[CONTRIBUTIONFROH THE VENABLE LABORATORY OF THE UNIWRSITY
OF
NORTHCAROLINA]
ACYLOINS. I. REACTION OF ACYLOIN ENOLATES WITH PRIMARY ALKYL HALIDES JOHN C. SPECK, J R . ~AND R. W. BOST Received June 7, 1946
The available data concerning the reaction of alkyl halides with intermediates in the acyloin condensation indicate that, depending upon the conditions, alkylation of the so-called acyloin enolates may result in the formation of either of two types of products. Kharasch and co-workers (1) have noted the occurrence of dissociation plus carbon-alkylation in liquid ammonia solution, obtaining, for example, a 32% yield of ethyl isopropyl ketone in addition to 28% of isobutyroin upon hydrolysis of a mixture which resulted from the reaction of ethyl bromide with the condensation product of sodium and ethyl isobutyrate. An instance of oxygen-alkylation has, on the other hand, been described by Scheibler and Emden (2) in reporting that the formation of 2,3-diethoxy-l , 1,4,4-tetrabenzyl-2butene (I) occurred when the product from the reaction of potassium with ethyl (Y ,a-dibenzyl acetate was treated with ethyl bromide in ethyl ether.
(CsHsCH2)2CH
I I CO C2H5 I
COC2H6
( C sHbCH2>z CH
I Thus, it may be inferred that the diether of the corresponding enediol normally results from the alkylation of an acyloin enolate in solvents of low dissociating power, particularly since such a conclusion would appear to be supported by the analogy in Bachmann’s observation (3) of the conversion of bend-disodium to the dimethyl ether of a ,a’-stilbenediol by methyl iodide, as well as by reports (4) of similar transformations of other metal derivatives of aromatic a-diketones. In the investigation described in the present writing, acyloin enolates derived from esters of lower aliphatic acids were alkylated with primary alkyl halides, the solvent employed being either toluene or ethyl ether. No evidence of the formation of enediol ethers was obtained. Instead, the product in each case was an
R’ R-C-C-R
I
I
0 OH I1 1 Present address:.Kedzie Chemical Laboratory, Michigan State College, East Lansing, Mich. 788
ACYLOIN ENOLATES WITH ALKYL HALIDES
789
or-hydroxy ketone, the structure of which is represented by the general formula I1 where R designates the hydrocarbon residue of the aliphatic acid and R' the primary alkyl group appended during the displacement. The yields of these materials were nearly the same as those obtained in the preparation of the corresponding acyloins. Moreover, the degree of alkylation was apparently not affected by an excess of the alkyl halide. The first reaction studied was that of ethyl iodide with the isobutyroin intermediate. Upon separation of the resulting mixture, after hydrolysis, only traces of isobutyroin and diisobutyryl were isolated. The principal product was a colorless and, seemingly, pure liquid fraction, the boiling point of which was higher than that of the acyloin. Reactions of this substance with classification reagents revealed the probability of its containing active hydrogen and a carbonyl group; however, tests for unsaturation or an acyloin structure were negative. The Zeisel determination denoted the absence of ethoxyl groups, whereas the molecular weight and the carbon and hydrogen analysis mere in agreement with the molecular formula C1oHzoO2. It was therefore apparent that this compound was produced from a single carbon-alkylation. Furthermore, inasmuch as the product was not an unsymmetrical acyloin, the attachment must have occurred at the carbon of an antecedent carbonyl group. The only probable structure conforming to these requisites would be that of 2,5-dimethyl-4-ethyl-4-hydroxy-3-hexanone (111). Comparison of the physical properties of the material obtained in this alkylation reaction C2Hs
I
(CHa)zCHC-CCH(CH.q)2
II
I
0 OH I11 with those of I11 as prepared by the reaction of diisobutyryl with ethylmagnesium iodide2served to indicate that this assumption was correct. The formation of 4-ethyl-4-hydroxy-3-hexanone (V) upon alkylation of the propionoin intermediate with ethyl iodide and the dehydration of V to 4-ethyl-4hexene-3-one (VI) afforded conclusive evidence regarding the course of this alkylation reaction. Both compounds have been previously described ( 5 ) , and the identity of V, thus obtained, with a sample prepared by the reaction of ethyl magnesium iodide with ethyl oxalate (6) was established by determination of mixed melting points of the semicarbazones. In extending this alkylation by primary alkyl halides to the reaction of the butyroin intermediate with ethyl iodide and of the valeroin intermediate with n-butyl bromide, the results achieved were entirely analogous to those obtained 2 It has been shown by Bouveault, Bull. soc. chim., (3) 36,654 (1906),that, because of the proximity effect, the addition reaction of the Grignard reagent with diisobutyryl involves only one carbonyl group, This comparison was therefore accepted as indicating a proof of structure by synthesis.
