The Vespiary

The Hive => Chemistry Discourse => Topic started by: Antoncho on October 07, 2003, 02:38:00 AM

Title: An ultimate kitchen methylation procedure?
Post by: Antoncho on October 07, 2003, 02:38:00 AM
I suggest to discuss in details the best ways to methylate an aromatic hydroxyl. Namely, one situated on a benzaldehyde ring.

The procedure i am interested in should have the following features:

- high yield, naturally
- equimolar or close to equimolar ratio of methylating agent to aldehyde
- non-toxic, 'ecological' setup - i.e., no toxic fumes; using closed apparatus
- (now comes the best part :) ) no need for a stirring facility - like for someone who doesn't have a stirrer hotplate (a mech stirrer requires a non-hermetic setup and thus is very much undesirable). Certainly, the flask could bee shaken from time to time w/hand.
Alternatively, the rxn can bee carried under reflux.

Currently these are the modifications that seem to bee the most appealing:

1. DMS in acetone with K2CO3
- drawbacks: long rxn time (24h), no need for stirring is also questionnable (though the rxn is carried out at reflux)

BTW, here is one such patent designed specifically for 2-OH-5-MeO-benzaldehyde:

Patent US3867458 (

; it hasn't been posted here AFAIK and contains some pretty interesting discussion. E.g., it turns out that the rxn goes to completion in 3hr under reflux and in 7 days at RT. As well as some other details.

2. DMS in DMF at RT with K2CO3 as the base (a la Hest: (

-stirring is needed (?), also Hest says 'DRY DMF' - does this mean DMS will bee eaten by water unless DMF is DRY?

3. Solventless methylation with DMS or TMP, as in (

-drawbacks: need for efficient stirring.

4. Methylation with DMS in methanol, gradually adding aq. KOH, as in

Patent US4267382 (

-no stirring is needed and the setup can bee arranged hermetically; the yield is, however, unclear and DMS is used in appreciable excess. Don't remember if the proc has been posted, here it is:

400 ml. of methanol and 85.5 ml. of dimethyl sulphate are added to 79 g. of 2-hydroxy-4,6-dichloro-toluene and the resulting mixture is stirred and treated dropwise with 256.5 ml. of potassium hydroxide (25% w/vol.). The resulting mixture which heats up to boiling during this dropwise addition, is stirred under reflux for 4 hours and subsequently evaporated. The residue is taken up in 600 ml. of water. The aqueous solution is extracted three times with 600 ml. of ether. The ether extract is washed neutral with water, dried over sodium sulphate and evaporated under reduced pressure. After rectification, the residual 2-methoxy-4,6-dichloro-toluene boils at C./0.1 mmHg.

Actually, SWIM was thinking along the lines of cooking the stuff with DMS in EtOH/IPA/DMF, but instead of employing K2CO3, he wanted to see if perhaps a phenolate could bee first made with KOH, thus increasing heterogenicity of the rxn and abolishing need for vigorous stirring.

He tried it in EtOH/Vanillin (ethanolic KOH, RT, ~6hrs with occasional shaking) to recover a miserable ~30% yield.

Is the extra water (from both KOH/vanillin and 95% ethanol) to blame? DMS is susceptible to hydrolysis, so maybee that's why.

Now, it is also possible that the mistake was made during workup - 1st, SWIM treated the post-rxn mixture with aq ammonia to kill the remaining DMS.

Then, the solution was diluted with water rather than pouring it onto ice - and extracted with DCM. Nothing precipitated upon dilution, not even a second layer was visible. Maybee, veratraldehyde is too well soluble in aq. ethanol?

Generally, i would like very much for someone to comment upon

a) water sensitivity of DMS methylations - in alcohol as well as in DMF
b) Workup strategies and possible faults
c) the importance of stirring when using K2CO3

Thanks ahead for any input.

Title: Great initiative
Post by: Bandil on October 07, 2003, 03:08:00 AM
Hi Antoncho; great initiative with this thread.

I really don't have any experience with DMS, so i won't comment on that.

However, TMP has always treated me nicely, as it's very easy to work with. The link you posted (

, contains one of the original trials i made with TMP. I simply used 20% NaOH in water as a solvent, which worked out nicely. I think the reaction could be performed without stirring, as the mixture is refluxing in the end. Some swirling is definately needed at first, when the methylating agent is added, but afterwards, it should be a nice homogenious mixture.

