Synth: Acetamides

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Acetamide
G. H. Coleman and A. M. Alvaram
Organic Syntheses, vol. III, 1923, p3;
Organic Syntheses Coll. vol. I, p3;

CH3·CO2NH4 ? CH3·CONH2 + H2O

Procedure
In a. 5-L. flask is placed 3 kg. (2860 cc, 50 mol) of glacial acetic acid and to this is added a weight of ammonium carbonate corresponding to 400 g. (23.5 mol) of ammonia (Note 1). The flask is fitted with a one-hole stopper holding an efficient fractionating column 90 cm. long with condenser and receiver. An air condenser 150-200 cm. long may be used. The mixture in the flask is heated to gentle boiling and the heat regulated so that the distiln. rate does not exceed 180 cc. per hour. The distiln. is continued for 8 to 10 h, until the temp. at the head of the column reaches 110°. The distillate, which is a mixture of water and acetic acid, amounts to 1400-1500 cc. The receiver is changed, the heat under the flask is gradually increased, and the distiln. is continued at about the same rate until the temp. at the head of the column rises to 140°. The distillate, which amounts to 500-700 cc., is largely acetic acid and may be used in the next run.

The contents of the flask are transferred to a 2-L. flask for fractional distiln. (as described in Vol. I, p. 40), having a column 40-50 cm. long, and distilled at atmospheric pressure, using an air condenser. The fraction boiling below 210°, amounting to 250-300 cc., is collected separately. The material remaining in the flask is nearly pure acetamide and may all be distilled, 1150-1200 g. passing over at 210-216°. By redistilling the fraction boiling below 210°, the yield may be increased to 1200-1250 g. (87-90% of the theoretical amount). The acetamide thus obtained is pure enough for most purposes, but if a purer product is desired it may be recrystallized from a mixture of benzene and ethyl acetate; 1-L. of benzene and 300 cc. of ethyl acetate are used for 1 kg. of acetamide. Colourless needles melting at 81° are thus obtained (Note 3). The solvent and the acetamide it contains may be recovered by distiln.

Notes

1. Ammonium carbonate of commerce is often extremely impure, and care must be taken to obtain a representative sample for the determination of the ammonia content by titration with standard acid. The ammonium carbonate used in this preparation contained 27·2% ammonia, and 1470 g was used in each run.
2. Crystallisation of acetamide, by solution in hot methanol (0.8 cc per g.) and dilution with ether (8-10 cc per g.), has been recommended as the best purification method.
3. As acetamide is somewhat hygroscopic, it cannot be exposed to the air unless precautions are taken to have the air dry.
3. Other Methods of Preparation
Acetamide has been prepared by a, variety of methods, of which the more important are the following: by the rapid distillation of ammonium acetate ; by heating ammonium acetate in a sealed tube and distilling the product ; by treating acetic anhydride with ammonia ; by heating a mixture of ammonium chloride and sodium acetate to 240° ; by the action of cold aqueous ammonia on ethyl acetate ; by boiling a mixture of glacial acetic acid and ammonium thiocyanate for four days ; by saturating glacial acetic acid with dry ammonia and boiling ; by distillation of ammonium acetate through a reflux condenser filled first with glacial acetic acid and then with aniline until the temperature of the mixture reaches 220°. , by passing a stream of ammonia through heated acetic acid ; and from formamide and hydrogen at 200-500°.
The foregoing process is based on the method of W. A. Noyes and W. F. Goebel, in which equimolecular proportions of ammonium acetate and acetic acid are heated together, the acetic acid having been shown to accelerate both the dehydration of ammonium acetate and the hydrolysis of acetamide.

Chloro-acetamide (Acetamide, ?-chloro-)
by W. A. Jacobs and M. Heidelberger
Org. Syn. Coll. vol. 1 p 153.

ClCH2CO2C2H5 + NH3 ? ClCH2CONH2 + C2H5OH

Procedure

In a 2-L. round-bottomed flask fitted with a mechanical stirrer and surrounded by an ice-salt bath is placed 215 g. (1.75 moles) of ethyl chloroacetate (Note 1). Vigorous stirring is started, and to the cold ester (Note 2) 200 cc. of chilled aqueous ammonia (sp. gr. 0.9) is added. The solution is stirred in the cold for about fifteen minutes; then another 200-cc. portion of aqueous ammonia is added, and the stirring is continued for about fifteen minutes. The mixture is then allowed to stand for thirty minutes, filtered with suction, and washed with two 25-cc. portions of cold water to remove ammonium chloride. The yield of air-dried material melting at 118-119° (Note 3) is 128-138 g. (78-84 % of the theoretical amount).
This product contains traces of ammonium chloride which may be removed by crystallisation from water. When 100 g. of crude product is recrystallised from 400 cc. of water, about 80 g. of product is obtained. The recrystallized product melts at 119-120°

