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(Cesium's Voice:) Useful aldehydes can be prepared by alkylating corresponding phenolic aldehydes by a variety of agents (alkyl halides, alkyl sulphites or sulphates). However, the alkylating agents, e.g. dimethyl sulfate or methyl chloride, are themselves acutely toxic and require special handling procedures. In US Pat 4,453,004 a process for the preparation of an alkylated phenolic ether comprising reacting a phenolic compound at a temperature of at least the melting point of the phenol and in the absence of a solvent with trimethyl phosphate as an alkylating agent (with low toxicity and handling hazard) is described.
Examples of phenolic compounds that can be alkylated are such monohydric phenols as phenol and o, m and p-cresol; phenolic aldehydes such as protocatechualdehyde, vanillin, syringaldehyde, p-hydroxybenzaldehyde, 5-formylvanillin and salicylaldehyde; phenolic ketones such as p-hydroxyacetophenone, acetovanillone, acetosyringone, acetamidophenol and guaiacol; and phenolic acids such as vanillic acid, syringic acid and p-hydroxybenzoic acid. The alkylating agent may be essentially any compound which is a source of a one to four carbon atom alkyl group. It may be either a gas or a liquid. In general, the alkylating agents may be alkyl sulfonates such as methyl and ethyl p-toluenesulfonate and methyl and ethyl benzenesulfonate; trialkyl phosphates such as trimethyl and triethyl phosphate; and dialkyl sulfites such as dimethyl and diethyl sulfite. (Other alkylating agents which may be used are alkyl sulfates such as dimethyl sulfate, diisopropyl sulfate and diethyl sulfate; alkyl halides such as methyl chloride, methyl bromide, methyl iodide, ethyl chloride, ethyl bromide, ethyl iodide and similar propyl and butyl halides).
From US Pat 4,453,004
Example 1
In a three-neck flask (capacity 100 ml) equipped with a mechanical stirrer and reflux condenser, 5.00 g (0.033 mol) of vanillin and 5.00 g (0.036 mol) of anhydrous potassium carbonate were placed and the mixture was heated under a nitrogen atmosphere to 85°C. The mixture was a clear to amber melt of vanillin with carbonate in suspension. To this mixture was added 5.00 ml (0.043 mol) of trimethyl phosphate over about 5 minutes while maintaining the reaction temperature below 125°C. The mixture was maintained at about 80°C. for one hour and then cooled to 40°C. The mixture was poured into 20 ml water and extracted two times with 20 ml of methylene chloride. The combined extracts were dried over anhydrous potassium carbonate, filtered, and concentrated to give 5.4g (99%) of veratraldehyde as a pale oil.
Example 4
In an apparatus similar to Example 1, 15.2 g (0.083 mol) of syringaldehyde and 15.0 g (0.11 mol) of potassium carbonate were heated to 105°C under nitrogen and 15 ml (0.12 mol) of trimethyl phosphate were added over 10 minutes. The mixture was maintained at about 80°C. for 3 hours then cooled to 45°C. and quenched with 50 ml of H2O. The tan solid which precipitated was collected, washed with 3×50 ml of water and dried to give 15 g (92%) of 3,4,5-trimethoxybenzaldehyde.
