ESTERS FROM T H E REACTIONS OF ALKYL HALIDES AND SALTS OF CARBOXYLIC ACIDS Reactions of P r i m a v Alkyl Chlorides and Sodium Salts of Carboqlic Acids HENRY E. HENNIS, JAMES P. EASTERLY, JR., AND LEONARD R. THOMPSON Benzene Research Laboratory, The Dow Chemical Go., Midland, Mich.
L. R. COLLINS,
Various combinations of reactions of methyl, n-butyl, allyl, and benzyl chlorides with sodium acetate or propionate, benzoate, and salicylate to form esters were studied in detail. In general, triethylamine was a very necessary catalyst for all the combinations. A cocatalyst, sodium-iodide, was required to achieve high yields of methyl and n-butyl esters. With the exception of allyl salicylate, the use of sodium iodide did not increase the yields of esters derived from allyl and benzyl chloride. Good to excellent yields were obtained a t reaction temperatures of 75’ to 175’ C. and reaction times of 2 hours or less.
HE preparation of esters from the reactions of alkyl chlorides T a n d sodium salts of carboxylic acids could be important if the sodium salt of the acid were inexpensive and readily
RCOONa
+ R ’C1+
RCOOR
+ NaCl
(11
available. This condition would be fulfilled if the salt were the product of manufacture rather than the free acid. T h e preparation of sodium formate from carbon monoxide and sodium hydroxide and the Koibe sodium salicylate synthesis would be two examples of this. Furthermore, this method of ester preparation would be even more commercially attractive if a n alkyl chloride gave a cheaper R’ radical than the corresponding alcohol. Severe problems are encountered, however, in this reaction. T h e absence of suitable solvents for the extremely incompatible alkyl chloride and sodium salt of a carboxylic acid has been a n almost insurmountable obstacle. Mills, Farrar, and Weinkauff (1962) summed u p the entire problem eloquently: “Although a well known textbook method, the reaction of simple alkyl halides with alkali metal salts of carboxylic acids in suitable solvents to produce esters is of little preparative value, owing to poor yields and conversions, along with competing side reactions of dehydrohalogenations.” Clues were available in the literature to indicate that reactions having fairly high yields might be possible if the right catalysts and conditions were found. A German patent (1913) described the reaction of potassium benzoate and benzyl chloride to prepare benzyl benzoate in the presence of catalytic quantities of triethylamine. Reaction conditions were surprisingly mild, 95” to 100’ C. and 30 minutes. Emerson et al. (1947) reported a 9370 yield of p-ethylbenzyl acetate from the reaction of p-ethylbenzyl chloride and fused sodium acetate in glacial acetic acid. However, benzyl chloride is a relatively reactive alkyl halide. Kester et al. (1943) obtained 60 to 90% yields of glycidol esters from the reactions of epichlorohydrin; however, the high yield reactions were restricted to the sodium salts of high molecular weight acids (soaps). Rueggeberg et a / . (1946) and Thorp et al. (1947) also used amine catalysts to drive the reaction of sodium benzoate and benzyl chloride to give benzyl benzoate in nearly quantitative yields in a few hours under mild conditions. This process was successfully scaled up to the pilot plant by the same investigators. T h e most comprehensive study to date in this area was performed by Yamashita and Shimamura (1957). Most of their