Notes

1. The ethyl chloroacetate used may be a commercial grade which boils at 141-146°. The ethyl chloroacetate and the chloroacetamide have the usual irritating effect of chloroacetyl compounds.
2. The temperature is best maintained at 0-5°. At higher temperatures there is more replacement of the chlorine and the yields are considerably lower.
3. Traces of moisture lower the melting point considerably.
3. Methods of Preparation
Chloroacetamide can be prepared from chloroacetyl chloride and dry ammonia gas, and by the treatment of ethyl chloroacetate or methyl chloroacetate with cold aqueous ammonia solutions. The procedure described was developed from the methods of Scholl14 and Troger and Hille.14

The Preparation of Acetamide
M. A. Rosanoff, Louise Gulick, & Herbert K. Larkin
JACS 33, 974-77, 1911

Methods Used Hitherto. Acetamide has long been prepared by the action of aqueous ammonia upon ethyl acetate, as originally proposed by Dumas, Malaguti and Leblanc. The reaction mixture has no effect upon iron, and so the process can be carried out on a considerable scale in iron autoclaves.
The preparation of amides from the ammonium salts of the corresponding acids was first introduced by Dumas. The details of this method, as now generally employed for the preparation of acetamide on a laboratory scale, were worked out by Hofmann. Hofmann sums up the condition of the preparative method at the time he undertook its amelioration, in the following words:
”If, however, the preparation of amides by treating esters with ammonia. leaves much to be desired, the yields obtained by the distillation of ammonium salts are even less satisfactory. Experiments on the preparation of acetamide by this method have been published by Kündig, who obtained, in the most favourable case, using glacial acetic acid saturated with ammonia gas, something over 25 % of the theoretical yield. In all these distillations streams of ammonia escape at first, which naturally reduces the yield of amide. Petersen, who, at Bunsen's suggestion, modified the experiment by distilling a mixture of equivalent quantities of fused sodium acetate and sal ammoniac, states that acetamide may thus be easily and advantageously prepared, but says nothing concerning the percentage yield. When this experiment was repeated, perfectly pure acetamide was obtained directly, but in this case, too, a large quantity of ammonia was lost and the final yield of acetamide amounted to only 20 % of theory."
Hofmann's method, as given in its optimum form by Gattermann, consists in neutralizing 75 grams of acetic acid with ammonium carbonate and heating in sealed tubes for five hours at 225°. The reaction product is subjected to fractional distillation; the fraction passing over between 180° and 230° is collected separately and on solidification pressed out on a drying-plate. The pressed-out crystals are redistilled, yielding about go grams of almost pure acetamide.
This operation, however, cannot be carried out on a large scale. We quote from Hofmann ': "Unfortunately, this operation cannot be carried out, like the treatment of esters with ammonia, in iron autoclaves, as these are strongly attacked. Acetamide will, therefore, be best prepared in the future, as heretofore, by treating the ester with ammonia at ordinary temperatures."
One or two modifications of the Hofmann method have been proposed since 1882. Thus, Schultze warms ammonium acetate with acetic anhydride, using no less than 130 grams of anhydride to too grams of the acetate. This, however, is not only costly, but unquestionably yields much diacetamide together with acetamide. Keller distils ammonium acetate in a current of ammonia. We have tried out this method, but with no satisfactory results: unless one carries out a great many redistillations, which is disproportionately laborious, the yield is very small (generally about 12 % of the theory).
New Method. - Hofmann's: method has two disadvantages: first, the acetate must be heated in sealed vessels; secondly, iron vessels cannot be employed.
From the viewpoint of chemical statics, there is very little advantage in raising the temperature to 2200. According to Menschutkin, the maximum percentages of acetamide formed at different temperatures are as follows:

