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3. p-Spinastenol yields a saturated alcohol, 4. New esters of a-spinastenol, 16-spinastenol

spinastanol, on absorption of one mole of hy- and spinastanol are described.
drogen. MICH.
AUGUST6, 1934



Preparation of 1,3-Diketones by the Claisen Reaction


Rather large quantities of a number of 1,3-di- perature. Once under way the reaction goes
ketones were needed in this Laboratory for studies rapidly and unless the reaction mixture is watched
involving the relation of their structures to the very carefully, and rapidly cooled, goes with vio-
mode of cleavage by water, alcohol and hydr0gen.l lence. It is, of course, not difficult to use so-
Our experience in the preparation of these dike- dium if only a fraction of a mole is involved.
tones (see Table I) by the condensation of an ester The formation of a P-keto ester through the
with a simple ketone according to the Claisen re- interaction of two molecules of ester may be
action has, we believe, illuminated somewhat the avoided to a greater extent with sodium ethoxide
preparational process. than with sodium. In certain attempted prepa-
Sodium ethoxide, especially by the procedure rations of CHaC(0)CHzC(O)C(CH3)~ through
marked “A” in the experimental part, appears the condensation of ethyl acetate and pinacolone
to be preferable to sodium as a condensing agent.2 with sodium, a product having a good boiling
Only in the case of diacetylmethane was sodium range for the diketone contained as much as 50%
definitely superior with respect to the yield of acetoacetic ester while that from sodium ethoxide
products calculated upon the basis of the amount contained no ester. Sodium also tends to pro-
of monoketone used. If the yields were calcu- duce acyloins. For example no diketone was ob-
lated upon the basis of the sodium ethoxide or tained as a result of the use of sodium with ethyl
sodium the comparison would be in all cases very hexahydrobenzoate and acetone, instead the acy-
unfavorable to sodium since as shown by Kutz loin, CsHl1C(O)CH(OH)C~Hl1,was isolated in
2 g. atoms of sodium are required as contrasted 70% yield accompanied by a 5-6% yield of dicy-
with 1 g. molecule of sodium ethoxide. clohexylglycolic acid.
Even though sodium gave a higher percentage Three methods are available for the isolation
conversion of monoketone to diketone, the re- and purification of the diketone. The purifica-
agent suffers under certain disadvantages that tion is readily made if the diketone is a solid such
greatly militate against its use. The condensa- as are acetylbenzoylmethane, furoylbenzoyl-
tion of an ester with a ketone using sodium as methane, etc., which precipitate upon acidifica-
the condensing agent is a hazardous operation. tion of the reaction mixture. Morgan and others
One serious accident and several minor ones have have recommended the separation of the liquid
occurred in this Laboratory in connection with diketones as the copper salts. However, we have
the preparation. The serious accident was due found that in most cases it suffices to extract the
to contributory negligence upon the part of the diketone from an acid solution and then to purify
operator but even the most skilled and experi- it by fractionation through a Widmer column.
enced occasionally allow a reaction to become too Presumably the preparation of the copper salt
violent. The difficulty lies in the fact that usu- of the diketone is intended to eliminate any p-
ally reaction occurs slowly if at all when the re- keto ester present in the reaction product. It
actants are mixed a t 0-5’) but it does begin in is unnecessary to form the copper salt, (a) if no
most cases as the mixture warms up to room tem- p-keto ester is present, or (b), if the P-keto ester
(1) For references see Sprague, Beckham and Adkins, THIS differs sufficiently in boiling point from the di-
JOURNAL, 66, 2669, 2676 (1934).
