A mild and efficient procedure for the preparation of acid chlorides from carboxylic acids. Jang, Doo Ok; Park, Doo Jin; Kim, Joonggon.
Tetrahedron Letters (1999), 40(29), 5323-5326.
Abstract
Various carboxylic acids are converted into the corresponding acid chlorides by treatment with trichloroacetonitrile and triphenylphosphine in methylene chloride at room temp. Aryl acids show higher reactivity than alkyl acids under the conditions.
Typical Experimental Procedure:
To a mixture of benzoic acid (122 mg, 1.0 mmol) and trichloroacetonitrile (288 mg, 2.0 mmol) in CH2Cl2 (1 mL) under argon was added Ph3P (524 mg, 2.0 mmol) in CH2Cl2 (1 mL) dropwise at room temperature. The reaction mixture was stirred for 40 min (TLC showed the dissappearance of benzoic acid). The reaction mixture was then treated with cyclohexylamine (99 mg, 1.0 mmol) followed by triethylamine (0.42 mL, 3mmol). The reaction mixture was allowed to react for 30 min. The mixture washed with water. Organic layer dried over MgSO4. Column chromatography on silica gel (hexanes/EtOAc, 2:1) to give N-cyclohexylbenzamide (197 mg, 97 %).
Table 1 - Results in various solvents, procedure as above
------------------------------------------------------------------------------------------
Solvent Yeild
----------------------------------------------------------------------------------------------------
CHCl2 97%
CHCl2 (0C) 95%
toluene 92%
THF 94%
CH3CN 99%
EtOAc 89%
Et2O 77%
--------------------------------------------------------------------------------------------------
An attempt to use carbon tetrachloride as the chlorine source failed, 0% yeild.
Table 2 - Results with other acids
-------------------------------------------------------------------------------------------------------
Acid reaction time(h)a yeild
---------------------------------------------------------------------------------------------------------
p-bromo benzoic 2 90%
p-methoxy benzoic 2 90%
p-(t)-butyl benzoic 1 95%
p-nitro benzoic 2 80%
acetylsalicylic 2 70%
trans-Cinnamic 2 83%
2-octenoic 4 79%
(the following used 4 equivalents each CCl3CN and PPh3, instead of 2)
n-octanoic 4 80%
2-bromoisovaleric 2 76%
-----------------------------------------------------------------------------------------------------------
a - time required for dissappearance of benzoic acid on TLC
A rapid, mild and acid-free procedure for the preparation of acyl chlorides including formyl chloride. Villeneuve, G. B.; Chan, T. H.
Tetrahedron Lett. (1997), 38(37), 6489-6492.
Abstract
Carboxylic acids are converted by hexachloroacetone and triphenylphosphine at -78 °C in methylene chloride to the corresponding acyl chlorides. Formic acid can be used to generate formyl chloride at -78 °C in order to perform formylation under very mild conditions.
Experimental
N-benzylbenzamide: To a mixture of benzoic acid (122 mg, 1.0 mmol) and hexachloroacetone (132 mg, 0.5 mmol) in CH2Cl2 (2 mL) was stirred under argon and cooled to -78C. Ph3P (262 mg, 1 mmol) in CH2Cl2 (1 mL) was added dropwise and the mixture stirred for 20 min. The acylchloride solution was then treated with a solution of benzylamine (107 mg, 1 mmol) in CH2Cl2 (1 mL) dropwise followed by truethylamine (101 mg, 1 mmol) in CH2Cl2 (1 mL). This was allowed to reach room temperature and the solvent removed under vacuum. The residue was suspended in 20% EtOAc in hexane (4 ml) and silica gel added to obtain a pasta.(Their cookin
). Purified by column chromatography with same solvent.
Yeild 187 mg, 95%.
N-4-methylphenylformamide: Procedure same as above except reagents were formic acid 100% (92 mg, 2 mmol), hexachloroacetone (264 mg, 1 mmol), Ph3P (524 mg, 2 mmol), p-methylanaline (107 mg, 1 mmol) and TEA (202 mg, 2 mmol).
Yeild 119 mg, 88%.
Use of oxalyl chloride and bromide for producing acid chlorides, acid bromides or acid anhydrides. III.Adams, Roger; Ulich, L. H.