Temperature Max. % acetamide formed.
125.0° 75.1
140.0° 78.2
155.0° 81.5
182.5° 82.8
212.5° 84.0
Obviously, almost as much acetamide could be obtained at 140° as at 220°. The reason that the higher temperature is generally employed is that at lower temperatures the reaction is impracticably slow.
This suggested the possibility of rendering the old method simple and convenient by employing a suitable catalytic agent.
The most appropriate catalyst, apparently, was suggested by the following simple considerations. From the fact that the hydrolysis of amides is catalyzed by acids, the inference was drawn that acids would also hasten the opposite reaction, i. e., amide formation. Mineral acids could not be used, as they would take up the ammonia from the ammonium acetate. Organic acids generally would yield their own amides in addition to acetamide. Acetic acid alone could do no harm and might be confidently expected to Promote the reaction catalytically.
Theoretically it was also clear that, by increasing the volume of the reacting mixtures, the acid catalyzer would improve the yield, since the reaction involves the formation of two molecules (amide and water) from a single molecule (ammonium acetate). This might be expected to counterbalance the slight diminution of yield produced by the temperature lowering.
Experiment soon showed that in the presence of an excess of acetic acid the amide formation really took place with considerable velocity in open vessels. It remained to determine the essential details of the preparation, and this required a large number of trials. The following directions will be found to yield satisfactory results.
First, good dry ammonium acetate is prepared by neutralizing glacial acetic acid with pulverised ammonium carbonate at about 50°, allowing to cool, draining off the crystals, and pressing them out twice or three times with filter paper. The product so obtained contains very nearly 98 % of the pure salt.
100 grams of this ammonium acetate (corresponding to 75 grams of acetic acid) and 113 grams glacial acetic acid (ratio: I mol. acetate to 1.5 mols. acid) are boiled in a one-litre flask with reflux condenser for 5 hours. The product is rapidly distilled over with minimum loss and subjected to fractionation (again out of a 1-litre flask) with the aid of a two-bulb Wurtz stillhead. This operation should be carried out as slowly as possible. Three fractions are collected separately:
(1) the fraction passing over below 180°,
(2) the fraction passing over between 180° - 213°;
(3) the fraction passing over above 213°
During the distilling of fraction 3 the stillhead is unnecessary. The second fraction (180°-213°) is slowly redistilled with the Wurtz stillhead, and the portion passing over above 213° is added to fraction 3, the remainder being added to fraction 1. The original product is thus divided into a low-boiling and a high-boiling fraction. The former may again be neutralized with ammonium carbonate and the resulting salt used for a new preparation. The high-boiling fraction, on thorough solidification, is twice pressed out with filter paper. The dry crystals (practically pure acetamide) weigh over 60 grams, or 20 grains more than the product obtained by the use of sealed tubes according to the Hofmann-Gattermann directions. The yield is, however, slightly variable, depending on the quality of the ammonium acetate used and especially on the care with which the fractionation is carried out.
It is obvious that the above directions permit of transforming ammonium acetate into acetamide on as large a scale as may be desired, and should lead to a considerable reduction of the present price of acetamide.
In order to make certain that the low temperature employed did not after all materially diminish the yield, some experiments were carried out on the following plan: 100 grams of our fairly dry ammonium acetate and 113 grams of acetic acid were heated for 3 hours (experiments have shown that even 2 hours would have sufficed) at 225° in sealed tubes. The product was subjected to fractional distillation as described above. The yield was about 56 grams. There is, certainly, no advantage in using sealed tubes.
Our product boils at 214-216°, which shows it to be nearly pure acetamide.

Prep. of Acetamide
(Mann & Saunders)

By heating ammonium acetate. Decomposition to acetamide and water occurs. Water is removed by distilling it off. A major side reaction is the decomposition of ammonium acetate to acetic acid and ammonia. This decomposition can be prevented by adding acetic acid.

50 g of ammonium acetate and 50 g of glacial acetic acid are placed in a flask fitted for refluxing with an air condenser. The flask is slowly heated so that a few drops per minute of liquid distil (water plus acetic acid). After about 4 hours the residue in the flask contains acetamide and acetic acid. It is transferred to a distilling flask with an air condenser and distilled. Acetamide fraction boils at 213o - 230o.

Recrystallisation

About twice its weight in alcohol is added to the acetamide and the mixture heated in a beaker on a water bath until the amide has dissolved. On cooling colourless needles of acetamide separate. These are filtered and sucked dry on a Buchner funnel.

Note - Acetamide: Mp. 82°; Bp. 223°. Very soluble in water, alcohol and ether.

(Re-Post...originally posted by cherrie-baby)

Guest · Mon Feb 14, 2005 6:52 am

There's always the Urea+ GAA,
In vogels, Straight forward, no sidereactios,

A great way if your on the path to methylamine,.

Have a look here

http://12.162.180.114/dcd/chemistry/eleusis/methylamine27.html--Acetamide1

syn

IndoleAmine · Dreamreader Deluxe

I am content with throwing some bought ammonium acetate into a beaker situated in a 160°C oil bath and waiting several hours until everything volatile has evapped.... Wink

i_a

Guest · Wed Jun 08, 2005 7:59 pm

I_A.

So then what about vineagar and ammonia sulfate, to make ammoinia acetate, or any ammonia base, carbonate etc,

syn