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., L. R. COLLINS,

AND LEONARD R. THOMPSON
Benzene Research Laboratory, The Dow Chemical Go., Midland, Mich.

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 cor-
responding 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 Wein-
kauff (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 com-
peting side reactions of dehydrohalogenations.”
Clues were available in the literature to indicate that reac-
tions 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 chlo-
ride to prepare benzyl benzoate in the presence of catalytic
quantities of triethylamine. Reaction conditions were surpris-
ingly 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 per-
formed 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 ammo-
nium 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 neces-
sary.
Experimental
Reactions of Methyl Chloride. In a Parr Series 4500 1-
liter 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 reac-
tion 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 precipi-
tated 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 perchloro-

VOL. 6 NO. 3 SEPTEMBER 1967 193

ethylene to remove last traces of product. T h e organic solu-
tions were combined and washed with 200 ml. of water, 200 ml. Table I. Ester Refractive Indices
of 570 sodium bicarbonate solution, and again with 200 ml. of
water. T h e solvent was removed by stripping under reduced Lit. nD
Ester n% (T em p., “C.) Lit. Ref.
pressure (-25 mm.) and the product isolated by vacuum dis-
tillation. Fractions of similar boiling points and refractive Methyl benzoate 1.5141 1.5146 (25) Hoffman and Weiss
indices were combined and yield figures calculated. The (1956)
products were exceptionally pure ; GLC chromatograms indi- Methyl salicylate 1 .5340 1 .5352 (25) Hoffman and Weiss
(1956)
cated 99+% purity. The refractive indices of our esters and n-Butyl propionate 1.3990 1.4000 (25) Hoffman and Weiss
literature values are tabulated in Table I. (1956)
Reactions of n-Butyl, Allyl, a n d Benzyl Chlorides. These n-Butyl benzoate 1.4951 1.4955 (25) Hoffman and LVeiss
reactions were also run in a Parr Series 4500 1-liter medium (1956)
pressure apparatus. However, these alkyl chlorides, being n-Butyl salicylate 1 ,5092 1.5099 (25) Hoffman and Weiss
liquid at room temperature, were weighed and charged at the (1956)
beginning of the run. Each run utilized 2.0 moles of alkyl Allyl propionate 1.4079 1.4105 (20) Jeffrey and Vogel
chloride, 2.0 moles of carboxylic acid sodium salt, 50 grams of (1948)
Allyl benzoate 1.5152 1.5184 (20) Brown and Cope
methyl ethyl ketone, 5 grams of triethylamine, and 5 grams of (1964)
sodium iodide. Reaction time was 2 hours and the products Allyl salicylate 1 ,5316 - -
were isolated, purified, and analyzed in the same manner as Benzvl acetate 1.4991 1.5105 (20) Criegee et al. (1957)
described for methyl benzoate and salicylate. Again all Benzyl benzoate 1.5669 1.5685 (20) Rueggeberg e; al. ’
products were 99+y0 pure via gas-liquid chromatography. (1946)
T h e refractive indices of our esters and literature values are Benzyl salicylate 1.5787 1.5787 (25) Ma et al. (1933)
listed in Table I.