(2) Nothing in this paper should be construed as in conflict with ketone so that it may be separated by fractiona-
the conclusion of McElvain and others that the acetoacetic ester or tion. Analysis of the products has shown, for
Claisen condensation is dependent upon sodium ethoxide even when
sodium is the reagent added. example, that isovaleryl-, trimethylacetyl- and

isobutyrylacetylmethanes prepared through the analyze about 2y0 low in carbon. The reason
use of sodium ethoxide in the cold contained no for this is as follows. The keto forms of @-keto
@-ketoester. The purity of the compounds was esters do not form copper salts but their enol forms
not increased and the yield of diketone was low- do, so that if the reaction mixture from the Clai-
ered when the copper salt method of purification sen condensation is acidified and copper acetate
was used. added immediately a good deal of the copper salt
Quite a different situation was encountered if of the enol ester as well as of the diketone is pre-
sodium was used in the preparation of the dike- cipitated. If, however, the mixture is allowed
tone. When the copper salt was not used for the to stand until the enol has gone to the keto form
purification of trimethylacetylacetylmethane the then the copper salt of the diketone may be rela-
analysis of the product was about 7% low for tively free of the copper salt of the keto ester.
carbon and 1% low for hydrogen, indicating the The impure copper salt may of course be purified
presence of about 50% of acetoacetic ester. If by recrystallization (from methanol) but ob-
the copper salt of the diketone was properly pre- viously it is better to prepare the diketone by a
pared the regenerated diketone gave a good method which does not bring about its contamina-
analysis for carbon and hydrogen. However, the tion by the keto ester.
formation of a copper salt of a diketone does not The variations in yields of diketones given in
ensure that the regenerated and fractionated di- Table I are, with a few exceptions, not very large.
Methyl Ethyl Reagent
R R' ketones (moles) ester (moles)" moles Yield, %
' B. p., 'C. Mm.
Me8.C Me Me (2) Acetate (6) NaOEt (2) 3514 134-136
Me Me Me (2) Acetate (12) Na (4) 58 133-136
CPr' Me i-Pr (1) Acetate (3) NaOEt (1) 40 161-164
i-Pr Me i-Pr (0.5) Acetate (3) Na (1) 54 160-162.5
t-Bd Me t-Bu (1) Acetate (5) Na (2) 25 164-167
t-BU Me t-Bu (1) Acetate (3) NaOEt (1) 15-25 164-167
i-B~4 Me ~ - B u(4) Acetate (8) NaOEt (4) 60 71-76 18
i-Bu Me i-Bu (2) Acetate (12) Na (4) 64 74-77 17
i-Bu Me ~ - B u(1) Acetate (3) NaOEt (1) 56 74-77 17
Et3 Me Et (2) Acetate (12) Na (4) 35 154-157
Pr3 Me n-Pr (2) Acetate (12) Na (4) 45 87-90 38
n-Bu' Me n-Bu (2) Acetate (12) Na (4) 56-62 79-81 17
s-Bu' Me s-Ru (2) Acetate (12) Na (4) 47 96-100 45
Cyclohexyls*' Me Cyclohexyl(O.25) Acetate (2.5) Na (0.5) 50 101-105 7
Furyla Me Me (2) Furoate (2) NaOEt (2) 40-45 107-110 10
Tetrahydrofuryl Me Me (0.4) Tetrahydro-
furoate (0.4) NaOEt (0.4) 60 95-97 8
Ph' Me Ph (2) Acetate (4) NaOEt (2) 65-70
134-136 16
Ph Me Ph (2) Acetate (12) Na (4) 65 M. p. 59-60
Mesityl' Me Mesityl (0.5) Acetate (1.5) NaOEt (0.5) 70 143-146 8
M. p. 46-47
Ph Ph (1) Furoate (1) NaOEt (1) 55 160-165 3
M. p. 68
p-Biphenyl Me $-Biphenyl (0.5) Acetate (7.0) NaOEt (0.5) 50 M. p. 156157
Except where 12 moles of ester were added, diisopropyl ether or toluene were used as the reaction mediums.