J. Am. Chem. Soc. (1920), 42 599-611.
Abstract
cf. C. A. 12, 587. Aromatic or aliphatic acids warmed with 2.5 mols. (COCl)2 (A) are converted quickly and practically quant. into the corresponding acid chlorides, even in C6H6 as solvent. p-HOC6H4CO2H gives a complex condensation product. Certain NO2 derivs. of BzOH yield double anhydrides of 2 mols. of the aromatic acid and 1 of (CO2H)2, even after refluxing several hrs. with excess of A. Instead of the acid, the Na salt can be added gradually to 1-1.5 mols. of A in C6H6; in fact, this method of prepg. acid chlorides appears to be more general than that from the free acids and is generally preferable, as a smaller excess of A is required. Those NO2 acids which give double anhydrides, as mentioned above, yield the chlorides exclusively when used in the form of their Na salts. Acid chlorides are also readily formed from the anhydrides and A alone or in C6H6 refluxed a few hrs.
The method of prepn. of aromatic acid anhydrides by the action of 1 mol. A on 2 mols. of the acid in C6H6 described in the earlier paper is apparently general. Again certain NO2 derivs. of BzOH behave peculiarly, giving double anhydrides of (CO2H)2 which, when melted, decomp. into the simple anhydrides. With aliphatic acids the yields are not so good; in most cases some of the acid is unchanged and the chloride is obtained as a by-product. In prepg. anhydrides also, the Na salt of the acid, suspended in C6H6, may be used instead of the free acid; in the case of aliphatic compds., this is the better method. The mechanism of these reactions can be represented as follows: RCO2H + A --> (RCO2CO)2 + 2HCl; (RCO2CO)2 --> (RCO)2O + CO2 + CO; (RCO)2O + A --> 2RCOCl + CO2 + CO. In the case of the Na salts, the chlorides and simple anhydrides are possibly formed directly, without passing through the double anhydride stage. In the 2 cases tried (As2O2. and CrO3) the inorg. acid chlorides were obtained by refluxing the oxides with a slight excess of A.
A also proved to be an excellent reagent for producing the Beckmann rearrangement in ketoximes. (COBr)2 acts like A. The following compds. were prepd. by the methods given above (the figures represent the % yields): Chlorides: valeryl 95, hydrocinnamyl 98, benzoyl 98, o-bromobenzoyl 93, p-bromobenzoyl 94, lauryl 99, salicylyl 98, chloroacetyl 80, phenylacetyl 74. p-Nitrobenzoic oxalic anhydride, yellowish crystals, m. 169-70°, decompg. into (p-O2NC6H4CO)2O, immediately decompd. by C5H5N. 2,4,6-Trinitrobenzoic oxalic anhydride, slightly yellowish crystals, m. 228-30°, decompg. into C6H3(NO2)3 (not (O2N)3C6H2CO2H), and is decompd. by Na2CO3, into (O2N)3C6H2CO2Na. Anhydrides: From the free acids: butyric 56, phenylacetic 46, cinnamic 76. From the Na salts: benzoic, m- and p-nitrobenzoic, o-chlorobenzoic (the yields with aromatic compds. are 75-90%), chloroacetic 54, butyric 79, valeric 92, lauric 80. AsCl3 and CrCl3 were obtained in 95 and 80% yield, resp. BzNHPh, MeOC6H4CONHPh and p-MeC6H4CONHPh were obtained in over 90% yield by warming Ph2C:NOH, Ph(MeOC6H4)C:NOH and Ph(MeC6H4)C:NOH, resp., for 10 min. in Et2O with 0.75 mol. A. Bromides (from the Na salts; yield, generally over 90%): benzoyl; o-chlorobenzoyl, b37 143-5°; m-isomer, b40 143-7°; p-isomer, b27 141.3°; o-bromobenzoyl, b18 166-8°; p-isomer, b18 135-7°; p-iodobenzoyl, crystals from CCl4, m. 54-5°, becomes very dark in 2 days, even in sealed tubes; o-methylbenzoyl, b37 133-6°; m-isomer, b52 136-7°; p-isomer, b42 145-9°; p-methoxybenzoyl, b27 183-6°; m-nitrobenzoyl, yellowish crystals from CCl4, m. 42-3°, b18 165-7°, p-isomer, yellow crystals from CCl4, m. 63-4°; 3,5-dinitrobenzoyl, yellow crystals from CCl4, m. 59-60°; cinnamyl, yellow crystals, m. 47-8°, b40 180-4°; phenylacetyl, b50 150-5°. These bromides can be obtained also, although not with as good yields nor in as pure state, with PBr5.