Table II. Effect of Catalysts on Yields

Yield, 70
Results and Discussion
Sodium Temp., Et&,
Chloride Salt oC.a Nul* Et3N Nul
Exploratory experiments soon established that triethylamine
was an effective catalyst and that sodium iodide was often of Methyl Propionate 75 6 80 96
Benzoate 75 0 87 96
some aid. Methyl ethyl ketone solvent was chosen for the sol- Salicylate 100 0 60 98
vent because low molecular weight ketones favorably shift the n-Butyl Propionate 150 Trace 9 87
equilibrium of the reaction of alkyl chlorides and sodium io- Benzoate 150 0 17 85
dide to give the more reactive alkyl iodide; this is because of Salicylate 175 Trace 18 92
Allyl Propionate 100 2 88 80
R C 1 + NaI eRI + NaCl Benzoate
Salicylate
100
125
Trace
Trace
93
15
93
87
the insolubility of sodium chloride in this solvent (Conant and Benzyl Acetate 125 13 98 97
Benzoate 100 2 86 89
Hussey, 1925). However, only enough methyl ethyl ketone Salicylate 125 2 90 89
(50 grams per 2 gram moles of reactant) was used to aid in giv- a Optimum reaction temperature. A trace of product indicates enough
ing a movable slurry. Once the reaction was started, the ester ester in the distillation residue to be detectable by odor.
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 very reactive alkyl chlorides and react readily under the condi-
ketone. T h e elimination of the ketone solvent which would tions of these experiments. T h e exception to this generaliza-
require recovery and recycle has obvious commercial usefulness. tion was the allyl chloride-sodium salicylate system where the
Further exploratory experiments indicated that 5 grams each use of sodium iodide increased the yield from a low of 15% to
of triethylamine and sodium iodide were sufficient to give good a respectable 8?y0.
yields of ester in a reasonable length of time. T h e next series of A final important point is that the effects of sodium iodide
experiments were designed to find optimum temperatures for and triethylamine are not additive. There appears to be a n
each system. These reactions were then repeated a t their interplay of the two catalysts. O n e of the more extreme exam-
optimum reaction temperatures in the presence of only one ples of this is in the n-butyl chloride-sodium propionate system.
catalyst a t a time to find the effectiveness of triethylamine and T h e use of sodium iodide alone gave only a trace of product and
sodium iodide alone and also in the absence of any catalysts the use of triethylamine alone gave only a 9% yield of n-butyl
whatsoever (Table 11). propionate. However, a combination of the two catalysts gave
Triethylamine was a very necessary catalyst in every system. an 87% yield.
Yields were extremely low to nil without it, even in the presence Some very interesting alkyl chloride reactivity-structure rela-
of sodium iodide. I t can be inferred that triethylamine would tionships can be realized from the available data. However,
be a necessary catalyst in the reaction of an alkyl iodide with a one can use only those reactions where triethylamine was the
sodium salt of a carboxylic acid under these conditions; how- only catalyst in the system. These systems utilizing sodium
ever, this supposition was not put to a n experimental test. iodide would have alkyl iodides present and one would un-
T h e use of sodium iodide and triethylamine together has a very wittingly be comparing alkyl iodide species. I t can be safely
favorable effect in some instances. T h e good yields of methyl assumed that the alkyl chlorides studied are reacting by the
esters were increased to high yields. T h e very poor yields of same mechanism, the SN2 mechanism, because all are primary
the n-butyl esters with triethylamine alone were increased to chlorides and the solvents, methyl ethyl ketone and the ester,
high yields when both catalysts were used simultaneously. Thus are poor ionizing solvents.
sodium iodide is a n extremely helpful catalyst in reactions Methyl chloride is considerably more reactive, as expected,
where relatively unreactive alkyl chlorides are involved. So- than n-butyl chloride. This relationship has been well estab-
dium iodide was, with one exception, of no use in the reactions lished in relative rate constants of S,2 halide exchange reactions
of allyl and benzyl chloride. Allylic and benzylic chlorides are (Gould, 1959). Allyl and benzyl chloride are generally more

194 l&EC PRODUCT RESEARCH A N D DEVELOPMENT

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 reac-
tion site carbon, facilitate SN2 reactions. Except for the allyl
chloride-sodium salicylate system, no iodide catalysis was re-
quired to obtain high yields of product. T h e allyl chloride-
sodium 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 dis-
crepancy. 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 con-
sumed in ester formation were recovered.
Considerable effort was expended in varying reaction condi-
tions 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 phenom-
enon. 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 rela-
tively 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, cin-
chonine, 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-ethylpiperi-
dine (Ladenburg, 1898), and from the cyclization of 2-ethyl-
glutaric dialdehyde with hydroxylamine (Chumakov et al.,
1965) ; it may be produced with 24% yields from tetrahydro-
furfuryl alcohol, monoethylamine, and ammonia (Butler et a/.,
1966), or with 51% yields, from 2,6-diethoxy-3-(l-ethoxy-
ethyl) 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-ethyl-
picolinic 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 2-
picoline 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 NO. 3 SEPTEMBER 1967 195