ketone will be free of 0-keto ester. For example The methyl ketones .containing an isobutyl,
a sample of trimethylacetylacetylmethane was phenyl or mesityl group gave the highest yield
purified through the copper salt and found to (65-70%) of diketones, while most of the others
(31 Adkias, Kutz and Coffman, THISJOURNAL, 62, 3218, 4036
gave yields in the neighborhood of 50%. How-
(1930). ever, in seven cases attempts to prepare dike-
(4) Morgan and Drew, J . Chem. Soc., 126, 743 (1924). tones with sodium ethoxide failed. The ethyl
(5) Courturier, Comfit. rend., 1603928 (1910).
(8) Claisen and Ehrhardt, Ber., 22, 1014 (1889). esters of trimethylacetic and valeric acids would
(7) Godchot, Comfit. rend., 161, 1132 (1910). not condense with pinacolone nor with methyl
(8) Fuson end Woodward, THISJOURNAL, S6, 3474 (1933).
(9) Semmler and Ascher, Bm., 42, 2359 (1909). n-butyl ketone. The ethyl esters of neither

Salt of diketone" Alkyl halide Times, Yield,
R Moles R' Halogen Moles hours % B. p., OC. Mm.
Ph1' 1 Et I 2.0 10 50 128-132 7
Ph 1 n-Bu I 1.6 36 50 156-160 10
Ph 0.5 n-Heptyl I 1.0 43 53 178-183 8
Ph12 1 Benzyl c1 5.5 41 50 210-217 10
Mela 1 Et I 1.5 2 30 168-172
t-Bu 0.5 Et I 1.5 40 45 77-78 17
t-Bu .5 Benzyl c1 3.0 40 47 155-163 10
;-Bu .25 (Benzyl)* c1 11.0 8 22 165-174 1
;-Bu .5 n-Bu I 1.0 40 56 113-1 17 11
Me .63 Benzyl c1 2.0 4 45 143-146 10
Me .16 (Benzyl), c1 1.0 5 39 200-220 10
M. p. 111-112
Except for benzyl chloride, 500 CC. of acetone or dioxane was used as a solvent per mole of diketone. The dibenzyl
diketones were made by first preparing the monobenzyl compounds and then realkylating. The yields given are for the
second alkylation.
*ban, % Hydrogen, %
Formula Calcd. Found Calcd. Found
pPhenylbenzoylacet ylmethane C16Il402 80.63 80.65 5.92 6.05
Tetrahydrofuroylacetylmethane CsHirOa 61.54 61 38
I 7.69 7.48
n-Butylbenzoylacetylmethane CMHBOZ 77.02 77.16 8.32 8.54
n-Hept ylbenzoylacetylmethane Ci~Ha4Of 78.40 78.21 9.30 9.41
n-Butylacetyltrimethylacetylmethane Ci~HuOz 72.66 72.3 11.19 11.08
Benzylacet yltrimethylacetylmethane CtsHooOr 77.53 77.5 8.68 8.45
Ethylacetyltrimethylacetylmethane CloHl~Ot 70.53 70.7 10.65 10.3
Dibenzylacetyltrimethylacet ylmethane CnnHda 81.94 81.9 8.13 7.5

hexahydrobenzoic nor a-phenylacetic nor ethyl moved frequently at first t o make sure that condensation,
p-phenylpropionic acids would condense with as evidenced by the evolution of heat or the disappearance
of sodium ethoxide, had begun. After all the ketone had
acetone. been added the reaction mixture was stirred for two t o
The alkylated 1,8diketones (Table 11) were three hours in the ice-bath and then allowed t o stand at
prepared by the reaction of the sodium salt of room temperature for twelve t o sixteen hrs. The mixture
the simple diketone with an alkyl halide in ace- was then cooled in an ice-bath and an equal volume (or
more if the solid did not dissolve) of ice water added. The
tone or dioxane according to the method of Wey-
aqueous and organic layers were separated and washed 2-3
gand. The sodium salt of the simple diketone times with ether and water, respectively. The combined
as obtained in its preparation may be used but aqueous layers were acidified with 65 cc. of glacial acetic
it is not so readily soluble in acetone so that the acid per mole of sodium ethodde used in the condensation.
reaction time must be extended. The enol con- The above is the preferred procedure.
tent of the diketones prepared as described in B. The condensation was also carried out under a reflux
by adding the ketone during fifteen to thirty minutes t o
this paper are reported elsewhere.' the estersodium ethoxide-solvent mixture without cooling.
