[CONTRIBUTION FBOY THE
GEOBGEHERBERT JONESCHEMICAL LABORATORY O F THE UNIVERSITY OF CHICAGO]
THE RELATIVE REACTIVITIES OF ALDEHYDES AND KETONES M. S. KHARASCH
AND
JOSEPH H. COOPER’
Received September 21, lO&
Numerous studies of the relative reactivities of carbonyl groups have been reported (1). For the most part, such comparisons have been based upon the relative rates of condensation reactions (e.g., oxime or hydrazone formation). Results obtained by such methods are, however, none too trustworthy. Among the sources of error inherent in these procedures are (a) the slight solubilities of products assumed to be “insoluble”, (b) the reversibility of the reactions investigated, (c) the susceptibility of these reactions to the influence of solventsand catalysts (particularly acids), and (d) the hydrolysis of the reaction products. Conant and Bartlett (lb) have studied the velocity of formation of various semicarbasones under controlled catalytic conditions; they paid due regard to hydrolysis velocities and equilibria. Their investigations have been extended by Westheimer (2). Hibbert (3) has studied the reaction of alpha-naphthol with methylmagnesium iodide in the presence of several different ketones. In the present investigation, the attempt is made to avoid the defects and complications inherent in many earlier studies of carbonyl reactivity by submitting pairs of carbonyl compounds to a competitive reactlion with a compound which reacts irreversibly and without catalyst to yield stable and readily assayable products. For reasons which will hereafter become obvious, each pair of carbonyl compounds investigated consisted of one aldehyde and one ketone. The reaction studied may be represented as follows:
+
10 CaHsMgBr 4- 7 RCHO 7 R’COR” --$ (10 - z - y)CsH5MgBr (7 - z)RCHO (7 - y)R’COR’’ zRCH. (CgH6)OMgBr yR‘C(C6HK)R“OMgBr
+
+
+
+
Phenylmagnesium bromide was chosen as the test reagent (a) because it does not reduce aldehydes and ketones, and (b) because its rate of reaction with carbonyl compounds is low enough to permit accurate determination of relative reaction velocities (4). The amount of secondary alcohol formed by addition of the Grignard reagent to the aldehyde, and the amount of unchanged aldehyde and ketone were determined analytically. The amount of tertiary alcohol formed by addition of the Grignard reagent to the ketone was determined by difference. The results are expressed in terms of “reactivity ratios” ( A I K ) , in which A represents the mole proportion of aldehyde, and K the mole proportion of ketone reacting. The scale of relative reactivities recorded in Table I is derived from averaged reactivity ratios by arbitrarily setting K for cyclohexanone a t 1.0. 1 This work was done in 1936 and submitted t o the Graduate School of the University of Chicago in partial fulfillment of the requirements for the doctorate degree in 1937. 46
47
REACTIVITIES OF ALDEHYDES AND KETONES
The “reactivity ratio”, aa here defined, would be expected to vary with the individual Grignard reagent employed. To bring out more strikingly the differences in reactivity, a Grignard reagent (say naphthylmagnesium bromide) which adds to carbonyl groups more slowly than does phenylmrtgneaium bromide should be used. On the other hand, with very rapidly reacting Grignard reagents, the observed differences between the reactivities af the various carbonyl groups should be less marked. This latter prediction has been verified by comparing the reiative reactivities of cyclohexanone and benzaldehyde towards both phenylmagnesium bromide and benzylmagnesium chloride. It was found that TABLE I RELATIVE REACTIVITIES OF ALDEHYDES AND KETONES WITH PHENYLMAQNESIUMBROMIDE
I
CARBONYL COMPOUND
W u T m mAcTIvIT+
Acetone Acetaldehyde Benzaldehyde Pinacolone Cyclohexanone
15.5 10.8 5.4 4.8 (1.0)
~
~
~
The reactivity ratios for the various pairs of compounds used in the competitive reaction may be found in the experimental part. 5
TAB:LE I1 RATESOF FORMATION OF SEMICARBAZONES VELOCITY CONSTANT OF P O W T I O N CARBONYL COXPOUND
Acetate (2) Buffer
Acetone Acetaldehyde Benzaldehyde Pinacolone Cyclohexanone
5.92
1
C h l o r ~ ~ (’)~ ~ t e Water (Ib) pH 7
23.2
...
...