work also dealt with reactions of benzyl chloride; however, they pointed out that the reaction of cetyl chloride and sodium acetate gave a 92.87, yield in the presence of pyridine and sodium iodide. T h e sodium iodide was presumably added to convert the relatively unreactive cetyl chloride to the more reactive cetyl iodide. These investigators chose to use the amount of chloride ion liberated as an indication of reaction progression. Thus they ignored chloride ion liberation from the reaction of the amine catalysts to form quaternary ammonium salts and from dehydrohalogenation of alkyl chlorides with 0-hydrogens-e.g., cetyl chloride. Reactions of alkyl halides with amines are facile. Thus, if 0.1 to 0.2 mole of amine catalyst is used per mole of alkyl chloride, one cannot place much reliance on any reaction of low yield (10 to 20y0 or less). T h e chloride ion present could come entirely from reaction with the amine. Thus, a reinvestigation with more reliable analytical techniques and with a larger variety of starting materials to broaden the scope of the reaction appeared necessary. Experimental
Reactions of Methyl Chloride. In a Parr Series 4500 1liter medium pressure apparatus were placed 2.0 moles of the carboxylic acid sodium salt, 50 grams of methyl ethyl ketone, 5.0 grams of triethylamine, and 5.0 grams of sodium iodide. Some of the reactions \\ere run without the triethylamine or the sodium iodide. T h e mixture was stirred and heated to reaction temperature. An electrically heated methyl chloride reservoir was connected to the reaction appayatus and methyl chloride was fed into the reaction mixture. T h e methyl chloride pressure was maintained a t 200 p.s.i. during the reaction period of 2 hours. It was often necessary to pass cold water through the vessel jacket or even to reduce stirring to control the exothermic heat of reaction and to maintain the desired reaction temperature. After a 2-hour reaction period, the reaction mixture was cooled and excess methyl chloride was vented. Water (400 ml.) was added to dissolve the precipitated sodium chloride and the aqueous and organic layers were separated. T h e reaction product of methyl chloride and sodium propionate was analyzed in a specific manner because methyl propionate is a low boiling material and therefore subject to severe losses because of evaporation. The aqueous layer was extracted with methylene chloride to remoke last traces of product. T h e organic layers were combined and mixed thoroughly and then analyzed via mass spectrometry to determine the amount of methyl propionate present and thus the extent of reaction. I n the reactions of methyl chloride and sodium benzoate and salicylate, the aqueous layer was extracted with perchloroVOL. 6
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ethylene to remove last traces of product. T h e organic solutions were combined and washed with 200 ml. of water, 200 ml. of 570 sodium bicarbonate solution, and again with 200 ml. of water. T h e solvent was removed by stripping under reduced pressure (-25 mm.) and the product isolated by vacuum distillation. Fractions of similar boiling points and refractive indices were combined and yield figures calculated. The products were exceptionally pure ; GLC chromatograms indicated 99+% purity. The refractive indices of our esters and literature values are tabulated in Table I. Reactions of n-Butyl, Allyl, a n d Benzyl Chlorides. These reactions were also run in a Parr Series 4500 1-liter medium pressure apparatus. However, these alkyl chlorides, being liquid at room temperature, were weighed and charged at the beginning of the run. Each run utilized 2.0 moles of alkyl chloride, 2.0 moles of carboxylic acid sodium salt, 50 grams of methyl ethyl ketone, 5 grams of triethylamine, and 5 grams of sodium iodide. Reaction time was 2 hours and the products were isolated, purified, and analyzed in the same manner as described for methyl benzoate and salicylate. Again all products were 99+y0 pure via gas-liquid chromatography. T h e refractive indices of our esters and literature values are listed in Table I.