Experimental:
Action of Oxalyl Chloride on Organic Acids-Preparation of Acid Chlorides.The general procedure by which acid chlorides are produced from acids by means of oxalyl chloride is as follows: In a round-bottom flask, the neck of which is ground to fit the bottom of a reflux condenser, is placed one mole of the organic acid and 2 to 2.5 moles of oxalyl chloride. In some cases, an evolution of gas starts immediately, indicating that the reaction is taking place; in other cases slight warming is necessary before gases are evolved. After once starting, the reaction proceeds spontaneously for 15-20 min. or sometimes even longer. After this period of time a small flame is again applied and the mixture refluxed for about 2 hours. The reaction mixture is then distilled under atmospheric pressure till the excess of oxalyl chloride is collected and then generally under diminished pressure (preferably in a flask such as is described by Noyes
1 without the separatory funnel attached, however) to obtain the acid chloride. By this method the series of acid chlorides which are given in the table below were produced:
---------------------------------------------------------------------------------------------------------------
Acid / Acid wt. / wt. oxalyl Cl / Acid Cl wt. / Yeild %
---------------------------------------------------------------------------------------------------------------
n-Valeric. .......... 25 77 28 95
Hydrocinniamic....... 35 60 38 98
Benzoic.............. 25 60 28 98
o-Bromobenzoic....... 25 40 25 93
p-Bromobenzoic....... 10 13 10 94
Lauric............... 25 40 27 99
Salicylic ........... 15 28 16.5 98
Monochloroacetic .... 25 80 24 80
Phenylacetic. ....... 35 70 30 74
---------------------------------------------------------------------------------------------------------------
It is noticeable that only in 2 cases, namely monochloroacetic acid and phenylacetic acid, do the yields drop below 90%. Monochloroacetic acid forms an anhydride with extreme ease in the presence of almost any sort of dehydrating agent and small amounts were isolated in the above reaction. Phenylacetyl chloride is not very stable and extremely reactive, giving certain amounts of tarry material, probably condensation products between several molecules. The yields, however, in both cases, are very much better than are obtained with other acid chloride reagents with the possible exception of thionyl chloride.
The preparation of these acid chlorides can be carried out if desired in benzene as a solvent (about 50 cc. of benzene being used for a 25 g. portion of acid); thus, both benzoic and monochloroacetic acids gave satisfactory results under these conditions. In the case of salicylic acid, because of the instability of the acid chloride, the preparation of this latter compound was not attempted except with benzene as a solvent, and after the reaction had taken place the benzene and excess of oxalyl chloride were removed by distilling off under diminished pressure at room temperature. The action of oxalyl chloride upon p-hydroxybenzoic acid was carried out but complex condensation products were obtained and no acid chloride was produced.
When excess of oxalyl chloride reacts with m-nitro, p-nitro-, 3,5-dinitro-, and 2,4,6-trinitrobenzoic acids, the acid at first goes into solution and in the course of a few minutes a solid separates. After refluxing for 2 hours the reaction mixture is treated directly with benzene, the solid filtered, washed with dil. sodium carbonate solution (except in the case of the trinitrobenzoic acid), dried and washed with hot benzene. The benzene filtrates from the original reaction mixture are evaporated and a small amount of solid material is always obtained, This is unchanged acid. Of the 4 nitro compounds produced, the double anhydride of m-nitrobenzoic acid
2 and 3,5-dinitrobenzoic acid have already been described in previous communication and the decomposition points here agree with those previously obtained. The double anhydrides of oxalic and p-nitrobenzoic acid as well as of 2,4,6-trinitrobenzoic acid, however, are new.
Action of Oxalyl Chloride on the Sodium Salts of Organic Acids - Preparation of Acid Chlorides.The general procedure by which acid chlorides are produced from the sodium salts of acids and oxalyl chloride is as follows. A round-botton flask is used which has 2 openings; the one is a neck ground to fit a reflux condenser and the second is a side tube(1.5 cm in diameter and 2.5 cm long). This second side tube is cork-stoppered and is used for the addition of solid sodium salt. In the flask with the reflux condenser attached is placed 1.2 to 1.5 moles of oxalyl
chloride dissolved in benzene (20 cc. of benzene is used when about 10 g of oxalyl chloride is needed). One mole of the dry sodium salt of the acid is now added in small portions through the side arm. Upon each addition, gases are evolved. After all of the sodium salt has been added,
the mixture is refluxed for 2 hours with occasional stirring to be certain that the reaction is completed. At the end of this time the sodium chloride and any traces of unchanged sodium salt of the organic acid are filtered off, The filtrate is distilled and after recovering the benzene, the acid chloride, if solid, is crystallized or if a liquid, vacuum distilled, In this way yields of: acid chloride varying from 75% to over 90% are easily produced. In the experiments carried out to test the method only small
amounts (10 to 20 grams) of the sodium salts of the acid were used and consequently the loss involved in a distillation or crystallization was proportionately large. It is probable that if 100 gram lots of acid chloride
should be made, the yields would be consistently over 90%. The compounds are practically pure as obtained directly from the benzene, but in the experiments described the products were either recrystallized or once distilled. By this method, the following acid chlorides were made: cinnamyl, phenylacetyl, benzoyl; and the following substituted benzoyl
chlorides: p-chloro-, o-bromo-, p-bromo-, p-methoxy-, m-nitro-, p-nitro-, and 3,5-dinitro-. The constants agreed in every case with those appearing in the literature.
