[CONTRIBUTION FROM THE
RICHARDSON CHEMISTRY LABORATORIES, TULANE UNIVERSITY]
PREPARATION OF KETALS. A REACTION MECHANISM C. A. M A c K E N Z I E
AND
J. H . STOCKER
Received July $0, 1966
The use of orthoformates in the preparation of ketals is a standard operating procedure. Relatively few of the many preparations have employed orthoformates other than triethyl orthoformate. Post (1) has stated the yields decrease with an increase in size of the trialkyl part of the molecule. Dykstra (2) claimed good yields with the tripropyl and tributyl orthoformates although exact values were not given and the experimental details were not reported. Starting from the commercially available triethyl orthoformate and a ketone, two routes are available to any given ketal above the diethyl derivative. The orthoester may be treated with an alcohol of higher boiling point than ethanol and the interchanged orthoformate then may undergo reaction with the ketone. Alternatively, the diethyl ketal may be prepared and, in turn, be treated with the higher alcohol (3). Both methods have been employed. The orthoformate-alcohol interchange does not require a catalyst (4).In one instance, a ketal-alcohol interchange has been reported in the absence of a catalyst (5). It has been known for a long time that the preparation of a ketal requires four reagents-orthoformate, ketone, alcohol, and acidic catalyst. The need for these reagents has been discussed by Post (6). A direct, single step, preparation of ketals from triethyl orthoformate, ketone, alcohol, and p-toluenesulfonic acid has been successfully carried out in this laboratory in a number of cases. Heating the four components together and steadily removing the lower-boiling materials through a packed column produced the higher analog of the diethyl ketal directly: R /OCZH6 H-C-OCzH6
\
0 CzH5
+ R
\ C=O /
+
2R'OH
R
H"
OR'
Ethyl formate was the initial distillate; usually more than 90% of the calculated amount was collected. The reaction proceeded well with the four ketones investigated-two dialkyl, one alicyclic, and one alkyl-aryl. Alcohols employed were 1-butanol, 1-pentanol, and 1-octanol. The attempted use of benzyl alcohol gave rise to large quantities of dibenzyl ether. The yields ranged from 73% to 89 % except for the dibutyl ketal of acetophenone which was obtained in 52 % yield. Results are listed in Table I. 1695
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MACKENZIE AND STOCKER
99
22
.
3
u3
m a uw)
P-
. .
33
3
2 w2
hu)
@?bi
M
*
h
. . .
344
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1955
PREPARATION OF KETALS
1697
Triethyl orthoacetate was substituted successfully for the triethyl orthoformate. An earlier investigation (1) reported that only traces of acetal were formed from the reaction between acetaldehyde and triet,hyl orthoacetate. An extension of this single step procedure led to the direct preparation of a vinyl ether. These compounds are frequently prepared from the previously isolated ketals. In the one preparation performed continued distillation of the reaction mixture, without neutralization of the acid catalyst, produced a vinyl ether: OC~HS
V
+
CdHoOH
+
/ H-C-OC2HS \
H ' __f
Oca&
Secondary monohydric alcohols could not be substituted successfully in the single step procedure for the primary alcohols. In fact, it was not found possible
to prepare a ketal of a secondary alcohol by an entirely different method (7) (isopropenyl acetate and 2-butanol). The use of acetone, triethyl orthoformate, a catalyst, and 2-butanol gave rise to diethyl ketal but no secondary butyl ketal. When the orthoester employed was sec-tributyl orthoformate, a reaction did not occur and the orthoester was recovered unchanged. A search of the literature failed to reveal a single example of a secondary alkoxy ketal. The dicyclohexylthioketal of 2-butanone is known, however (8). It is of further interest to note that Nieuwland and coworkers (9) were unable to prepare ketals by the addition of secondary or tertiary alcohols to acetylene compounds; the reaction was successful with primary alcohols. Construction of a model of a secondary ketal shows it can be assembled but there is restricted rotation at the carbonoxygen bonds of the alkoxy groups. Cyclic ketals (dioxolanes) of, for example, acetone and 2,&butanediol are known (10); these possess a ring structure that presumably does not demand the same freedom of rotation. By contrast, the tri-secondary alkyl derivatives of orthoformates are known (4) and the ditertiary alkyl derivatives of acetals have been prepared (11). CATALYST EFFECTS
Triethyl orthoformate, heated at reflux in the presence of p-toluenesulfonic acid (0.05 mole-%) for 20 hours, is recovered to the extent of 80%. Since a corresponding amount of sulfuric acid completely destroys the orthoester (8) the result is interpreted as showing the loss of the catalyst. Several preformed orthoformate runs (in which the triethyl orthoformate was subjected to an alcohol interchange reaction without isolation of the new