I really think that the MSDS for TMP is alot nicer than that of DMS  :) . TMP is also a less common methylating agent(=less suspicious) and not rated Tx as DMS is(which means that no permessions are required to buy it).

I definately think that TMP is a worthy candidate for kitchen methylation's. Maybe someone should try it out without stirring? I see no problems with it!


Title: OTC
Post by: hest on October 07, 2003, 03:13:00 AM
Iff we are talkin OTC Wather and acetone is the solvent's (and they both work's greath) The base could bee, KOH,NaOH or K2CO3. they all work good.
Adding the phenol to the basic solution has to bee done cold due to formation of quinones (o all those nice colluers). 1 mole base/ phenolic group is enough and the 5-10% extra ( 3,1 mole base for 1 mole trihydroxy-something). Reflux is neede but stirring is'nt. Usual you disolve your phenole into cold wather, bring it into reflux (or atlest 60-70°C) and then drip your DMS into the solution. Iff posible seal the O2 from the air outh, then your solution will bee much less blac. When you have refluxet for 12 houers ther is no DMS back (it's quite toxic), you can seperate your methoxybenzaldehyde from the still basic wathersolution, make the accid and then ekstract your phenol (if there is annye).
Title: Ok, but...
Post by: Antoncho on October 07, 2003, 05:27:00 AM
Thank you, guys! Hopefully, you won't bee the only ones who care to share their thoughts...

Anyway, Bandil - i really have nothing to add to your post, of course, TMP would bee the alkylator of choice; unfortuantely, in Russia it's a complete unknown - you can't find a single supplier even online!

SWIM was fortunate enough to lay his hands on some DMS.

2 Hest: thanx a lot for your concern! Would you mind making some more comments?

Reflux is neede but stirring is'nt. Usual you disolve your phenole into cold wather, bring it into reflux (or atlest 60-70°C)

What do you mean by that? Is the high temp really necessary? Doesn't that contradict with your favorite procedure with DMF/DMS/K2CO3 at RT?

OTOH, i remember reading somewhere that such methylations should bee performed as quickly and energetically as possible to obtain the best yield...

and then drip your DMS into the solution.

Actually, this is precisely what i am trying to avoid: having to drip in DMS. I'd rather have as little contact w/it as possible, i'd prefer to have it in the rxn mixtr from the beginning - and add drop by drop something else - like base.

Or not to drip in anything at all, adding all at once. Does anyone has an idea as to what role and importance has the order of addition of the reactants?
I understand that DMS is preferrably added not all at once to avoid its decomposition, but if the rxn medium is relatively non-aqueous, is it really that important?

When you have refluxet for 12 houers ther is no DMS back

Is there anything wrong with adding NH3 to quench the leftover DMS?

Title: DMS
Post by: GC_MS on October 07, 2003, 06:48:00 AM
Or not to drip in anything at all, adding all at once. Does anyone has an idea as to what role and importance has the order of addition of the reactants?

Just a small tip if you wouldn't have (much) experience with DMS: DO NOT ADD ALL DMS AT ONCE TO YOUR ALKALINE REACTION MIXTURE (nor add all base to DMS). The Trevi fountain will be nothing compared to what you'd see. The reaction is pretty exothermic.

Title: Quenching DMS
Post by: Rhodium on October 07, 2003, 09:18:00 AM
Is there anything wrong with adding NH3 to quench the leftover DMS?

Do NOT add ammonia to a solution of a much wanted benzaldehyde - you'll form the imine! First extract the benzaldehyde, then quench any residual DMS in the spent mother liquors.

If you're afraid of DMS, simply use gloves - its vapor pressure is very low, so there is no risk of inhaling any of it.

From the DuPont website:

The vapor pressure of dimethyl sulfate at 20°C (68°F) will give a saturated vapor concentration in air of 710 parts per million by volume. Higher temperatures will give correspondingly higher concentrations of vapor in air.

Table: Vapor pressure of dimethyl sulfate vs. temperature (


DuPont Dimethylsulfate Bulletin (36 pages) (

Title: DMS
Post by: hest on October 08, 2003, 07:28:00 AM
Methylation in DMF is a different case. DMF is a great solvent for this, so high temp. Is not ness.
When you reflux your water (or acetone) it’s also a way to destroy the DMS. When DMS had been refluxed for 2-3 hours it all decomposed. It's the basic car. of ammonia wich destroy the DMS, so NaOH will do the job for you.
Dripping is a must. Mixing is not good  ;D
Title: Do NOT add ammonia to a solution of a much...
Post by: Antoncho on October 09, 2003, 12:50:00 AM
Do NOT add ammonia to a solution of a much wanted benzaldehyde - you'll form the imine! First extract the benzaldehyde, then quench any residual DMS in the spent mother liquors.