Action of Oxalyl Chloride on Organic Acid - Preparation of Organic Acid Anhydrides.The general procedure by which acid chlorides are produced from acid anhydrides by means of oxalyl chloride is as follows. In a round-bottom flask of the type used for the production of acid chlorides from organic acids and oxalyl chloride, is placed one mole of the organic acid anhydride and 1.5 to 2.5 moles of oxalyl chloride. The mixtnre is gently refluxed for 2 hours. Evolution of gas takes place, as the reaction proceeds. At the end of the heating, the reaction mixture is distilled to free it from the excess of oxalyl chloride and the acid chloride which is thus obtained is purified by crystallization or distillation under atmospheric pressure or diminished pressure. By this general process, acetic, monochloroacetic, benzoic, m-nitro- and 3,5-dinitro-benzoic acid anhydrides were converted into the corresponding acid chlorides, and yields of 80-95% obtained.
Action of Oxalyl Chloride on Organic Acids - Preparation of Organic Acid Anhydrides.The general procedure by which acid anhydrides are produced from acids and oxalyl chloride is as follows. A benzene solution or suspension is made of 2 moles of aromatic acid (100 cc. of benzene for 25 g. of organic acid) and one mole of oxalyl chloride is gradually run in. The mixture is refluxed for 2 hours and then the benzene distilled off. The yields of aromatic acid anhydrides by this
method are very good, but in the aliphatic series they seldom amount to more than 50% to 70%. As by-products in these latter reactions are obtained free acid and acid chloride. The particular compounds which were studied were n-butyric acid (56% yield), phenylacetic acid (46% yield)
and cinnamic acid (76% yield). If these same reactions with the acids are carried out without benzene as a solvent, the yields are about the same as indicated.
Action of Oxalyl Chloride on the Salts of Organic Acids - Preparation of Organic Acid Anhydrides.The general procedure is to suspend 2 moles of the powdered, dry sodium salt of the acid in benzene (50 cc. of benzene for 25 g. of sodium salt) and then to allow 1 to 1.2 moles of oxalyl chloride to run in. The reaction takes place rapidly and after 2 hours refluxing, is complete. The sodium chloride is filtered off and the anhydrides are obtained by evaporation of the benzene. With some of the aromatic acids, the anhydrides are only slightly soluble in benzene and
consequently must be recovered from the mixture with sodium chloride by treatment with dilute sodium carbonate. The aromatic acid anhydrides as obtained from the benzene are washed with dil. sodium carbonate solution, dried and recrystallized while the aliphatic acid anhydrides are purified by distiliation with a good fractionating column. In the aromatic series, the yields are very good, amounting to 75% to 90%. In the aliphatic series, however, some acid chloride is produced although in smaller amounts than when anhydrides are made from the free acids and oxalyl chloride. The sodium salts of the following acids were converted to anhydrides as just described : benzoic, m- and p -nitrobenzoic, o-chlorobenzoic, monochloroacetic (54% yield), n-butyric (79% yield), n-valeric (91% yield), lauric (80% yield). The physical constants werc not different from thosc already given in the literature.
Action of Oxalyl Chloride on Certain Aromatic Ketoximes-Preparation of Substituted Acid Amides.Benzophenone oxime, anisyl-phenyl ketoxime and phenyl-p-tolyl ketoxime are treated in the following way:
One mole of the ketoxime is dissolved in a small amount of absolute ether. To the solution is added slowly 3/4 of a mole of oxalyl chloride. The mixture is kept warm for 10 minutes, during which time acid amide separates. At the end of this period half oh the ether is evaporated, the mixture cooled and the solid acid amide filtered. The yields of benzanilide, anisanilide and p-toluic anilide amount to over 90%.
Action of Oxalyl Chloride on Inorganic Acids - Preparation of Inorganic Acid Chlorides.In a gask similar to the one used in the previous experiments are placed arsenic trioxide (one mole) and excess of oxalyl chloride (2 moles). The reaction mixture is refluxed gently for 5 hours, during which time the oxide qradually goes into solution. The reaction mixture is then distilled, a small excess of oxalyl chloride collected first and then the arsenic trichloride, b.p. 130. The yield amounts to about 95%.