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orthoester) were made in which the addition of the catalyst was varied as indicated; the reagents used were acetone, l-pentanol, and triethyl orthoformate: (a) The catalyst was added with the triethyl orthoformate prior to preforming. I n the subsequent addition of ketone, no additional catalyst was added. Found: less than 13% ketal and 69 % orthoester. (b) The ketone and catalyst were added to the refluxing preformed orthoformate. Found: 68 % ketal and 30 % orthoester. (c) The ketone and catalyst were added a t room temperature to the orthoformate mixture. Found: 86% ketal and 7 % orthoester. The over-all single step preparation, carried out in the absence of catalyst produces interchanged orthoformate but no ketal. I n both the single step and preformed orthoformate preparation of ketals, colors were observed: red, purple, and green. A similar observation was reported by Royals and Brannock (12) with no further comment. Such colors tended to reach a maximum depth and subsequently changed to yellow. Addition of a non-aqueous base (sodium alkoxide) to reaction mixtures a t the peak of color development resulted in an immediate change to yellow. There is no color development in the non-catalyzed alcohol interchanges of either orthoformates or ketals. CONCERNING T H E EQUILIBRIUM NATURE O F THE REACTION
Adkins and co-workers (13, 14) have reported the preparation of diethyl ketals from triethyl orthoformate to be a reversible reaction, generally favorable to the products. The reverse reaction, the production of ketone and triethyl orthoformate, from a diethyl ketal and ethyl formate was examined in three cases and said to give good agreement with the forward reaction. The method of examination was indirect and in no case were the products of the reverse reaction isolated. In the present work the reaction was examined with the system: tri-n-butyl orthoformate, acetone, l-butanol, and p-toluenesulfonic acid. I n this reaction the acetone was the lowest-boiling component by a margin of over 50" yet it was never recovered in the distillation step in more than minute amounts. The reverse reaction, employing n-butyl formate, the dibutyl ketal of acetone, l-butanol, and p-toluenesulfonic acid was studied as follows: (a) At reflux and atmospheric pressure for 96 hours, permitting any acetone formed to distill freely. ( h ) At reflux and atmospheric pressure for 6 hours. (c) At reflux, 60" and 50 mm., for 18 hours. ( d ) At reflux, 60" and 50 mm., for 96 hours. No orthoester was found in any case, and varying amounts of ketal (0, 23, 75, 81% for a through d respectively) were recovered. About 17% acetone was isolated from both a and d. An appreciable amount of dibutyl ether was isolated from a. Failure to force the reaction to yield the desired products does not argue
DEC.
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PREPARATION OF KETALS
against the reaction as an equilibrium; however the results do indicate that if an equilibrium is involved it is greatly in favor of the ketal. When the forward reaction was carried out at room temperature and atmospheric pressure it proceeded to the extent of 80 % ketal formation in seven days. REACTION MECHANISM
A mechanism for the preparation of ketals from orthoesters, based in part on the experimental findings of Post and others, has been offered by Alexander (19) and modified by Royals (20). Royals suggests a ternary interaction of molecules and ions, a notably rare situation; Alexander proposes an uncatalyzed formation of a hemiketal. If the latter situation were true then the ketal should form in the absence of added catalyst since a catalyst is not necessary for the decomposition of the orthoester. Both authors indicate the sole purpose of the acid catalyst is to produce carbonium-oxonium ions from the orthoester. The present work indicates that the major function of the catalyst is not one of activation of the orthoester. The following equations, showing the catalyst as an activator of the carbonyl compound, seem more in accord with experimental facts than those of Alexander and Royals: 1. R*C=O 63
2. RzC-OH
63 + HQ S RzC-OH + CzH60H $ RzC-OH
I
@
+
H
+
CsH60H
OCA
I 3. HC(0CsHs)a
+
Q
H
0
H-C(OCzH5)z
OH
I
I1
OCA
I
4-, 0
5.
Rnc
I
OCiHli
+
CzH60H
+
HCOOCzHj R~C-OCZH~
I
+
@
+
CzH60I-I
H
OCzH6
The intermediate compound (I) is similar in appearance to the structure usually written in acetal reaction mechanism equations. In the case of the acetal the hydroxy group is removed as water by combination with a proton; with the hemiketal the carbonium ion is required. The experimental work now presented is in agreement with the idea that the alkoxy groups present in the ketal arise directly from the dominant (dependent on concentration and acceptability, i e . , secondary alcohols are not acceptable)
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alcohol in the media rather than from the alkoxy groups originally present in the orthoformate. EXPERIMENTAL PREPARATION OX KETALS
