aplication as a methylating agent with phenoxides is almost unknown to litterature. If MeONO2 could efficiently alkylate, it would be a viable alternative to MeBr with a lower toxicity (at least acute) for the mad scientist. Also MeONO2 in pure form does not appear to be very unstable, even hearty whacks with hammer did not yield a detonation. If the stuff is lighted on fire it burns with about the same vigour as any common organic solvent.

PainKilla - 18-3-2009 at 17:34

Yes, thin white/clear flaks are the best way to describe it. However it should be noted that 1,4-dimethoxybenzene and 4-methoxyphenol are somewhat difficult to distinguish visually, so extra effort should be taken to remove it during workup...

I would be surprised if methyl nitrate did not have as high or a higher toxicity than MeBr; being a methylating agent (albeit a poorer) one it will share the same long term toxicity, and furthermore has the toxic properties of nitrates in general... I remember seeing older literature mentioning that methyl nitrate is quite toxic... I am also sure that it was used as a methylating agent until several explosions occured (late 1800's) but I can't remember the source of that - it may even be on this forum somewhere... So it's sensitivity as an explosive cannot really be ignored (although methanol solutions, up to a point, you might be OK). I would advise caution to anyone using it as a methylating agent.

Really, any reactive methylating agent will be toxic, so such synthesis should be performed under a hood/proper ventilation or outside no matter what...

Edit: Further searching yielded:

"Acute toxicity: Since bromomethane is a gas at ambient temperatures, the most significant route of exposure is inhalation [188]. The reported 1-hour inhalation LC50 in rats is 4.5 mg/L, and the 11-hour LC50 in rabbits is 8 mg/L [8]. Inhalation of 6 mg/L for 10 to 20 hours, or 30 mg/L for 1.5 hours is lethal to humans [8]. The compound is readily absorbed through the lung alveoli (gas exchange regions). Methyl bromide can be highly irritating to the mucous membranes of the eyes, airways, and skin with contact [17]. About 1000 human poisoning incidents caused by methyl bromide exposure have been documented, with effects ranging from skin and eye irritation to death [17]. Most fatalities and injuries occurred when methyl bromide was used as a fumigant. The lowest inhalation level found to cause toxicity in humans is 0.14 mg/L in air [17]. A typical delay in onset of symptoms following exposure combined with an odor threshold (level at which most people can smell it) well-above the level at which toxic effects occur, means that the victim may not realize a harmful exposure is occurring until it is too late [17]. Initial acute effects may include headache, dizziness, nausea or vomiting, chest and abdominal pain, and irritated eyes, nose, and throat [188]. With sufficient exposure, symptoms of slurred speech, blurred vision, temporary blindness, mental confusion, and sweating may occur [188]. More severe symptoms at even higher doses may include lung swelling; congestion; hemorrhaging of the brain, heart, and spleen; severe kidney damage; and numbness, tremors, and convulsions [188]. The nervous effects observed in lab animals included degeneration of key nerve cells in various portions of the brain and peripheral nervous system [188]. Death may occur from respiratory failure [188]. The rat oral LD50 (bromomethane administered as a liquid, or in solution) is 214 mg/kg [1], also indicating moderate to high toxicity."

Source: http://extoxnet.orst.edu/pips/methylbr.htm

Methyl Nitrate:

"Methyl Nitrate:
The rat 4-hour LC 50 of methyl nitrate vapor was experimentally determined to be 1275 ppm or 4 mg/liter and for mice the 4-hour LC50 for methyl nitrate is 5942 ppm or 18.7 mg/liter (Table 4). "

Source: attached pdf.

So methyl nitrate appears to be about as toxic as methyl bromide, using rats as the point of comparison.

[Edited on 18-3-2009 by PainKilla]

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Klute - 19-3-2009 at 00:27

Nice work! It's nice to see application to methyl nitrate! Indeed be cautious of storing largish quantities of it, it could be sensibilized by impurities...