From US Pat 4,065,504:
Example 1
A mixture of 100g of syringealdehyde (0.55 mol), 85.0g of sodium carbonate (0.80 mol) and 106.0g of dimethyl sulfate (0.84 mol) was placed in a round-bottomed flask equipped with a reflux condenser, a stirrer and a dropping funnel. The syringealdehyde was of about 99% purity and was obtained, by distillation, from a crude mixture of vanillin and syringealdehyde produced by alkaline oxidation of waste Kraft liquor. The dimethyl sulfate was of commercial quality (bp 75-77°C/15 mm) and the sodium carbonate was of reagent grade in some experiments and of commercial grade in others. The flask was kept in a silicone oil bath on a hot plate. The mixture as prepared at room temperature was a thick paste which could be kneaded but could not be mixed by the stirrer driven by an electric motor. When the temperature of the mixture reached 75°C the mixture became fluid and was easily stirred by the blades of the stirrer. The temperature was further raised to about 85°C and maintained at this temperature with stirring for a total of about 2 hours. After the initial 35 minutes of this period the reaction mixture began to thicken due to the consumption of dimethyl sulfate and, in order to maintain it fluid, water in 5 gram portions was added from time to time through the funnel while the stirring continued. In total about 60g of water were added to the mixture during the reaction period. At the end of two hours, the heating was discontinued and about 500 ml of hot water was added to the mixture. The mixture was acidified with concentrated hydrochloric acid and was then extracted three times with about 250 ml of benzene (toluene,...) and the combined extract was washed with water. The benzene was removed by distillation and the solid product was dried in a vacuum oven and weighed. The yield was 106.9 g of 3,4,5-methoxybenzaldehyde, representing a yield of 99.3% of the theoretical. Analysis by gas-liquid chromatography (g.l.c.) showed a purity of 99.85% with syringealdehyde as the only detectable impurity.
Example 2
50g of syringealdehyde (0.275 mol) 40g of sodium carbonate (0.38 mol) and 53.4g of dimethyl sulfate (0.42 mol) were placed in a round-bottom flask and heated substantially as in Example 1. When the temperature reached 75°C the reaction mixture became fluid but after 30 minutes at a temperature between 80-87° it began to thicken again. 30 ml. of water was then added dropwise while the temperature was maintained for 1.2 hours. On completion of the reaction 250 ml of hot water was added to the mixture. Then the mixture was cooled, the solidified organic material separated by filtration, washed with water and vacuum dried. The yield of 3,4,5-trimethoxybenzaldehyde was 99.6% with about 0.4% syringealdehyde remaining.
Example 6
On mixing 50 g of vanillin (0.329 mol), 48.0 g of sodium carbonate (0.453 mol), and 60.2 ml of diethyl sulfate (0.460 mol) a fluid mixture was obtained almost immediately. The mixture was maintained at 80° for 3.5 hr. Water (25 ml) was added in small portions over the last 2.0 hr. Work-up as in the previous examples yielded 58.06 gm. (98.1%) of 4-ethoxy-3-methoxybenzaldehyde which contained 2.4% vanillin.
Example 7
20.g of p-hydroxybenzaldehyde (0.164 mol) was reacted with 29.0 g of dimethyl sulfate (0.230 mol) and 22.0 g of sodium carbonate (0.20 mol) for 2 hr. at 75°-80°C. A total of 12 ml of water was added in small portions over the last hour. Work-up by addition of water, acidification and benzene extraction yielded 22.27 g of p-methoxybenzaldehyde (99.9%) containing not more than 0.1% p-hydroxybenzaldehyde.
30.5 g (0.3 moles) of Toluhydroquinone (2-Methylhydroquinone) was placed in a 250 mL RBF. This was placed in a water bath at room temperature. 110 mL 20% NaOH was added while stirring. The whole lot dissolved in a matter of seconds, and the mixture turned black/brown within seconds. After a minute 70 mL's of trimethylphosphate was added. The temperature remained constant during the next five minutes. A reflux condensor was attached and the waterbath was slowly heated to a gentle boil over the course of 30 min's. When the waterbath was boiling, the mixture refluxed slightly. This was continued for another hour.
After a hour, the mixture was removed from the waterbath and allowed to cool to almost room temperature. Next, the reaction mixture was added to a seperating funnel, containing 200 mL's of cold water. This was extracted three times with 3x75 mL's of DCM. The first extraction separated fine, but the following two caused heavy emulsion. A bit of NaCl was added, but it did not help a whole lot. Some carefull swirling got rid of the worst emulsion.
The DCM phase was very blackish looking, but two water washes took care of the worst color. The remaning DCM was deeply red in color. The DCM was placed in a large RBF and heated on an oil bath. The DCM was distilled off and the remaining viscous oil was distilled under vacuum. This yeilded a beautiful red-amber colored liquid, which boiled at 130-140°C. The total yeild was 31 grams (90% molar) of 2,5-dimethoxytoluene.