790
JOHN C. SPECK, JR. AND R. W. BOST
2CHsCHsC02Et
+ 4Na
--$
(CsH1002)'
+ 4Na+ + 2 0 6
IVIEt1 (HzO)
CH2 CHa
I
CH3 CH2 C-C=CHC&
Is
VI COzEt
I
c02m
+
3CHsCH2MgI
V
-P
with the isobutyroin and propionoin enolates, and the structures assigned to the products were, respectively, those of 5-ethyl-5-hydroxy-4-octanone and 6-butyl6-hydroxy-5-decanone. Thus, it appears that this reaction may be general in its application to the purely aliphatic acyloin enolates, although the complete establishment of its scope will necessitate its expansion to other members of the series. Since there was no indication that the reaction involves other than an ionic process, discussion of the mechanism will for the present be limited to consideration of the probably anonic intermediate, represented in the case of propionoin by the non-committal formula IV. The anion VI1 has been suggested by Woodward and Blout (7) in describing the condensation of the butyroin intermediate with ethyl acetate because of the general inadequacy of the older dienolate structure (VIII). e CHICHaCH2CH-C-CHCH2CHI t--) CH*CHZCH~CH-C=CHCH~CHI
I
0
e
II
I
0
I
0
0
0
0
VI1
R-C=C-R
I
0
I
0
e 0
VI11
It is possible that structures analogous to VI1 are involved in this reaction with alkyl halides, although such a process would require a rearrangement, inasmuch as the product from the expected alkylation of this form would be otherwise an unsymmetrical acyloin.
791
ACYLOIN ENOLATES WITH ALKYL HALIDES
Another possible structure for the reacting species in the alkylation is represented by IX. The present data do not constitute a basis for a choice between this form and that of VII. However, it is suggested, in view of the fact that analogs of VI1 cannot be formulated for systems without enolizable hydrogen, that resonance contributions of the type IX account for the stabilization of anions of aliphatic acyloins such as pivaloin which possess no a-hydrogen.
0
0
/ \
/ \
R-C-C-R
\ e 0 e
R-C-C-R
e
0
/
e
R-C-C-R
\ /
/
0
8
e \ R-C-C-R \ / 0
0
IX The investigation of the reaction of the pivaloin intermediate it9 well as that of other acyloin enolates, with alkyl halides has been temporarily interrupted. The authors look forward t o its continuation at the earliest opportunity. EXPERIMENTAL
All boiling and melting points are corrected. The fractionating columns employed for the separations described in this section, as well as for the purification of the esters and alkyl halides used as starting materials, were provided with means for adiabatic control and were packed with &-inch glass helices. The dimensions of the packed sections were either 10 mm. x 45 cm. or 10 m. x 60 cm. and the still-heads were of the total-condensation variable take-off type. Preparation of the acyloin intermediates i n ethyl ether. The method of Snell and McElvain (8)was modified for the preparation of these substances in ethyl ether, particular care being taken to add the ester to the sodium very slowly i n order t o minimize the occurrence of secondary reactions which result from the presence of an excess of the former reactant in the mixture. The following procedure was found t o give the best yields either in the subsequent alkylation reactions or upon hydrolysis to the acyloin: Sodium (46g., 2.0 g. atoms) was very finely powdered i n 300 ml. of dry xylene i n a 2-1. three-necked flask, equipped with a n efficient wire stirrer and a reflux condenser. After decanting the xylene from the powdered metal and washing it thoroughly with absolute ethyl ether, the sodium was suspended in 600 ml. of absolute ethyl ether, the mixture heated to the boiling point on a steam-bath and 1.0 mole of the appropriate ester gradually added, with stirring, over a period of six t o eight hours. At the end of the addition the heating and stirring were continued for twelve t o fourteen hours. The condensation was then practically complete, only a very small amount of unreacted sodium remaining in the mixture. Diisobutyryl. Isobutyroin (144 g., 1.0 mole) was dehydrogenated in the liquid phase at 280" over copper chromite catalyst (4 9.) with ethylene as the hydrogen acceptor (9). A high-pressure hydrogenation vessel having an approximate volume of 0.3 1. was employed for the reaction and the initial pressure of the ethylene was adjusted to 51.5 atm. a t 28". The reaction period was thirty hours. After removal of the catalyst the resulting mixture was subjected to fractional distillation, the yellow material boiling at 146-148" (atmospheric pressure) being collected as diisobutyryl; yield 38.2 g. (27%). Lower yields were obtained when the dehydrogenation was carried out over shorter periods. Alkylation of the acyloin intermediates with ethyl iodide i n ethy2 ether. Excepting where otherwise noted, all of these reactions were carried out as follows: T o the acyloin intermediate in ethyl ether, as formed from the reaction of 1.0 mole of ester, was added 156 g.