Experimental Part The reaction mixture was then refluxed on a steam-bath
for two t o five hours, and after cooling worked up as above.
Condensation of a Ketone and an Ester.-A. The C. Four atoms of sodium (finely powdered under
sodium ethoxide, ester and solvent (if any) were stirred xylene) was placed with the ester (12 moles) in a 3-necked,
for fifteen to twenty minutes and then cooled in an ice- 5-liter round-bottomed flask, provided with a reflux con-
bath. (The sodium ethoxide was prepared from equi- denser having an inner tube 2.5 cm. in diameter. The
molecular amounts of powdered sodium and ethanol in flask was surrounded by ice. the stirrer started and one-
ether or xylene.) The ketone was then added slowly over third of the ketone (total amount 2 moles) added. The
a period of one-half to one hour. The ice-bath was re- ice-bath was removed until the reaction had started as
(10) Weygand, BW., 61, 687 (1928). evidenced by the generation of heat. Great care must be
(11) Dieckmann, gbid., 46,2687 (1912); 55,2479 (1922). exercised in running this reaction as once started it is ex-
(12) Trotman, J . Chem. SOC.,117,94 (1926). ceedingly vigorous and may result in dangerous explosions,
(13) Morgan and Rawson, J . SOC.Chcm. Ind., 44,462 (1925).
(14) N o one of several operators has ever been able to duplicate as the heat is generated so fast that very large quantities of
the yield of 6 0 4 2 % reported by Kutz. vapors are quickly formed. For this reason great care
ADKINS Vol. 56

must be exercised that the temperature does not appre- ethyl acetate. The diketone may be distilled (b. p. 200-
ciably exceed room temperature. This was accomplished 210°, 3 mm.) but must be recrystallized before distillation
by a continual watching of the reaction flask by placing a since traces of undecomposed salt seemed t o cause a large
hand on the outside whenever the ice-bath was removed. amount of decomposition on distillation. The recrystal-
The time necessary for the reaction to start varies greatly, lized material melted 155-158' (60 g., 50%) and was yellow
sometimes only a few moments and sometimes six or eight but the distilled diketone was only faintly colored (and
hours. (In the preparation of trimethylacetylacetyl- melted 156-157'). It gave a red color with ferric chloride
methane the reaction did not start until the mixture was in alcohol solution.
heated.) At the first sign of reaction the ice-bath was re- The acyloin (b. p. 167-172', 16 mm., m. p. 46-47') ob-
placed and after the reaction was under way as evidenced tained as the result of the reaction of sodium and ethyl
either by the separation of a light yellow solid, or a very hexahydrobenzoate has been reported but not as a solid.16
marked darkening of the solution, the remainder of the The oxime had a m. p. of 157-158". The dicyclohexyl-
ketone was slowly added (one hour). Stirring was con- glycolic acid obtained from the same reaction was no doubt
tinued for two hours after the addition of the ketone, and produced by the benzilic acid rearrangement of the dike-
the reaction mixture allowed to stand in an ice-bath over- tone CBHIIC(O)C(O)C~HII.~~ The acid was characterized
night. Water and acid were then added as in the con- by analysis, neutral equivalent and conversion to dicyclo-
densation with sodium ethoxide. hexyl ketone. The latter was identified by its oxime,
Isolation and Purification of Diketone.-If the diketone m. p. 157-158O.l'
was a solid it was filtered from the acid solution obtained Alkylation of Simple 1,3-Diketones.-The method of
by the various processes given above and recrystallized. Weygand'o was used but the procedure was modified to the
If a liquid it was either extracted with ether or converted following. T o a suspension of 23 g. (one mole) of pow-
to the copper salt. dered sodium in 300 cc. of dry ether cooled in ice a solution
Extraction.-The diketone layer produced on acidifica- of 162 g. (one mole) of benzoylacetylmethane in one liter
tion was taken up in ether, and the water layer extracted of ether was added slowly with stirring. A yellow sodium
3 or 4 times with ether. The combined ether extracts salt precipitated and the mixture was allowed to stand
were washed with water and two or three times with satu- overnight. The ether was distilled and 500 cc. of dry
rated sodium bicarbonate solution. After drying over acetone or dioxane added. The solvent was refluxed until
calcium chloride and removing the ether the products were the salt all went into solution (ten minutes) and 312 g.