In the same way dry chromium trioxide (one mole) and oxalyl chloride (2 moles) upon refluxing for 5 hours gives an 80% yield of chromyl chloride, b.p. 114-116 at 748 mm.
Action of Oxalyl Bromide on the Sodium Salts of Organic Acids - Preparation of Acid Bromides.The general procedure by which acid bromides are produced from the sodium salts of the acids is exactly analogous to the method used for the preparation of acid chlorides from the sodium salts of organic acids and oxalyl chloride. The products are worked up in exactly the same way. The yields of acid bromides are in general over 90%. The following table contains a list of the bromides thus prepared with their constants and chemical analyses.
Other Reactions with Oxalyl Bromide.In order to determine whether oxalyl bromide might be used in place of oxalyl chloride for the production of acid anhydrides, benzoic acid, o- and p-chloro- and p-bromo-
benzoic acids were treated in benzene in the proportion of 2 moles of acid to one mole of oxalyl bromide. The directions followed were exactly analogous to those used with oxalyl chloride and in every case very good yields of the corresponding anhydrides were produced.
In order to show that excess of oxalyl bromide on the organic acids will yield acid bromides in the same way that oxalyl chloride yields acid chlorides, n-butyric acid (one mole) was refluxed with an excess of oxalyl bromide (2 moles) as described under the reaction between organic acids and oxalyl chloride. After the evolution of gas stopped, the reaction mixture was refluxed for 2 hours and then distilled in the usual way. The bromide was produced in good yields.
The Action of Phosphorus Pentabromide upon Aromatic Acids and the Salts of Aromatic Acids.One mole of phosphorus pentabromide is suspended in benzene and one mole of organic acid is added. The mixture is refluxed for 1 to 2 hours, at the end of which time the reaction is complete. Upon distillation under diminished pressure, phosphorus oxybromide comes over first and then the acid bromide. In this way benzoic and o-chlorobenzoic acids were converted to the acid bromides. The yields amounted to about 50%. The constants were the same as those already mentioned.
If the phosphorais pentabromide is suspended in benzene (50 cc. of benzene to 25 g. of acid) and the dry sodium salt or the acid is added gradually, a rapid reaction takes place and after refluxing a short time is complete. The sodium bromide is filtered off and the benzene filtrate distilled, first under atmospheric pressure to remove the benzene, then under diminished pressure to remove the phosphorus oxybromide and finally the acid bromide. The yields of pure product amount to 60-75%. By this method benzoic acid and its o- and p-bromo-, o- and m-methyl-, m-nitro-, 3,5-dinitro derivatives were converted in to the corresponding acid bromides.
Summary1. Organic acids when treated with 2 moles of oxalyl chloride alone or in benzene as a solvent are converted almost quantitatively into acid chlorides.
2. The sodium salts of organic acids when added to 1.2-1.5 moles of oxalyl chloride in benzene are converted almost quantitatively into acid chlorides.
3. Certain nitro derivatives of benzoic acid when treated as in (1) are converted into double anhydrides of oxalic acid and the aromatic acid; when treated as in (2) are converted into acid chlorides as is the case with other acids.
4. Organic acid anhydrides when treated with oxalyl chloride are converted almost quantitatively into acid chlorides.
5. Certain inorganic oxides are readily converted by oxalyl chloride into the corresponding acid chlorides.
6. Aromatic organic acids (2 moles) when treated in benzene solution with oxalyl chloride (one mole) are converted almost quantitatively into acid anhydrides. Aliphatic organic acids under the same treatment are converted to acid anhydrides only to the extent of 50-70%, some unchanged acid and acid chloride being by-products.
7 . The sodium salts of aromatic organic acids (2 moles) when suspended in benzene and treated with oxalyl chloride (one mole) are converted almost quantitatively into acid anyhydrides. In the aliphatic series, the yields of acid anhydride are not so good as in the aromatic series,
but much better than are obtained by the action of oxalyl chloride on the free organic acid.
8. Certain nitro derivatives of benzoic acid when treated as in (6) are converted into double anhydrides of oxalic acid and aromatic acid; when treated as in (7) are converted into acid anhydrides as is the case with other acids.
9. The Beckmann rearrangement in ketoximes is readily produced by the action of oxalyl chloride.
10. If organic acids or the salts of organic acids are treated with oxalyl bromide under the same conditions as in (1), organic acid bromides are produced. Several new aromatic acid bromides are described.
11. Organic acids are converted into their anhydrides by oxalyl bromide when treated as described in (6).
Reference{1} J. Am. Chem. Soc. 39, 2718 (1917).
{2} J. Am. Chem. Soc. 40, 424 (1918).