Ehhh... Actually, i was well aware of such a possibility - but, the imine, won't it get extracted  into the NP phase as well, and won't it bee turned into the BA again once it's washed with an acid?

Then, don't you think that DMS will get extracted into the NP as well?

2 hest:

It's the basic car. of ammonia wich destroy the DMS, so NaOH will do the job for you.

No, it isn't the 'basic character' of NH3, the rxn goes like that:

Me2SO4 + NH3 __> MeNH2 + HMeSO4

I'm aware that NaOH will decompose DMS as well, but the rxn with NH3 proceeds much faster: in all lab manuals i've read DMS spills are advised to bee treated with aq. NH3.

Dripping is a must.

Even in case of DMF? Why?

Mixing is not good

What? :o  Please, elaborate on that!

Title: No significant amount of DMS left at workup...
Post by: Rhodium on October 09, 2003, 02:04:00 PM
Read the entire PDF on DMS I posted above, the excess base will convert any excess DMS to monomethylsulfate salts, which are essentially harmless (monomethylsulfate is used as counterion in many fabric softeners).
Title: You want something really OTC?
Post by: ning on October 17, 2003, 09:38:00 AM
Most carboxylic acid esters seem to be useable to methylate. What is Ning jabbering about? Methyl or ethyl oxalate! It will methylate phenol to anisole in 79% yield at reflux in DMF (153 degrees). I bet other solvents will work. Particularly xylene, which boils at around 137 degrees. Or kerosene. Distill out the nonane. Or just screw the solvent and melt-phase them. Most interesting substituted benzenes seem to have a high enough boiling point.
There, I gave up the cat. My secret is out.
Just extract oxalic acid from zud (or cane sugar...), dry it , ester it with ethyl or methyl alcohol and sulfuric acid (Org Syn CV2, pg. 414 , 68-76%) and it will alkylate Hydroxyls (syringealdehyde? Vanillin?), Sulfurs (2C-T-something?), and Nitrogens (having trouble finding ethylamine? How about N-Methyl formamide?), all in decent yield. Oh, the ref.
Alkylation with Oxalic Esters. Scope and Mechanism. Bergman, et al. Tetrahedron Vol 46, No. 17, pp. 6113-6124, 1990

Fairly new paper. High yields, safe chemicals, all obtainable from the supermarket. Now that is some seriously OTC methyl-ethyl-alky-lation.

Have fun! ;)

Oh, and what was that about carboxylic acids? Well, as I was searching beilstein, oxalic acid ester was not the only one I saw. Carbonic acid dimethyl ester was used (Alkyl Methyl Carbonates as Methylating Agents. The O-Methylation of phenols, Perosa et al. SynLett 2000, No.1, pg.272), but it seems to have a low boiling point, and I have no idea how to make it. From seltzer water? That would be a new one.
Phthalic acid alkyl ester was used, and it seemed attractive, high melting point, no pressure bomb, etc. (King & Wright, J. Chem. Soc 1939, pg.1168, need a microfilm for that one...) Only problem was, they used "Potassium salt of phenol...", now that sounds like it might need...potassium! Or at least KOMe or something. Noting the success of the Oxalic acid paper using Na2CO3, it might be worth a try, but who has frickin' Pthalic acid lying around? I know its a hugely popular industrial chemical, but I don't have any...
And finally, I remember seeing acetic acid ester. Unfortunately, I couldn't get that paper. I'll give a ref on request, I didn't write it down (some russian journal, I think.) Anyway, I couldn't help noticing how all of these alkylating esters were of the form X-COO-R , with R being what you want to alkylate with. I might have even seen formic acid ester, which would have the same advantage as the carbonic acid ester, namely, it decomposes to CO2, thereby sparing you the need to have a stoichiometric amount of base to absorb the acid liberated by the methylation process (I think). This could be handy if you need to use some really strong base, and you don't want to use more than a small amount.