5.1 0.41 24.9
145. 1.48 fast
6.02 301. 2.05 0.088 36.
the value (5.4) A / K for benzaldehyde and cyclohexanone with phenylmagnesium bromide, falls to about 1.5 with the more rapidly reacting benzylmagnesium chloride. It is of interest t o compare the data for the carbonyl compounds recorded in Table I with the rates of formation of their semicarbaaones as determined by Conant and Bartlett (lb) and by Westheimer (2). Acetaldehyde, which, in the semicarbazone experiments a t pH 7, is the most reactive compound tested and sixty times as reactive as acetone is, in the Grignard experiments, next below acetone in reactivity. Cyclohexanone, the second most reactive compound in semicarbaaone formation a t pH 7 and about five hundred times as reactive as pinacolone under those conditions, wasI in the Grignard experiments, the least
48
M. S. KHARASCH AND J. H. COOPER
active carbonyl compound and about one-fifth as active as pinacolone. These figures indicate a decrease in the relative reactivity of the cyclohexanone in the ratio of 1 to 2500. The results cited emphasize a point which has long been clear to many investigators. If the order of reactivity of various substances is determined by catalyzed reactions (proton, general acid catalysis, etc.) the order thus obtained need not agree with that determined by non-catalyzed reactions. Furthermore, in order clearly to bring out relative reactivities, a very slow-acting reagent should be used. Incidentally, in the course of preliminary experiments, it was found that the Michler's ketone test (5) for residual Grignard reagent is unreliable in the presence of relatively large proportions of rapidly condensing carbonyl compounds such as benzaldehyde. Further details are given in the experimental part,. EXPERIMENTAL PART
Reagents. All carbonyl compounds were carefully purified by well-established methods. Condensation products used for comparisons and for checking of analytical techniques were prepared by the same reactions used in this study: benzohydrol, b.p. 180'/20 mm., m.p. 68' ; 1-phenylcyclohexanol, m.p. 59-61' ;phenyldimethylcarbinol, b .p. 93-97'/18 mm., m .p. 29-30'; phenylmethyl-tert.-butylcarbinol, b.p. 111-114°/10 mm.; phenylmethylcarbinol, b.p. 95-98"/17 mm.; phenylbenzylcarbinol, b.p. 166-169"/10 mm., m.p. 66-67'; l-beneylcyclohexanol, b.p. 155-158"/20 mm., m.p. 53-55'. Grignard reagents were prepared by gradual addition of one-fifth mole of halide in 50 cc. of ether to 5.2 g. of high-grade magnesium turnings covered by 50 cc. of ether. The ethereal reagent was siphoned through a sintered-glass disc into a volumetric flask, made up to volume, and an aliquot withdrawn for acid titration (6). General experimental method. The Grignard reagent solution was added to a cooled and agitated solution containing an equimolecular mixture of the carbonyl compounds in such a proportion that the ratio IOG: 7A: 7K was attained. Upon conclusion of the addition, the mixture was allowed t o stand a t room temperature for the predetermined time (30 minutes or 4 hours). The mixture was then hydrolyzed, and the entire product extracted several times with ether. Assay of products. Secondary alcohols in mixtures with tertiary alcohols were determined by the acetylation method of Freed and Wynne (7). This method of analysis usually yielded results within 5% of the calculated values; in many cases, an accuracy of about 2% was readily attained. Sample determinations of secondary alcohols in known mixtures are given in Table 111. Analysis for benzaldehyde. Benzaldehyde was determined in mixtures with secondary and tertiary alcohols by the 2,4dinitrophenylhydrazine method of Ferrante and Bloom (8). The results obtained in two such determinations are given in Table IV. Analysis for pinacolone. Pinacolone was determined in the same way as benzaldehyde, save that the greater solubility of its 2,4-dinitrophenylhydrazone made the following modification necessary. The sample was dissolved in 10 cc. of methanol and tieated with 10 cc. of the precipitating agent (2,4-dinitrophenylhydrazine). After 5 hours, 10 cc. of 6 N sulfuric acid was added, and the mixture was allowed to stand overnight. The precipitate was then collected on a weighed eintered glass (100-mesh) funnel, washed first with 10 cc. of a 2 N sulfuric acid methanol mixture (one volume of 6 N sulfuric acid plus two volumes of methanol), and finally with 10 cc. of 20% methanol. The product was dried in an electric oven at 75'.