Anyway, for p-methoxyphenol, I had great results recrystallizing it using AcOEt and petroleum ether, leaving the two layers to slowly diffuse:

But nothing beats distillation of the phenol. Trying to cristallize an impur product is very problematic here.

the problem being that you might get a mixture of dimethoxybenzene and p-methoxyphenol. You could try adding 2 eq or more and aiming for complete methylation.

Ebao-lu - 19-3-2009 at 03:00

Quote:

the problem being that you might get a mixture of dimethoxybenzene and p-methoxyphenol. You could try adding 2 eq or more and aiming for complete methylation.

And wash off the unreacted phenol with base prior to crystallization. Maybe by adding IPA to the final base solution, you can get rid of phenol that will remain in solution and the dimethoxybenzene will be extracted with IPA layer. Then dilute IPA with water and crystallize

Nicodem - 19-3-2009 at 23:58

Beautiful work as always, Smuv!
If you still work on this, I can only suggest to try with a different solvent. Acetone is fine for alkylations of phenols, but not always and not with weak electrophiles. Besides, if K2CO3 is not well dried and finely powdered the reaction on some phenols, particularly the less acidic, tends to be slow. Of course, it is pointless to use higher boiling polar aprotic solvents like acetonitrile due to the instability of MeONO2, but maybe you could try with KOH or K2CO3 in methanol and a higher proportion of methyl nitrate. Hydroquinone is certainly not the best substrate for trying out and optimizing this reaction as it tends to be oxidized so easily, and as a dihydric phenol it distorts the yields and usefulness of the reagent for other substrates. Maybe you could try with some other phenol that also forms a solid product (like vanillin, etc.).

smuv - 20-3-2009 at 11:50

More methyl nitrate was synthesized on a 2x scale compared to the previous experiment. Not all the oxides were removed from the HNO3 and therefore the product came out as a pale yellow oil. Yield around 60mL give or take (based on gradations on the sep/addition funnel). Tests to see if this product is less stable than the other cleaner product will be undertaken.

p-methoxyanisol - MEK
5.5g Hydroquinone (.05 mol)
9.6mL MeONO2 (.15 mol)
18.2g K2CO3 (.13 mol)
50 mL Methyl ethyl Ketone

Proceeded as previously, the mix took longer to darken than previously; stirring was held at a faster rate. Water pressure dropped overnight and in the morning no water was flowing through the condenser, the reflux was low enough that the solvent level was about the same although some MeONO2 may have been lost. After pouring into 500mL of NaOH sol and holding on an ice bath, the yield looked like almost nothing, scratching did nothing and the stuff was allowed to stand for a few hours; about half the solution was filtered, at which point it was noticed that the filtrate contained many little flakes, the filtrate was combined with the unfiltered product which finally initiated crystallization. Washed rigorously with water and conc NaOH in filter funnel. Yield 1.7g.

Thank you all for the positive feedback; I understand hydroquinone is not the optimal substrate, experiments w/ vanillin, tylenol and hydroquinone will be attempted overnight (using acetone for the tylenol, MeOH for the others).

By the way can p-methoxyanisol be efficiently steam distilled?

@Klute, beautiful pictures; nice work.

@Painkilla, good find w/ the toxicity data. One nice thing about MeONO2 though is that it is a liquid. That being said, at this point it seems that MeBr is a better choice as a methylating agent in terms of efficiency.

@Nicodem, thanks for the tips. There would probably be no problem using acetonitrile if it were more readily available, As I have unsuccessfully tried many times to detonate MeONO2 without a primary.

@Ebao-lu, further purification of p-methoxyanisol will be carried out when more is available and a distillation more feasible.

[Edited on 3-20-2009 by smuv]

Klute - 21-3-2009 at 04:25

Yes, if my memory serves right, (MeO)2Ph is easily steam distilled, as an oil that quickly solidifies, you might want to use hot water int eh condenser, or use a air condenser (I did that to distill the p-methoxyphenol)

Good luck with further experiemnts! Can't wait to hear more!