So we had this series:

HCOO-Me          Formic acid ester
Me-OCOO-Me       Carbonic acid ester
MeCOO-Me         Acetic acid ester
Me-OCOOCO-Me     Oxalic acid ester
Ph-(COO-Me)2 (?) Pthalic acid ester

So go on folks! You all with good labs, experiment! The oxalic acid one is nice for me, but wouldn't it be cool to do, say, citric acid? Also, I get the feeling that the weaker the acid, the better it alkylates. Certainly, weak acids would be easier to esterize, right?

Tokka! Rhaazaar! Go! Play! Have Fun!

[Ed]: I wanted to add the probably obvious fact that we would want to use relatively larger, stable, weak acids, so their esters would alkylate at lower temperature, they wouldn't decompose, and they would boil at a high temperature. Oxalic ester should fulfill that. I don't know about acetic ester, and if citric ester worked (didn't decompose), it would be good too, I think.
Also, in the carbonic acid paper, they talk about using assymetric esters to take advantage of steric effects to select what gets alkylated rather precisely. The paper "Selective Mono-O-alkylation of 2,6-Dibromohydroquinone, Dorman, J. Org. Chem. 1966, 3666" talks about selective methylation also, although it uses DMS. I can't really understand it well though, full of equations and stuff.
Title: SWIM's opinion
Post by: imp on October 17, 2003, 01:48:00 PM

Generally, i would like very much for someone to comment upon

a) water sensitivity of DMS methylations - in alcohol as well as in DMF
b) Workup strategies and possible faults
c) the importance of stirring when using K2CO3

a) Not very water sensitive at all. SWIM always uses an acetone solvent right out of the can (doesn't dry it), and anhydrous finely powdered Na2CO3. Also, since SWIM's DMS is homemade it too is usually wet. (If DMS is homemade, wash it with a concentrated NaHCO3 solution before putting it in the flask).

b) Workup is simple. Distill the acetone at atmospheric pressure, then add water to the flask and let stir for about an hour. Many times the benzaldehyde will from a suspension of oily droplets throughout the mixture. Now place the flask in an icebath with stirring for another hour. As soon as you place it in the icebath, the oily droplets will all crystallize at once. It is fun to watch.

c) Don't know, never used K2CO3. SWIM always applys magnetic stirring with Na2CO3, but is not sure how necessary it is.

As far as GC_MS...

ust a small tip if you wouldn't have (much) experience with DMS: DO NOT ADD ALL DMS AT ONCE TO YOUR ALKALINE REACTION MIXTURE (nor add all base to DMS). The Trevi fountain will be nothing compared to what you'd see. The reaction is pretty exothermic.

SWIM has never exprienced that, ever! Has always added the DMS all at once. Even when washing the DMS with NaHCO3 solution, SWIM notices very little fizzing. Maybe because it was freshly made and kept in the freezer??

Lastly, you should really stop making such a big deal of the toxicity of DMS. It is not that bad at all. SWIM has gotten a small droplet on the arm once, washed it right away with ammonia and has been fine since. Dangers with reduced pressure distillation of MeOH/H2SO4 with an aspirator were largely unfounded.

Title: one problem i see with DMS as a ultimate ...
Post by: stratosphere on October 18, 2003, 03:11:00 PM
one problem i see with DMS as a ultimate kitchen procedure is last i checked they where not exactly handing that stuff out at the local grocery or hardware store.

some plants contain CH3SSCH3 which would be excellent, but i somehow doubt its in quantities worthy of extraction.

a methyl ester thats available in large supply is plexi-glass, although im not sure off the top of my head how to best  impliment that in methylation procedure.
Title: More on that ester stuff...
Post by: ning on October 23, 2003, 02:47:00 PM
Since everyone is just *begging* me to type up this paper on the revolutionary OTC methylating agent dimethyl oxalate [sarcasm sarcasm], here it is:

Alkylation with Oxalic Esters. Scope and Mechanism.

Abstract: Alkyl oxalates are well suited for use as standard synthetic reagents in N-, O-, or S- alkylations and often display an interesting regioselectivity. The mechanism seems to be a direct alkylation of the substrate anion.