Results and Discussion
Exploratory experiments soon established that triethylamine was an effective catalyst and that sodium iodide was often of some aid. Methyl ethyl ketone solvent was chosen for the solvent because low molecular weight ketones favorably shift the equilibrium of the reaction of alkyl chlorides and sodium iodide to give the more reactive alkyl iodide; this is because of R C 1 + NaI
eRI + NaCl
the insolubility of sodium chloride in this solvent (Conant and Hussey, 1925). However, only enough methyl ethyl ketone (50 grams per 2 gram moles of reactant) was used to aid in giving a movable slurry. Once the reaction was started, the ester formed served as the solvent because it was in excess of the ketone. Thus the ester is also a favorable solvent for the reaction depicted in Equation 2. I n fact, the ester was tried as the “solvent” and found to be as effective as methyl ethyl ketone. T h e elimination of the ketone solvent which would require recovery and recycle has obvious commercial usefulness. Further exploratory experiments indicated that 5 grams each of triethylamine and sodium iodide were sufficient to give good yields of ester in a reasonable length of time. T h e next series of experiments were designed to find optimum temperatures for each system. These reactions were then repeated a t their optimum reaction temperatures in the presence of only one catalyst a t a time to find the effectiveness of triethylamine and sodium iodide alone and also in the absence of any catalysts whatsoever (Table 11). Triethylamine was a very necessary catalyst in every system. Yields were extremely low to nil without it, even in the presence of sodium iodide. I t can be inferred that triethylamine would be a necessary catalyst in the reaction of an alkyl iodide with a sodium salt of a carboxylic acid under these conditions; however, this supposition was not put to a n experimental test. T h e use of sodium iodide and triethylamine together has a very favorable effect in some instances. T h e good yields of methyl esters were increased to high yields. T h e very poor yields of the n-butyl esters with triethylamine alone were increased to high yields when both catalysts were used simultaneously. Thus sodium iodide is a n extremely helpful catalyst in reactions where relatively unreactive alkyl chlorides are involved. Sodium iodide was, with one exception, of no use in the reactions of allyl and benzyl chloride. Allylic and benzylic chlorides are 194
l&EC PRODUCT RESEARCH A N D
DEVELOPMENT
Table I. Ester Refractive Indices Lit. nD Ester n% (T em p., “C.) Lit. Ref. Methyl benzoate 1.5141 1.5146 (25) Hoffman and Weiss (1956) Methyl salicylate 1 .5340 1 .5352 (25) Hoffman and Weiss (1956) n-Butyl propionate 1.3990 1.4000 (25) Hoffman and Weiss (1956) n-Butyl benzoate 1.4951 1.4955 (25) Hoffman and LVeiss (1956) n-Butyl salicylate 1 ,5092 1.5099 (25) Hoffman and Weiss (1956) Allyl propionate 1.4079 1.4105 (20) Jeffrey and Vogel (1948) Allyl benzoate 1.5152 1.5184 (20) Brown and Cope (1964) Allyl salicylate 1 ,5316 Benzvl acetate 1.4991 1.5105 (20) Criegee et al. (1957) Benzyl benzoate 1.5669 1.5685 (20) Rueggeberg e; al. ’ (1946) Benzyl salicylate 1.5787 1.5787 (25) Ma et al. (1933)
-
Table II. Effect of Catalysts on Yields Yield, 70 Sodium Temp., Et&, Chloride Salt oC.a Nul* Et3N Nul Methyl Propionate 75 6 80 96 Benzoate 75 0 87 96 Salicylate 100 0 60 98 n-Butyl Propionate 150 Trace 9 87 Benzoate 150 0 17 85 Salicylate 175 Trace 18 92 Allyl Propionate 100 2 88 80 100 Trace 93 93 Benzoate Salicylate 125 Trace 15 87 Benzyl Acetate 125 13 98 97 2 86 89 Benzoate 100 Salicylate 125 2 90 89 a Optimum reaction temperature. A trace of product indicates enough ester in the distillation residue to be detectable by odor.