Several attempts have been made to achieve an OTC preparation of Dimethylsulphate (DMS). Beside its toxidity no convincing method for its preparaton is known in the Hive. In the Houben-Weyl1 a short sidenote is made in the section for the alkylation of phenols, other neutral alkyl esters of inorganic acids can also be used instead of the DMS but they haven't found any wide applications.
One of these neutral esters for methylation is the Trimethylphosphate (CH3O)3PO (TMP for this write-up) for which a preperation from the dimethyl phosphos acid ester is described in2. In3 an example using TMP for the preparation of the 3,4,5-trimethoxybenzaldehyde from syringaldehyde is described.
Based on the fact that in2 it is mentioned a mix of mono- and dimethyl phosphoric acid esters can be prepared from P2O5 and methanol, Uemura started to evaluate this patent in more detail:
In a 500 ml two-neck RB flask a thermometer, a stirring bar and 3 mol MeOH (96 grams, not ml!) are inserted. The flask is put with ice-water to cool down the MeOH to about 5°C. In the meantime a first batch of 40g P2O5 is weighted and immediatly put in a tightly closed wide-mouth jar4.
When the MeOH has been cooled down, a spatula P2O5 from the jar is added to the stirred MeOH, the jar closed again immediately. This is a exothermic rxn and the temperature immediately rises to 8-9°C. Carefully within one hour the first batch of 40g can be added in a manner the temperature does not go higher than 15°C.
A second batch of 50g P2O5 is weighted and also added in small amounts within the next 1.5 hrs.5 The last batch (50g) is added as the other twos before, now allowing the temp to raise to 25°C. For the whole addition 4-5 hours are required6. At the end of the addition, white sticky flocks are swimming in an oily ester mix7. To dissolve this precipitate and to complete the rxn, the ester mix is heated on a hot waterbath for 1 hour. When the ester mix has cooled down almost all flocks disappeared. It is now partially neutralised very carefully9 with 26g of a 50% NaOH-H2O solution which takes about 15-20mins.
Vacuum destillation is now setup. The flask is heated slowly, a vacuum of 30mbar is applied9. The inside temp climbes to 170°C up to which water and some MeOH destilles over. The end of the H2O destillation can easily be recognised, when the water droplets in the condensor disappear. Then stop heating, cool down, release vacuum, attach clean receiver flask. Heating again, vacuum to 25mbar, the pyrolyse starts at 188°C temp of the flask content. Up to 210°C the TMP destills over as a water-clean liquid. When the temp has reached 200°C the flask starts to foam. Destillation comes to an end and the temp in the flasks drops again even with further heating10.
Heating was stopped, the vacuum released after the apperatus has cooled down. In the flask the NaH2PO4 solidifies but can be removed when water is added and poured away regulary.11
The amount of TMP received have been 45.6g. This a yield of 35%12. Specific weight of received destillate is 1.2g/ml. Lit. says it's 1.21 which is fully within the error range. The smell of the TMP should be familiar to anybody who visited car-service stations. Since it's used as an additive to gasoline/oils, when you smell it you will recognize it.
For illustration - as usual - some pics:
Methylation of Hydroquinone: 1,4-dimethoxybenzene
0.05 mol (5.5g) Hydroquinone are dissolved in 22ml of a 20% NaOH solution in water in a 100ml flask equipped with a stirrbar sitting in a water bath. No atmospheric protection caused the stirred solution to turn from clear to yellow and brown. Within 2 min, 14ml (16.8g=0.12mol) TMP are added via a pipette under stirring. The waterbath is switched on and slowly heated to reach 60DegC after 30 mins. After this time, the reaction still smells from TMP. Heating is increase an the stirred mix is heated in a boiling water bath for 45mins. After about an hours total time, oily dimethoxybenzene appears and the vapour smells of the ether. The dimethoxybenzene now seperates as a slight yellow oil on top of the mixture. No smell of TMP anymore.
No yields determined so far, work-up not finished yet, but it works!
Nothing to say but it works! If you can't get DMS take this route.
Yield for TMP could be better, but with 45 g you can methylate 0.33 mol of a phenolic group!