The alkylating properties of oxalic esters have been known at least since 1960, when Sakakibara alkylated phenols at high temperatures. (1,2) A few more cases can be found in the literature (3-6), but no systematic studies have been made to explore the use of oxalates as standard synthetic reagents. This can be attributed partly to the reaction temperature and the basic conditions which make them unsuitable for sensitive substrates, and also because it does not appear to present much of a mechanistic challenge, i.e. it seems to be a textbook example of an SN2 reaction. In a semi-empirical quantum chemical study we have used this as a probe for criticism of the Frontier Molecular Orbital (FMO) theory and obtained support for the expected SN2 mechanism. (7)
Qing-Hua et al (5) observed that dimethyl oxalate is considerably less toxic than traditional methylating agents. It should therefore be very well suited to large-scale methylations. This fact, together with promising results from our initial study(8), led us to investigate the scope and mechanism for the reaction more closely.

Results and discussion:

The results of the alkylations using dimethyl, diethyl, di-sec-butyl and dibenzyl oxalate are summarized in table 1. When the substrate has more than one nucleophilic center, the position of alkylation is indicated.
Alkylation of o-mercaptoaniline yields the S-alkylated product, as expected. Methylation of 4-nitro imidazole gives an easily purified isomeric mixture, where the 1-alkyl-4-nitro isomer dominates in a ratio of 4:1, as determined by H1 NMR. As comparison, it has been shown that dimethyl sulfate reacts with 4-nitro imidazole in acidic media to give mainly the 1-alkyl-5-nitro isomer in an isomeric ratio of 350:1 (9a) In basic solutions the reaction yields mainly the 1-alkyl-4-nitro product (ratio 3:1)(9b).

Indoles are strongly nucleophilic at the 3 position, and many alkylating agents will alkylate indoles at that site. Oxalic esters selectively monoalkylate various indoles at the 1-nitrogen. Purines were monomethylated at the 9-position.
Methylation of benzotriazole yielded a mixture of 1- and 2-methyl benzotriazole (ratio 2:1) This is to be expected from alkylation of benzotriazole under alkaline conditions, although other alkylation methods may give widely differing ratios (10).
Anthranilonitrile, a primary amine, has been monomethylated in good yield (11). The mechanism in this case seems to involve the alkylation of an intermediate oxalimide, and the subsequent cleavage to the monoalkylated amine (scheme 1). The intermediates have been independently prepared and subjected to the reaction conditions, in all cases yielding the expected N-methylanthranilonitrile. (11)

Scheme 1:
Ph(CN)(NH2) + DiMeOxalate & KO-tBu --> [ Ph(CN)(NH-COOCOMe) --> Ph(CN)(N(Me)-COOCOMe) ] --> Ph(CN)(NH-Me)

*** Note--can we see the conversion of, say, MDA to MDMA? huh?

Lespagnol(3) has shown that phenothiazine is alkylated by oxalate in neutral and acidic media, but the substrates in our study gave only low yields of acylated products in the absence of a base strong enough to deprotonate the substrate.
It can be argued that all alkylations proceed via acylated intermediates as shown in scheme 2.

Scheme 2:

Nu-  +  R.OCOOCO.R --> (Nu)(R.O)(O-)COCO.R --> NuR + R.OCOOCO-

In order to test this, two acylated indoles, namely methyl 1-oxo-1-(N-indolyl)-acetate (I) and ethyl 1-oxo-1-(N-indolyl)-acetate (II) were prepared by dehydrogenation of the corresponding indolines. (12)

if I or II were intermediates in the alkylation reaction, then reflux with potassium t-butoxide and oxalate in DMF should yield the alkylated indoles. Since indole is methylated in 10 minutes under these reaction times, the acylated indoles ought to react in even less time. The reaction was monitored by TLC for a few hours in both cases. It was noted that if the amount of t-butoxide exceeded the amount of oxalate in the mixture, or if undisolved t-butoxide was present, the reaction yielded alkylated indoles, but if a slight excess of oxalate was present, no alkylation product was formed. Adition of dissolved indole to this unreactive mixture yielded N-alkyl indole almost immediately. Thus we infer that indoles are alkylated under conditions that will not affect the acylated substrates, which consequently are not intermediates in the alkylation reaction. The fact that excess t-butoxide could break down I and II to N-alkyl indoles is attributed to liberation of free indole anion by the base. The inhibition of this liberation by excess oxalate can be explained if t-butoxide and oxalate form a much less nucleophilic complex in solution. Such complexes have been isolated by Adickes(13) To further demonstrate this liberation of indole anion, ethyl 1-oxo-1 (N-indolyl)-acetate II was mixed with a 3-fold excess of DiMeOxalate and 4-fold excess of KOt-Bu in DMF. This mixture was refluxed overnight and then analyzed by GC. Less than 1% of the alkylated indole was N-ethyl indole. As expected, N-methylindole dominated (>99%).
As a final study of the mechanism, di-sec-butyl oxalate and sec-butyl tosylate were prepared from the same optically active (S)-sec-butanol. Both compounds were used to alkylate p-thiocresol using similar conditions. The products were essentially identical, although not enantiomerically pure. Since tosylates are expected to alkylate mainly with inversion, the oxalates obviously alkylate in the same way.
It is notable that the substrate anions can be expected to undergo reversible addition to the acyl carbon of the oxalate in the presence of alkoxides. The alkylations may be dependent on this reversibility to minimize byproducts.