very reactive alkyl chlorides and react readily under the conditions of these experiments. T h e exception to this generalization was the allyl chloride-sodium salicylate system where the use of sodium iodide increased the yield from a low of 15% to a respectable 8?y0. A final important point is that the effects of sodium iodide and triethylamine are not additive. There appears to be a n interplay of the two catalysts. O n e of the more extreme examples of this is in the n-butyl chloride-sodium propionate system. T h e use of sodium iodide alone gave only a trace of product and the use of triethylamine alone gave only a 9% yield of n-butyl propionate. However, a combination of the two catalysts gave an 87% yield. Some very interesting alkyl chloride reactivity-structure relationships can be realized from the available data. However, one can use only those reactions where triethylamine was the only catalyst in the system. These systems utilizing sodium iodide would have alkyl iodides present and one would unwittingly be comparing alkyl iodide species. I t can be safely assumed that the alkyl chlorides studied are reacting by the same mechanism, the SN2 mechanism, because all are primary chlorides and the solvents, methyl ethyl ketone and the ester, are poor ionizing solvents. Methyl chloride is considerably more reactive, as expected, than n-butyl chloride. This relationship has been well established in relative rate constants of S,2 halide exchange reactions (Gould, 1959). Allyl and benzyl chloride are generally more
reactive than methyl chloride and certainly much more reactive than n-butyl chloride. T h e phenyl and vinyl groups, being capable of delocalizing positive or negative charge a t the reaction site carbon, facilitate SN2 reactions. Except for the allyl chloride-sodium salicylate system, no iodide catalysis was required to obtain high yields of product. T h e allyl chloridesodium salicylate reaction is a n exception of some magnitude. T h e explanation that, in general, the salicylate anion was the least reactive nucleophile studied does not rationalize this discrepancy. Side reactions depleting starting materials are not the primary cause for the low allyl salicylate yield, because 91% of the allyl chloride and 7870 of the sodium salicylate not consumed in ester formation were recovered. Considerable effort was expended in varying reaction conditions in the attempt to gain some insight into this discrepancy. T h e yields in all cases remained low whenever sodium iodide catalysis was avoided. We are a t present engaged in studying the reactions of substituted allyl chlorides with a variety of carboxylate anions to see if this is a general or specific phenomenon. T h e results of this work will be reported later.
Literature Cited
Badische Anilin- und Soda-Fabrik, German Patent 268,261 (Dec. 22, 1913). Brown, H. C., Cope, 0. J., J . A m . Chem. SOC. 86, 1801 (1964). Conant, J. B., Hussey, R. E., J . A m . Chem. SOC.47,476 (1925). Criegee, R., Dimroth, P., Schempf, R., Chem. Rer. 90, 1337 (1957). Emerson, W. S., Heyd, J. W., Lucas, V. E., Lyness, W. I., Owens, G. R., Shortridge, R. W., J . A m . Chem. SOC. 69,1905 (1947). Gould, S . E., “Mechanism and Structure in Organic Chemistry,” p. 276, Henry Holt, New York, 1959. Hoffman, F. W., Weiss, H. D., J . A m . Chem. SOC.79, 4759 (1956). Jeffrey, G. H., Vogel, A. I., J . Chem. SOC.1948,p. 658. Kester, E. B., Gaiser, C. J., Lazar, M. E., J . Org. Chem. 8, 550 11943). Ma, T.-S., Hoo, V., Sah, P. P. T., Science Repts. Natl. Tsinghua Univ. A2, 133 (1933); C. A. 28, 133 (1934). Mills, R. H., Farrar, M. W.. Weinkauff, 0. J., Chem. Znd. (London) 1962. D. 2144. Rueggdderg, W. H. C., Ginsberg, A., Frantz, R. K., Znd. Eng. Chem. 38, 207 (1946). Thorp, I. D., Nottorf, H. A., Herr, C. H., Hoover, T. B., Wagner, R. B., Weisgerber, C. A., Wilkins, J. P., Whitmore, F. C., Znd. Eng. Chem. 39, 1300 (1947). Yamashita, Y., Shimamura, T., Kogyo Kagaku Zasshi 60,423 (1957) (English transl.). RECEIVED for review February 13, 1967 ACCEPTED July 14, 1967
A NEW SYNTHESIS OF 3-ETHYLPYRIDINE JEAN HERZENBERG, ROMANO C O V I N I , MARCELLO P I E R O N I , AND ADRIANO
NENZ
Centro Ricerche di Bollate, Montecatini-EdiJon S.P.A., Milan, Ztaly
A new, simple and economic synthesis of 3-ethylpyridine is the water vapor oxidative demethylation of 2-methyl-5-ethylpyridine (MEP), an inexpensive commercial product obtained from acetaldehyde and ammonia. The use of a Ni-AIz03 catalyst (containing 41% Ni) with a Hz0-MEP molar ratio of 60 to 80, a t about 3 7 0 ” C., and with a contact time of 90 to 110 seconds (referred to MEP alone), gives 3 4 to 41% conversion with the high selectivity of 9 3 to 95% of 3-ethylpyridine. Side reactions give 3.9 to 2.6 mole of 2-picoline, up to 0.4 mole % of pyridine, and less than 2% ring cleavage. 3-Ethylpyridine has not found a technical use, probably because of the lack of an inexpensive synthesis; when produced a t a relatively low price it could become the starting material for other pyridine derivatives, such as 3-vinylpyridine.