792
JOHN C. SPECK, JR. AND R. W. BOST
(1.0 mole) of freshly-distilled ethyl iodide i n one portion. The reaction mixture was then refiuxed, with stirring, for twenty-four hours. At the end of this period t h e mixture was decomposed by the gradual addition of 225 ml. of distilled water and the ether layer separated. The ether solution was washed successively with two 100-ml. portions of distilled water, 100 ml. of 5% hydrochloric acid, and 100 ml. of 5% aqueous potassium bicarbonate and dried over sodium sulfate. The products were then isolated from this solution by fractional distillation. Tests with classifiation reagents. Tests with the following reagents, which were carried out according t o standard procedures, were negative : (a) alkaline potassium permanganate solution, (b) bromine-carbon tetrachloride solution, (c) Fehling's solution. The reaction of sodium with the materials under investigation was slow a t room temperature; upon warming the mixtures the evolution of hydrogen was vigorous. No evidence of reaction was observed upon treatment of I11 with either phenylhydrazine or 2,4-dinitrophenylhydraaine. However, all of these a-hydroxy ketones, upon prolonged heating with a solution of semicarbazide hydrochloride and sodium acetate i n dilute ethanol, gave high-melting, crystalline products which were not characterized, but which were probably the substituted 4,5-dihydro-3(2)-as-triazonesresulting from cyclization of the semicarbazones. Attempts to isolate the intermediary semicarbazones were unsuccessful excepting in the case of V. ~,6-Dimethyl-~-ethyl-~-hydroxy-~-hexanone (IZI). ( a ) From the reaction of the isobutyroin intermediate with ethyl iodide. After removal of the solvent by ordinary distillation, the following fractions were obtained from the mixture which resulted from the alkylation of the isobutyroin enolate according to the foregoing general procedure : BOILING POINT
FRACTION
"C
WEIGHT, C.
.
him.
32.5 34-35.5
t o 109 110-11.5
1 2
Residue
FRACTION
I
trace 72.0 4.9
BOILING POINT
"C.
65-88.5 88.591 91-108.5 108.5-110
I
WEIGHT, G.
Mm.
35 35 35-33.5 33.5-34
5.7 5.8 1.9 13.1
ACYLOIN ENOLATES WITH ALKYL HALXDES
793
Fractions 1 and 2 were yellow in color and consisted, principally, of isobutyroin resulting from the reduction of diisobutyryl. Fraction 4, which was colorless, represented a 30% yield of 2,5-dimethyl-4-ethyl-4-hydroxy-3-hexanone (based on diisobutyryl) ; b.p. 70.5-71' (3.5 mm.); n: 1.4386. A n a l . Calc'd for C10H2002:C, 69.72; H, 11.70. Found: C, 69.87; H, 12.14. 4-EthyEJ-hydrozy-3-hexanone ( V ). ( a ) From the reaction of the propionoin intermediate with ethyl iodide. This alkylation of the propionoin intermediate in ethyl ether by the foregoing general procedure gave 42.3 g. (58.8%) of 4-ethyl4-hydroxy-3-hexanone; b.p. 88-89" (34.5mm.). ( b ) From the reaction of ethylmagnesium iodide with ethyl oxalate. The experimental details of this synthesis of V have not been previously reported; hence, they are included here. T o the Grignard reagent prepared from 58.3 g. (2.4 g. atoms) of magnesium turnings and 382 g. (2.45 moles) of ethyl iodide in 800 ml. of ethyl ether was gradually added, with stirring, a Holution of 111g. (0.76 mole) of ethyl oxalate in 500 ml. of ethyl ether, during a period of one hour. After refluxing the resulting mixture for hour, decomposition was effected by the gradual addition of 25% aqueous ammonium chloride. The ether solution was then decanted from the aqueous mixture, washed with distilled water and dried over sodium sulfate. The mixture was separated by fractional distillation, the yield of 4-ethyl3-hydroxy-3liexanone boiling a t 176-177.5" (742 mm.) being 59.6 g. (54.3%) (based on ethyl oxalate). A fraction boiling at 94-95.5' (4 mm.) weighed 9.4 g. and represented a 7.1% yield of 3,4-diethyl-3,4-hexanediol. The semicarbazone of V was prepared by refluxing a mixture of 2.9 g. of the ketone, 2.8 g. of semicarbazide hydrochloride, 3.5 g. of sodium acetate, 5 ml. of 95% ethanol and 7 ml. of distilled water: for two hqurs. At the end of this time the mixture was cooled and 20 ml. of mater added in order to complete the precipitation of the semicarbazone. The weight of thecrude derivativewas 2.8 g.;m.p. 172-175". Two grams of this product was recrystallized from 65 ml. of boiling water and the material thus obtained recrystallized