Table 1:
Literature yields are only from alkylation reactions. In several cases there are better non-alkylative methods available for synthesizing these compounds.

Substrate    Oxalate   Base  Where  Yield  Lit.Yield Ref

Phenol       Me        Na2CO3  O    79%      -
Phenol       Et        Na2CO3  O    67%      -
Phenol       Sec-bu    K2CO3   O    25%      6      (14)

p-thiocresol Me        t-buOK  S    76%     81      (15)
"            Et        Na2CO3  S    66%     91       "
"            sec-bu    Na2CO3  S    67      48      (16)
o-mercapto   Me        K2CO3   S    64      54      (17)

4-Nitroimidazole  Me   t-BuOK  1    59      -       (9b)
Anthanilonitrile  Me   "       N    85      53      (11)
2-Aminobenzophenone "  "       N    60      70      (24)
Indole            Me   "       N    88      95      (18a)
Indole            Bn(?)"       N    86      95       "
4-Nitroindole     Me   EtOK    N    91
"                 Et   EtOK    N    94
"             sec-Bu   K2CO3   N    5       .        .
Nitroindole       Me   EtOK    N    98
Isatin            Me   K2CO3   N    61      80       (19a)
imidazole         Me   t-buOK  1/3  43/40   71/42     (20)
Benzotriazole     Me   t-buOK  1/2  59/35   69/38  (10a,23)
Purine            Me   "       9    37      30        (23)
Adenine           Me   "       9    43      95        (21a)
Carbazole         Me   "       N    95      78        (22)
"                 Et   "       N    97      85        "
"                 Bn(?)"       N    86      97        "

Experimental (***Snipped, way too long***)


Phenol (0.94g 10mmol) was boiled with sodium carbonate (4g) in DMF (30mL) for 10 min. after cooling, dimethyl oxalate (2.36g 20mmol) was added, and the mixture was refluxed for 30 min. (ning's note--DMF boils @ 153 deg.) The solution was then poured into aqueous ammonia and extracted with ether. The ether solution was washed with water, dried (MgSO4) and evaporated. Yield 0.85g (79%) Bp 150-1 deg.

Ethyl phenyl ether:
Phenol (0.94g 10mmol), diethyl oxalate (2.92g, 20mmol) and potassium carbonate (4g) were refluxed in DMF(30mL) for 1h. The reaction mixture was poured into aqueous ammonia and extracted with ether. The extract was washed with brine, dried (MgSO4) and evaporated. The product (0.82g 67%) distilled at 62deg/ 8mm Hg.

sec-butyl phenyl ether:
phenol (4.7g 50mmol), sec-butyl oxalate (14.14g 70mmol), potassium carbonate (13g) and pyridine (1mL) were refluxed in DMF (30mL) under N2 for 17h. water (30ml) was added and the solution refluxed for 30 min, the solution was then extracted with light petroleum. The extract was washed with aqueous NaOH and then evaporated. The residue was distilled at 10mm Hg, bp 76-7deg. yield 1.87g (25%)

....blah blah blah

there's more if you want it, but I think this is the most important bit.
Have fun...

Now here is the question....can this methylate hydroquinones, or will it oxidise them instead? I guess wait and see...
Ning especially likes how efficient the ethylation is.
All you lucky guys with dimethylsulfate, great.
But I bet diethylsulfate is a little harder to come by...
Or t-butylsulfate, etc. etc. etc.
By the way, they used just about stoichiometric amounts of oxalate for all the alkylations. If one were to use two times the ethyl-oxalate, could they di-ethylate an amine?
"If you can ester it, you can do it!" seems to be the motto for this type of reagent.