A . Single step procedure. A solution of 0.3 mole of triethyl orthoformate, 0.25 mole of ketone, approximately 1.5 moles of alcohol (higher-boiling than ethanol), and 300 mg. of p-toluenesulfonic acid was slowly heated so that the removal of ethyl formate through a 30-50 cm. glass helices-filled column began after one hour. Ethyl formate and ethanol then were removed a t a steady rate until the head temperature indicated removal was complete. A few ml. of a dilute solution of sodium in the higher-boiling alcohol was added t o the slightly cooled solution which then was washed three times with 60 ml. of water and dried over potassium carbonate. The dry solution was fractionally distilled. B . Preformed orthoformate procedure. A solution of 0.3 mole of triethyl orthoformate and approximately 1.5moles of alcohol (higher-boiling than ethanol) was heated and the ethanol was removed through a 30-50 cm. glass helices-filled column until the theoretical amount had been distilled [3 hours for replacement by 1-butanol, 7 hours for 2-butanol, contrast with longer times of Alexander (4)]. The mixture was cooled t o 50" or less and 0.25 mole of ketone and 300 mg. of p-toluenesulfonic acid were added. The mixture was heated slowly so that refluxing was obtained in 60-90 minutes. The mixture was cooled, neutralized, and the product was isolated as in ( A ) . ALCOHOL INTERCHANGE WITR KETALEI
A . Dibutyl ketal of acetone and 1-penlano1 without added catalyst. The dibutyl ketal of acetone (47.6 g., 0.25 mole) and 100 ml. of 1-pentanol were slowly heated t o reflux and 1-butanol was removed along with increasing amounts of 1-pentanol through 45 cm. of glass helices over a period of 4 hours. The remaining mixture was fractionated through a shorter column to yield 41.1 g. (76%) of the dipentyl ketal, 6 1.4202, b.p. 119-122". B. Dibutyl ketal of acetone and I-pentanol in the presence of added sodium I-pentoxide. The procedure in ( A ) was altered by the substitution of 30 ml. of 1-pentanol containing 0.6 g. of dissolved sodium metal for a similar amount of 1-pentanol. Less than 1 ml. of material was distilled on a rise of the head temperature to 130". No dipentyl ketal was found; 90% of the dibutyl ketal was recovered. C. Diethyl ketal of diethyl ketone and ethylene glycol without added catalyst. The diethyl ketal of diethyl ketone 32 g. (0.20 mole) and 37.2 g. (0.60 mole) of ethylene glycol were heated and the theoretical amount of ethanol was removed through 30 cm. of glass helices over a one-hour period. The reaction mixture contained two-phases until removal was more than half complete. Continued distillation a t reduced pressure gave 24 g. (94%) of 2,2diethoxy-1,3-dioxolane, b.p. 61.3" a t 50 mm., 2 1.4190. Literature values: b.p. 46-47" at 35 mm., n: 1.4130 (21). Preparation of 1-(i-butoxy)cyclohexene-1.A procedure was used analogous to ( A ) except the reaction flask was equipped with a capillary for subsequent reduced pressure distillation. A 20-cm. glass helices-filled column was used. Cyclohexanone (9.8 g . , 0.10 mole) 20 g. (0.14 mole) of triethyl orthoformate, 66.6 g. (0.60 mole) of 1-butanol, and 500 mg. of p-toluenesulfonic acid were placed in the reaction flask and were heated a t a rate such that distillation began in one hour. A total of 19 g. of water wm removed in reaching a distilling temperature of 82" over a period of 75 minutes. The pressure in the system then was slowly reduced t o maintain a distillation temperature of 50-70". The product was redistilled at 81-83' and 10 mm. The product tested satisfactorily for unsaturation. Yield 7.1 g. (46%), n? 1.4574.
NEWORLEANS18, LOUISIANA
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1955
PREPARATION OF KETALS
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REFERENCES (1) POST,J. Org. Chem., 6,244 (1940). (2) DYKSTRA, J. Am. Chem. SOC.,67,2255 (1935). AND NIEUWLAND, J. Am. Chem. SOC.,67, 544 (1935). (3) KILLIAN,HENNION, (4) ALEXANDER AND BUSCH,J. Am. Chem. SOC., 94,564 (1952). (5) POST,J. Am. Chem. SOC.,66,4176 (1933). ( 6 ) POST,The Chemistry of the Aliphatic Orthoesters, American Chemical Society Monograph 92, Chapt. 3, Reinhold Publishing Corporation, New York, 1943. (7) CROXALL, GLAVIS,AND NEHER,J. Am. Chem. SOC.,70, 2805 (1948). (8) MOCHEL, AGRE,AND HANFORD, J. Am. Chem. SOC.,70, 2268 (1948). A N D NIEUWLAND, J. Am. SOC.,68,80 (1936). (9) KILLIAN,HENNION, (10) NEISHAND MACDONALD, Can. J. Res., 26B, 70 (1947). J. Am. Chem. SOC.,62, 2892 (1930). (11) HINTONAND NIEUWLAND, AND BRANNOCK, J . Am. Chem. SOC.,76,2050 (1953). (12) ROYALS (13) PFEIFFERAND ADKINS,J. Am. Chem. SOC.,63, 1043 (1931). AND ADKINS,J. Am. Chem. SOC., 60,235 (1928). (14) CARSWELL J. Am. Chem. SOC.,71,2736 (1949). (15) CROXALL, VANHOOK,AND LUCKENBAUQH, (16) POSTAND ERICKSON, J . Am. Chem. SOC.,66, 3851 (1933). J . Am. Chem. Soc., 67, 159 (1935). (17) MICHAELAND CARLSON, (18) EISTERT AND MERKEL,Chem. Ber., 86, 895 (1953). Principles of Ionic Organic Reactims, John Wiley and Sons, Inc., New (19) ALEXANDER, York, N. Y., 1951, p. 216. (20) ROYALS,Advanced Organic Chemistry, Chapter 9, Prentice-Hall, Inc., New York, N. Y., 1954. (21) BERGMANN AND PINCHAS, Rec. trav. chim., 71, 164 (1952).