Eclectic - 21-3-2009 at 06:20

And this is safer than using glyceryl trinitrate as a methylating reagent?

Sauron - 21-3-2009 at 10:33

I wonder if MeONO2 will react with KSCN to give MeSCN and KNO3?

Usually MeI or DMS are used.

panziandi - 21-3-2009 at 11:10

@ Eclectic ... "glyceryl trinitrate as a methylating reagent?" ... That wouldn't be a methylating reagent, it would introduce the glyceryl or propan-1,2,3-triyl group opposed to the methyl group, if it even works!

@ Sauron ... yest another potential route to CCl4 for you hey

, I dont see why it shouldn't react, worth a small scale experiment?

This is looking like quite an interesting methylation reagent I must say! Unsure of the toxicity, but it sounds more fun and nicer than than methyl iodide and dimethyl sulphate!

Eclectic - 21-3-2009 at 11:15

Yes indeed...I should have said as a synthesis reagent.

Would methyl nitrate really be that much less sensitive an explosive than nitroglycerin?

[Edited on 3-21-2009 by Eclectic]

Sauron - 21-3-2009 at 11:30

We already know what to expect from dimethyl sulfate and iodomethane. While I have no phobia of them I have had a sibling die of primary brain cancer and would rather not follow her.

It seems that if you do not distill MeONO2 things are not so bad,

MeSCN is expensie and is usually made either from MeI which is likewise costly or ammonium thiocyanate, also costly. Making ammonium thiocyanate starts with CS2, cosrlt.

MeOH and conc HNO3 are cheap as dirt. The economics are pretty compelling.

kclo4 - 21-3-2009 at 12:26

Very interesting! I had no idea methyl nitrate could be used as a methylating agent. Does this mean it is also carcinogenic and more dangerous then just its explosive properties?

Sauron - 21-3-2009 at 12:55

I would be surprised if it were NOT carcinogenic. All methylating agents are AFAIK. Higher alkylating agents much less so.

JohnWW - 21-3-2009 at 13:45

Quote:

Originally posted by Sauron
I would be surprised if it were NOT carcinogenic. All methylating agents are AFAIK. Higher alkylating agents much less so.

As I remember, there are two distinct types of methylating agent -
(a) ionic alkali and alkaline-earth metal methyls such as CH3Li (formed by the reaction of CH3Br with Li), and including Grignard reagents such as CH3MgBr, from which the CH3- carbanion adds nucleophilically to an electron-deficient structure (including to a carbocation formed by the ionization of an alkyl halide, one reaction of CH3Li being with CuI and another alkyl halide to produce a methylated alkane); and
(b) methyl esters of strong mineral acids, such as (CH3)2CO3, (CH3)2SO4, and now it appears CH3NO3, which in the course of reactions in a suitable solvent undergo slight ionization (as do also methyl halides, which are effectively in this class) to CH3+ carbocations which then electrophilically add to an electron-rich structure.
If the latter class of methylating agents are mostly carcinogenic, it would have to be due to addition of CH3+ carbocations to electron-rich functional groups, such as -NH2 or -OH, in the peptide groups in proteins.

[Edited on 22-3-09 by JohnWW]

Sauron - 21-3-2009 at 13:59

Your definition is incomplete. It does not account for methyl halides such as MeBr and MeI which surely are methylating agents and certainly are not methyl esters nor are they metal alkyls. Methyl halides are not esters of the corresponding mineral acids.

Formatik - 21-3-2009 at 15:36

Quote:

Originally posted by Eclectic
Yes indeed...I should have said as a synthesis reagent.

Would methyl nitrate really be that much less sensitive an explosive than nitroglycerin?

They have same sensitivity. Impact sensitivity: 0.2 N m (NG: also 0.2 N m). Friction sens. is also same as NG: up to 36 kp = 353 pistil load no reaction (NG same). Source: Meyer, Köhler, Homburg.