For all who didn't know, oxalic acid can be had from certain types of sink and counter cleaners. It's solubility in water varies by > 100x from 0 to 100 degrees, making it a sucker for large scale recrystalization. Just pour your BKF/zud into a boiling pot calculated for (weight of can)'s worth of acid when boiling hot, let all disolve, decant off hot water into beaker leaving sand and crap behind, put in fridge/freezer, filter out crystals and wash.
The soap should stay in the water, the sand will stay in the pot.

Just ning's 20 won...

Title: i was under the impression that carboxy acid...
Post by: stratosphere on October 23, 2003, 04:30:00 PM
i was under the impression that carboxy acid anions where quite poor leaving groups, granted oxolic acid is more acetic and hence probobly a better leaving group then say acetic acid, but woudn't methylation with di-methyl oxolate require higher temps and longer reaction times then methyl iodide for instance?
Title: It does....
Post by: ning on October 24, 2003, 08:58:00 AM
Indeed, I believe methyl iodide needs only room temperature?
They were refluxing this thing at 150 degrees or so for a few hours. However, for many systems, this probably isn't a problem.

So MeI is probably a better choice for certain applications, and surely if you can get it, is good. But if you want the ULTIMATE OTC methylating agent, I assert, methyl oxalate is probably it.

Title: An absolutely failed attempt...
Post by: Antoncho on October 24, 2003, 10:16:00 AM
I want to share something with you, bees.

Today SWIM decided to try out the following variation of methylating vanillin (which he actually made up :) ):

- to dissolve vanillin in DMF
- to add an equimolar amt of conc. aq. KOH to form phenolate
- add DMS therein and leave overnight

Well... Vanillin dissolved like a charm. When SWIM added alkali the soln turned slightly cloudy, but not much (24mls DMF per 6g vanillin per 4,5mls 36% KOH) and some water - 2 or 3mls - appeared as the lower layer ::)

SWIM decided to add some MgSO4 to suck the water and thus minimize chances of DMS hydrolysing.

When he did that, he noticed that the mixture smelled strongly of dimethylamine ;D  ::)  :(  >:(  :o  ;D

Naturally, after that all was dumped into the sink...

WTF??? SWIM would've never thought that DMF would bee hydrolysed on the fly with aq. KOH.... which should bee, above all, instantly neutralized with vanillin's phenolic group. Was he totally naive at that?

Yes, temp rose remarkably during addition of KOH - up to 45 C, maybee.

Please, comment, SWIM's absolutely lost ;D !


P.S. Dimethyl oxalate is surely a nice alternative to regard - but the yields are on the low side even with phenol, which is much more active than aromatic aldehydes... So don't think it'd work well - maybee, under some other conditions.
Title: Why did you add water?
Post by: Rhodium on October 24, 2003, 04:51:00 PM
I believe that the only thing in error was the addition of KOH as an aqueous solution - if you had kept the reaction mixture anhydrous, I believe that no hydrolysis would take place (KOH is soluble in DMF). Reactions involving hydroxides, alkoxides and other bases are routinely performed in DMF, but usually water is kept to a minimum to avoid side-reactions.
Title: and speaking of OTC, isn't methyl oxalate is...
Post by: stratosphere on October 26, 2003, 12:23:00 PM
and speaking of OTC, isn't methyl oxalate is in the "fuel" in glow sticks?
Title: really??!!
Post by: ning on October 28, 2003, 06:37:00 AM
Ning did NOT know this! What an interesting twist 'twould be! Must do searching....
Good call!
Title: the chemistry of glow sticks
Post by: Rhodium on October 28, 2003, 06:47:00 AM
No, the "fuel" is usually hydrogen peroxide, and as an energy transfer medium a diphenyl oxalate is usually used, see the following explanation by Uncle Al for details: (

Title: awww, too bad
Post by: ning on October 29, 2003, 09:43:00 AM
thought to get a good one on that...
Title: Finally, a working procedure.
Post by: Antoncho on October 30, 2003, 05:36:00 AM
Well, let me tell you several things.

First, DMF is indeed quickly decomposed by conc. aqueous alkali at RT! ([confused] can anyone approve or disprove this fact? - SWIM is still unsure if his DMF might have some (Me2NH2)HCOO in it). On contrast, when a solid alkali, such as KOH is added, no smell is observed (doesn't dissolve much, either).