fractionated through a Widmer column. (two moles) of ethyl iodide was added over a period of
Copper Salt.-The acidified reaction mixture, after be- thirty minutes. The solution was refluxed on a steam-
ing allowed t o stand for a n hour or so, was poured into an bath until it was neutral t o moist litmus. This required
ammoniacal solution of copper acetate (using 100 g. of from eight to ten hours. The acetone and excess ethyl
copper acetate in 500-600 cc. of concd. ammonium hy- iodide were distilled off and sufficient water added to dis-
droxide per mole of ketone originally used). After stand- solve the precipitated sodium iodide. The product was
ing for two hours, the copper salt was filtered off and taken up in ether and after washing with water, it was
washed with water until the wash water was practically dried with calcium chloride and fractionated.
colorless. The copper salt was decomposed by shaking Summary
with 20% sulfuric acid and ether. The ether solution of
the diketone was washed with saturated bicarbonate, dried A number of 1,3-diketones have been prepared
over calcium chloride and fractionated. by the Claisen or acetoacetic ester condensation
I n the preparation of benzoyl-p-phenylbenzoylmethane from an ester and a monoketone. Sodium eth-
it was necessary to modify the procedure in the following oxide is concluded to be a better condensing agent
respects. The p-phenylacetophenone was dissolved in
500 cc. of warm ethyl acetate and added t o a mixture of
than sodium for three reasons: (a) the reaction
sodium ethoxide and 200 cc. of ethyl acetate. The ethyl may be more readily controlled especially if a mole
acetate solution of the fi-phenylacetophenone must be or more of monoketone is being used; (b) less 0-
kept warm during addition, and it was necessary t o have keto ester and other products of side reaction are
the ethyl acetate-sodium ethoxide mixture refluxing be- formed; (c) only one-half as much sodium is re-
fore addition of the ketone solution in order that the pre-
cipitated sodium salt would not cake in the flask. Since
quired. If proper precautions were taken in the
the sodium salt is insoluble in water, it was filtered off preparation of the diketone there was no necessity
and washed thoroughly with hot benzene, dried, ground t o for the isolation of the diketone through the cop-
a fine powder, suspended in 1 liter of water containing 120 per salt. If the copper salt method of isolation
g. of acetic acid and vigorously stirred for four t o five is used, then the formation of a salt of the keto
hours The free diketone was filtered and washed with
distilled water until neutral to litmus. The crude di-
ester which may be present as an impurity must
ketone was air dried (67 g., 56%, m. p. 154156") and re- be guarded against.
crystallized from 500 cc. of ethyl acetate. However, the MADISON,
small amount of unchanged salt which remained in the
(15) Danilow and VeaUS-DdlOWa, Bcr., 63, 2661 (1928).
diketone was more conveniently removed by placing the (16) Snell and McElvain, THISJOURNAL, 63,750 (1931).
crude diketone in extractor and extracting with 500 cc. of (17) Marvel and Gauerke, ibid., 60, 1178 (1928).