Note: looking in Federoff, who contradict Meyer et al. and according to them, MeONO2 is considerably less shock sensitive than NG: with a 2kg wt, it explodes at 40 cm drop, vs. 4cm for NG. Even with kieselguhr, it's less sensitive than NG. I'll take their word over Meyer et al., so the previous claims about its shock sensitivity are void in my opinion. Though it is more sensitive to flame and heat, at least due to its higher volatility and somewhat lower decomposition temperature.

[Edited on 22-3-2009 by Formatik]

WARNING!

Sauron - 21-3-2009 at 19:59

After reviewing Davis's remarks on MeONO2 I must conclude that it is more sensitive to initiation than NG and a more powerful, though useless explosive with a higher VOD.

Therefore I must conclude that it is extremely hazardous and regardless of low cost and ease of preparation is utterly unsuitable for use as a methylating reagent.

I urge anyone and everyone to read Dsvis, Urbanski, Federoff etc the rest and draw your own conclusions.

[Edited on 22-3-2009 by Sauron]

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smuv - 21-3-2009 at 23:47

...Hydroquinone in MeOH, paracetamol in acetone

p-Methoxyanisol- MeOH/KOH

27mL MeONO2 (.42 mol)
15.4g Hydroquinone (.14 mol)
19.6g KOH
160mL MeOH

Brought KOH/MeOH to reflux, added hydroquinone at reflux (by removing condenser for a minute), sol turned light yellow, next allowed reflux to slacken a good bit and added MeONO2 portionwise through the condenser. The solution boiled a good bit upon addition and the condenser had trouble dealing w/ everything, therefore the addition was completed off of the hotplate with swirling; addition seemed exothermic as solution boiled throughout the entire addition. With addition the sol turned maroon, the color became so dark over the ~18h reflux by the end it looked black. Everything was setup for downward distillation and the bulk of MeOH/MeONO2 was removed (ca 80mL); distillation was stopped when the distillate no longer gave the characteristic white flame of MeONO2 (not sure why I bothered with the distillation really). After cooling, the sludge in the flask was redissolved into 50mL DCM/400mL 5% NaOH. The aq. layer was extracted further w/ 2x 50mL DCM. The aqueous phase was dark black w/ a thick consistency. The DCM extracts were pale, translucent, brown/maroon. The DCM extracts were washed w/ 5% NaOH until washings were ~clear and then w/ 2x water. The stuff was dried and filtered from desiccant and cake washed w/ DCM. The DCM distilled off at the water bath and the last traces were removed by via gentle heating under free flame. A dark brown/red oil remained which at first crystallized into flat squares and then some ugly junk. Yield is minuscule and was not even quantified. It smells something like p-methoxyanisole w/ some other hints to it that are difficult to describe.

(shitty pic of a shitty product)

p-methoxyacetanilide
~7g Paracetamol (see procedure) (~.05 mol)
6.4mL MeONO2 (.1 mol)
13.8g K2CO3 (.1 mol)
50mL Acetone

Paracetamol obtained from some weirdo gel caps which had a gelatin shell around a compressed 'tablet' of paracetamol. For 15x500mg capsules the gelatin shell was removed from the inner tablet and the tablet was crushed and dissolved into the boiling acetone, solution was filtered. The solubility of paracetamol in acetone was underestimated, therefore it is likely that not all the paracetamol was recovered.

Everything was mixed at RT and then brought to reflux w/ good stirring. After 18h the flask was removed from oil bath, the solution was clear faintly yellow. Upon cooling the solution solidified into an unpourable mass. The sol was again brought to boiling over a free flame and poured into 200mL water, 40 mL 5% NaOH was added (leftover from above rxn) and then NaOH pellets were added (very lazy...) solution was stirred on a still warm hotplate and began to boil vigorously, a yellow oil separated(!) above the aqueous layer, the beaker was placed into a water bath and quickly white/yellow crystals were noted floating above the solution. Sol was vac filtered and washed w/ copious amounts of strong NaOH and then w/ water. In total 4.3g of white crystals were isolated, which had a difficult to describe smell (maybe the smell inside old medicine bottles) and no taste. The identity of product was unknown (assumed to be anisidine based upon oil which separated) so a quick mp was taken; 125-126 w/ quick heating.