Second, a trial was conducted on vanillin using DMS in DMF/K2CO3. Everything was done a la Hest ( (

), xcept the mixtr was incubated for 5 hrs instead of 3 and an occasional shaking was employed instead of stirring. Result - nada. Got all vanillin back unchanged. SWIM also noted that when he added DMS to the mixtr it heated considerably - something that normally shouldn't happen. So the probable cause of failure seemed to bee the presence of dimethylammonium formate in DMF.

So SWIM took his DMF and boiled it for an hour, hoping to convert the formate to formamide. Do you guys think it'd work OK or something else is needed? In any case, both boiled and unboiled DMF showed absence of ammoniac smell when treated with granular KOH - so maybee SWIM was wrong about dimethylammonium salt... Could something else ruin the reaction? Like water?

SWIM has no doubts about the validity of Hest's procedures - and it drives him insane that he can't really figure why it didn't work. It must bee smth REALLY obvious - but SWIM's DMF seems to bee devoid of both significant qtties of water and dimethylammonium salts - otherwise there'd bee smell upon treatment with KOH, no?

Fortunately, SWIM beegan to consider the variation with acetone as solvent. Drying acetone is easy - it was refluxed for 5hrs over CaCl2 and distilled.

Initially he was reluctant to take this approach since the patent, quote from which can bee read at Rh's ( (

) stated a 24hr reflux was needed. Yikes (SWIM feeds his condenser from the kitchen sink which is normally used as such :) ).

But then he re-read

Patent US3867458 (

, mentioned in the beginning of this thread - and to his great surprize found out that, according to its authors, only 3hrs was needed! Upon careful analysis the following reasons for that discrepancy were found:

1. Solvent to reactant ratio is twice as high in the 24hr variation.
2. Na2CO3 + a little KOH is used as a base in the 1st patent, whereas the 2nd patent clearly says that 'in presence of Na2CO3 instead of K2CO3 the reaction does not proceed'.

Well, SWIM tried it and it worked! Unfortunately, he made a fatal mistake during workup (DO NOT add NaOH to a soln containing both acetone and aldehyde - aldol condensation) so the proper writeup is yet to come - but for now it's clear that this modification works well, gives no byproducts and does not require any stirring (after an hour or so the reaction begins to bump, which efficiently mixes the flask's contents).

SWIM would really like to master that DMF variation though... Really confused about what happened and how to prevent that (or, for that matter, how to efficiently test for presence/remove an ammonia salt from DMF). Any ideas, bees?

Title: Good point Antoncho
Post by: imp on November 02, 2003, 10:21:00 PM

he made a fatal mistake during workup (DO NOT add NaOH to a soln containing both acetone and aldehyde - aldol condensation)

SWIM is very glad someone else noticed this. Several years ago, SWIM had wondered why acetone was a safe solvent for benzaldehydes? Shouldn't aldol condensation occur? Of course not...

Firstly, fortunately benzaldehydes cannot undergo aldol condensation with themselves because they don't contain any enolizable hydrogens. Now, it is well known that enolates will attack the carbonyl function with relative ease. In this case, acetone + NaOH(aq) will form a small amount of the enolate which will attack the carbonyl funtion on the benzaldehyde forming an alkoxide. Finally, the alkoxide will be protonated by the water to the aldehyde alcohol, or aldol.

Crossed aldol condensations will happen on most every benzaldehyde, especially those that don't have any free phenol substituents...Piperonal, 3,4,5-tmb, benzaldehyde, anisaldehyde...

Now that we understand the mechanism of how the reaction works, all the ambiguity can be rationalized and explained...

The reason that these alkylations work and do not form aldol condensation products with acetone is simple. The reactions are performed under anhydrous conditions, not using aqueous base with the acetone. Also, none of them use NaOH as a base, but instead Na2CO3 or K2CO3 - which are quickly neutralized as the dimethyl sulphate trades off a +CH3 for a H+ forming methylsulphuric acid.

So, in general, acetone is a safe solvent to use with benzaldehydes so long as no aqueous hydroxide ions are present. This is also good for diazotization mixtures of aminobenzaldehydes, where acetone is a good solvent to help isolate pure diazo salts.

Also, with ketones, this aldol-type condensation will happen to a small extent, but it is very small. This can be explained due to the carbonyl bond being stronger in ketones than in aldehydes. Ketone + acetone is endothermic, Aldehyde + acetone is very slightly exothermic.

Hope this helped. SWIM always feels that is important to understand what is possible in a reaction mixture.