again from 55 ml. of boiling water. The recovery of the pure white semicarbazone was 1.4 g. (dried a t 80'); 1n.p. 177-177.5' [reported m.p. (5) 178'1. No deviation from this m.p.was observed for mixtures of the semicarbazone of V obtained in a with that of the product obtained in b. The dehydration of V was carried out in the following manner: T o 12.0 g. (0.083 mole) of V, obtained from the alkylation of the propionoin intermediate, was added 10 ml. of syrupy phosphoric acid (85%) and the mixture refluxed for three hours. The resulting mixture was then slowly distilled in an ordinary distillation apparatus until no more organic material appeared in the distillate. Fractional distillation of the upper layer of this distillate gave 1.9 g. (18%) of 4-ethyl-4-hesene-3-one (VI); b.p. 167-170'. The semicarbazone of this product, after two recrystallizations from 20% aqueous ethanol, melted a t 177.5-178' [reported m.p. (5) 178'1. 5-Ethyl-5-hydroxy-~-octanone. Alkylation of the butyroin enolate, prepated i n ethyl ether, with ethyl iodide by the foregoing general procedure gave 47.1 g. (54.7%) of 5-ethyl-5hydroxyl-octanone; b.p. 112-113.5' (32 nim.), 74.5-75" (3 mm.); n: 1.4336; dzs 0.8927; hI, calc'd 49.92, found 50.21. C, 69.72; H, 11.70. Anal. Calc'd for C,OH~OOZ: Found: C,69.38;H, 11.28. 6-Butyl-6-hydroxy-b-decanone.The preparation of the valeroin enolate in ethyl ether was unsatisfactory. The consistency of this intermediate was such that the sodium particles adhered together, virtually stopping the normal condensation by the time half of the ester has been added. Accordingly, this product was prepared in boiling toluene by a modification of the procedure described by Hansley (10). To 1liter of dry toluene in a 2-1. three-necked flask, provided with a wire stirrer and a reflux condenser, was added 23 g. (1.0 g. atom) of sodium and the reaction mixture heated to the b.p. i n an oil-bath. TOthis mixture was then gradually added 65 g. (0.05 mole) of ethyl n-valerate, with rapid stirring, over a period of 1.5 hours. During this time the mixture was kept boiling gently by maintaining the bath temperature at 105-110". Thestirringwas then continued a t this tempera-
794
JOHN C. SPECK, JR. AND R. W. BOST
ture for two hours in order t o complete the reaction. The resulting mixture was allowed t o cool to 85", and 137 g. (1.0 mole) of n-butyl bromide added in one portion. Stirring was then continued for sixteen hours while heating on a steam-bath at approximately 85". The warm reaction mixture was hydrolyzed by the addition of 200 ml. of distilled water and the toluene layer separated, washed twice with Q00-ml. portions of distilled water, once with 100 ml. of 5% hydrochloric acid and finally with 100 ml. of 5% aqueous potassium bicarbonate. The resulting solution was fractionally distilled, water being removed as the azeotrope. The principal fraction, boiling at 104.5105" (1.0 mm.), weighed 27.6 g. and repren: 1.4428; dy 0.8775; M, calc'd 68.39, sented a 48.4% yield of 6-butyl-6-hydroxy-5-decanone; found 68.96. Anal. Calc'd for C~rHesOt:C, 73.63; H, 12.36. Found: C, 73.36; H, 12.66. The forerun boiling above the b.p. of toluene in the above separation was negligible, and the high-boiling residue, which could not be distilled under these conditions, appeared t o be typical of that ordinarily obtained in the preparation of acyloins. SUMMARY
The reaction of acyloin enolates with primary alkyl halides, in either ethyl ether or toluene, was examined for four of the acyloins above acetoin. Instead of the production of enediol ethers under these conditions, the formation of CY ,a-dialkyla-hydroxy ketones, resulting from a single alkylation a t the carbon of a prior carbonyl group, was observed to occur. CHAPELHILL,N. C. REFERENCES (1) (2) (3) (4)
KHARASCH, STERNFELD, AND MAYO,J . Org.Chem., 6,362 (1940). SCHEIBLER AND EMDEN, Ann., 434,275 (1923). BACHMANN, J. Am. Chem. Soc., 66,963 (1934). Cf.STAUDINGER AND BINKERT, Helv. Chim. Acta, 6, 703 (1922); FUSONAND HORNING, J . Am. Chem. SOC.,62,2962 (1940). (5) BLAISEAND MAIRE,Compt. rend., 146,74 (1905). (6) MEERWEIN, Ann., 419, 152 (1919). (7) WOODWARD AND BLOUT, J . Am. Chem. SOC., 66,564 (1943). (8) Org. Syntheses, Coll. Vol. 11, 114 (1943). (9) REEVEAND ADKINS,J . Am. Chent. SOC.,62,2874 (1940). (10) HANSLEY,J. Am. Chem. SOC., 67,2303 (1935).