Most of the crude product product was dissolved into 25mL AcOH and brought to just under a boil; water was added portionwise (ca 15-20mL) until turbidity was persistent and then heated to a boil. Sol was allowed to cool at rt and then on ice bath. After vac filtration and washing cake w/ water and toluene (just because some had been used for solubility tests and it would have gone to waste if not used for something); the stuff dried quickly on the funnel (toluene helped) yielding a white free flowing powder predominantly composed of tiny crystals w/ an unrecognizable form (reminiscent of cubic...maybe rhombic?); product was odorless. The mp of the recrystalized product was 126-127c w/ a 'wetness' appearing a few degrees before hand. It is assumed that the recovered product is some impure form of p-methoxyacetanilide (mp 130-32).

(crude product)

(recrystallized; crystals are predominantly small and therefore un-photogenic)

Discussion
Not sure why an oil separated, but it definitely did, and it certainly recrystallized to form nice crystals. Can a moderately strong boiling NaOH approach 120c?

Theories as to other possible identities (considering mp) of this product are welcome. The stuff is very insol in even boiling Toluene and fairly soluble in even cold AcOH.

For the alkylation of hydroquinone...not sure why this was so trashy, after workup the aqueous layer didn't smell of p-methoxyanisol, so it is assumed that the workup was effective. Another thing, there seemed to be a lot of water soluble but methylene chloride insoluble junk in the rxn flask, maybe just potassium nitrate...but it really seemed like a lot!

@ Eclectic: use whatever you want to methylate whatever you want, do so as safely or recklessly as you want... An orgsyn procedure was followed to make an organic reagent. The flammability and stability of the reagent were characterized and deemed to be of acceptable stability for small scale reactions.

@Sauron: you have such a one track mind... the answer is YES!

p.s. this concludes any further research on this front for quite a while...

[Edited on 3-22-2009 by smuv]

DJF90 - 22-3-2009 at 03:41

Nice work smuv. Assuming the yellow oil is/contains your product would it not be possible to pipette it off whilst hot and then allow it to cool by itself? This may help prevent inorganic impurities, although you should probably dissolve the [crude] product in a suitable solvent, wash, then crystallise and recrystallise.

panziandi - 6-4-2009 at 08:04

I tried this experiment using p-bromophenol as a substrate, the product was coloured yellow/orange. I think it may be possible that with reactive rings nitration could occur as a side-reaction. Pros: methyl nitrate is cheap and very easily made. Cons, methylation yields are low with possible nitration and C-methylation.

0.1mol p-bromophenol dissolved in 20mL methanol, added to a warm methanolic solution of potassium hydroxide (0.1mol). 50% methyl nitrate/methanol added dropwise with refluxing for 1.5hr then left overnight. ppt of fine white crystals separated on cooling (KNO3), filtered and reduced by 50% on a water bath. A second crop of white crystals separated, filtered.

This is where things went wrong:

Reaction mixture was added to 4M sodium hydroxide 150mL, emulsion formed, sodium chloride added (15g) emulsion remained. After standing overnight appeared to be a fair quantity of oil on the bottom of teh liquid, however much emulsion was still present, added (STUPIDLY) CaCl2 causing a ppt to which much product adhered to. Solvent extraction of bulk of liquid isolated 1g of p-bromoanisole (approx 5% based on bromophenol) as a yellow oil.

NOTE:

I estimated ca 2mL perhaps a little more in oil had separated from emulsion and may be locked in the Ca crud. did not bother trying to isolate more product from the ppt Ca crud. Work up should have been to pour the reaction mixture into a larger volume of water, I think that quantity of base was not needed.