Ethylpyridine, a minor component of the lighter coal tar 3 - f r a c t i o n s , is also a degradation product of some alkaloids (Stoehr, 1882; Woodward et al., 1944), like brucine, cinchonine, and nicotine, and a by-product in the synthesis of other pyridine derivatives (Chichibabin, 1903 ; Gechele et al., 1960; Mahan, 1956; Mahan et a / . , 1957; Stoehr, 1882, 1891). I t results from the dehydrogenation of 3-ethylpiperidine (Ladenburg, 1898), and from the cyclization of 2-ethylglutaric dialdehyde with hydroxylamine (Chumakov et al., 1965) ; it may be produced with 24% yields from tetrahydrofurfuryl alcohol, monoethylamine, and ammonia (Butler et a/., 1966), or with 51% yields, from 2,6-diethoxy-3-(l-ethoxyethyl) tetrahydropyran (Chumakov et al., 1964). T h e synthesis of 3-ethylpyridine may be conveniently carried out, starting from simpler pyridine derivatives. A possibility is to methylate 3-picoline with methyl chloride in liquid ammonia and in the presence of Na amide; yields are 39 to 54% (Brown and Murphey, 1951). Or nicotinic acid may be used, which after esterification with ethyl alcohol, Claisen condensation with ethyl acetate, and subsequent hydrolysis, gives 3-acetylpyridine (Brown and Murphey, 1951 ; Burrus and Powell, 1945 ; Camps, 1902 ; Gilman and Broadbent, 1948; Kollof and Hunter, 1941); the latter may be suitably reduced, according to Fand and Lutomsky (1949). One of the most promising starting materials should be 2-methyl-5-ethylpyridine (MEP), which is a commercial
product much cheaper than pyridine and the picolines, and which can yield 3-ethylpyridine by elimination of the 2-methyl group. T h e point is to find highly selective conditions, so that the ethyl group can be preserved. I t has been suggested that the methyl group of M E P be condensed with formaldehyde, the hydroxyethyl derivative oxidized, and the resulting 5-ethylpicolinic acid decarboxylated (Koenigs and Hoffmann, 1925). This same acid may be obtained in 76% yields by direct oxidation of MEP, using selenium dioxide as an oxidizing agent (Jerchel et al., 1955). Decarboxylation yields are as high as 90%. I n previous work (Nenz et al., 1966, 1967), we studied the thermal hydrodealkylation of MEP, and found that 15% yields of 3-ethylpyridine may be obtained, with various amounts of pyridine, 2- and 3-picoline, and 2,j-lutidine. T h e present work deals with the oxidative demethylation of M E P in the presence of water vapor and a Ni-A1203 catalyst. An example of oxidative dealkylation of substituted pyridines due to water vapor is the conversion of a technical grade 2picoline to lower boiling materials, carried out by Meerwein et al. (1931) with 52% yields on cerium chromate, a t 620’ to 640’ C. A nickel on alumina catalyst was used by Balandin, Zamyshlyaeva, and coworkers to demethylate the isomeric picolines and 2,G-lutidine (Balandin et al., 1956 ; Zamyshlyaeva et al., 1965a, 1965b, 1 9 6 5 ~ ) ; in the case of 2-picoline, 60% conversion and 83y0 yields of pyridine were obtained. VOL. 6
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