Perhaps longer refluxing would have been better, I was limitted by time constraints.

p-bromoanisole should be colourless not yellow - leading me to suspect C-nitration, due to the small quantity of product I am not going to bother with a distillation etc or analysis of product(s).

[Edited on 6-4-2009 by panziandi]

smuv - 7-4-2009 at 19:23

Did you find your methyl nitrate addition to be exothermic?

As shown above, I as well got low yields adding the methyl nitrate at reflux. I wonder if by addition at reflux the methyl nitrate is for some reason more apt to be hydrolized to nitrate + MeOH as opposed to reacting w/ the phenoxide. Additionally I got lower yields w/ MEK as opposed to Acetone, which could signify the temperature instabilitys of methyl nitrate playing a role.

panziandi - 9-4-2009 at 05:44

I added a solution of methyl nitrate in methanol to the reaction mixture, which was at a gentle reflux, addition of the methyl nitrate solution did not seem to produce any additional heat.

There shouldn't have been any free hydroxide in solution, I used a stoichiometeric quantity which should have reacted completely to form phenoxide, but I suppose hydrolysis could be an issue.

There was a large ppt, likely KNO3, and also there was significant product in the form of an emulsion when I poured it into NaOH solution. I lost product in a messy workup. Perhaps pouring the solution into a larger volume of water would have been more suited. Also, just an idea but it may be good to steam distil the products out of the reaction?

I would try methylating you hydroquinone in a methanol system using a 10% excess of methyl nitrate and refluxing for 4-6hrs. Try forming the phenoxide by adding the phenol to a solution of KOH methanol. You should use a protective atmosphere for using polyhydroxy phenols in alkaline conditions since they oxidise rapidly.

smuv - 9-4-2009 at 07:34

Quote: Originally posted by panziandi

I would try methylating you hydroquinone in a methanol system using a 10% excess of methyl nitrate and refluxing for 4-6hrs. Try forming the phenoxide by adding the phenol to a solution of KOH methanol. You should use a protective atmosphere for using polyhydroxy phenols in alkaline conditions since they oxidise rapidly.

This was by and large already attempted (see prev page); just w/ more alkylating agent and a longer reflux; of course if Nitrogen was available it would have been used. One mistake that was made though, was the 85% purity of KOH wasn't accounted for, therefore slightly less than 2eq of KOH were used in reality.

I do agree though, a steam distillation would be the way to go for larger scale runs, assuming the product is volatile w/ steam.

A little late but...

smuv - 2-8-2009 at 12:53

I finally got around to taking an HNMR of the product from methylation of paracetamol. The product is indeed p-methoxy-acetanilide in good purity.

~7.4 - Ar-H (closest to amide) as well as N-H
7.24 - CHCl3
~6.8 - Ar-H
~3.8 - Acetyl protons
~2.1 Methyl

There is a slight impurity in the aromatic as well as some in the aliphatic regions however they are trivial. If someone wants to take a stab at identifying the impurities, be my guest.

Spectra:
Full
Aromatic

Nicodem - 3-8-2009 at 00:09

All the peaks are consistent with the literature values except for the missing NH broad singlet at 7.14 ppm. There are some impurities signal at that place... maybe it is so broad that it just flattened (if you would have integrated, maybe we could see if it partially hides beneath the AA'XX' signals). The water signal is a bit far for CDCl3 where it is usually at about 1.5-1.6 ppm, but not extraordinarily far from where it is expected. Anyway, thanks for confirming and sharing the results of your methylation via MeONO2. It was an interesting read.

smuv - 3-8-2009 at 19:32

Thanks.

I actually took a much better spectrum but was VERY rushed and only had time to print the aromatic region (and didn't save). In that spectrum the N-H peak is much clearer. By the time I got around to running the sample again a lot of the CDCl3 evaporated, I didn't bother refilling and ran the sample anyways, this is why the shim was so bad.

cleaner aromatic