49
REACTIVITIES O F ALDEHYDES AND KETONES
COMPETITIVE REACTIONS Addition of phenylmagnesium bromide to a mixture of benzaldehyde and cyclohexanone. The addition product was hydrolyzed with an equivalent quantity of 1N acetic acid. ExTABLE I11 DETERMINATION OF SECONDARY ALCOHOLS IN MIXTURES MOLE EQUIVS. OF CALC'D
SAUPLE
Benzohydrol Phenylcyclohexanol Phenylc yclohexanol Benzohydrol Phenylcyclohexanol Benz aldehyde Cyclohexanone Benzohydrol Benzohydrol Phenyldimethylcarbinol Phenyldimethylcarbinol Benzohydrol Phenylmethyl-tert .-butylcarbinol Phenylmethyl-tert .-butylcarbinol Phenylmethylcarbinol Phenylmethylcarbinol Phenyldimethylcarbinol Phenylbenzylcarbinol Phenylbenzylcarbinol Benz ylc yclohexanol Benzylc yclohexanol
I
1
(OH)
MOLE EQUIVS. OF (OH) FOUND
% ERROR
Secondary
Tertiary
0.486
0.697
0.457
-6.0
...
1.39
0.01
+0.7
0.761
0.242
0.800
f5.1
1.15
...
1.125
-2.2
1.30
1.36
1.28
-1.5
...
2.00
0.168
+8.4
1.25
0.800
1.16
-7.2
...
1.11
...
0.002 1.58
+0.2
1.68 1.62
2.40
1.59
-1.9
1.39
...
1.31
-5.8"
-6.0
2.03
3.49
1.76
-13.3a
...
2.19
0.04
+1.8
--NO.
SAMPLE
PIE1GHTJ
--
--. 1
2 ____-
1
Benzaldehyde Benzohydrol Benzaldehyde Benzohydrol Phenyldimethylcarbinol
"
0.196
WEIGHT OF PRODUCT, G.
M.Pa PROD&P"c
% BENZALDE-
0.525
235-237
99.5
0.510
234r236
95.5
HYDE FOUND
.m .196 * 10 .30
50
M. S. KHAMBCH AND J. H. COOPER
residue in the flask was extracted with ether, and the extract dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration, and the ether by distillation on a steam-bath. The residue (containing a small amount of unchanged aldehyde and ketone, as well as the products of reaction) was weighed, and a weighed sample taken for acetylation t o determine the total yield of benzohydrol. When the remaining residue was further distilled with steam, a white crystalline solid separated in the distillate. This solid was collected on a filter, washed with water, and dried. It was then weighed and thoroughly pulverized in a mortar t o ensure homogeneity. Weighed samples were taken for acetylation, and the percentage of benzohydrol in the Polid was determined. On the assumption* that this percentage corresponds to the total yield of benzohydrol relative to the combined TABLE V GRAVIMETRIC DETERMINATION OF PINACOLONE IN THE PRESENCE OF BENZHYDROL
1
SAMPLE
1
Pinacolone
2
Pinacolone Benzohydrol
G'
1
WEIGHT OF PRODUCT, 0.
I
M.P.'OP PRODUCT,
"c
1
%PPINACOLONE FOUND
0.149
0.404
123-125
96.7
.149 .20
.408
123-125
97.8
~
E
Reported melting point 125' (10).
PUN NO.
11 12 13(*)c
NOBMALITY OF QBIGNABD SOLUTION
1.19 N 2.09 N 0.694 N
YIELD
OF ALCOHOLS"
% Secondary
% Tertiary
42.8 41.7 32.6
8.3 7.4 5.0
ymm ?&
51.1 49.1 37.6
REACTIVITY BAT10 (.4/K)b
5.16 5.65 6.52
yields of benzohydrol plus phenylcyclohexanol, the total yield of phenylcyclohexanol in the experiment was calculated. The results of the experiments are listed in Table VI. 2 That this assumption was justified was shown by determining the steam volatilities of benzohydrol and phenylcyclohexanol. Sixty to 70% recovery of pure product in the distillate was realized in each case. That the relative steam volatilities of the two compounds are approximately equal was further shown by steam distilling a known mixture of the two and subsequently determining the percentage of benzohydrol in the solid distillate. This agrees within 5% of the calculated value for the original h o w n mixture. The procedure is further justified by the fact that more than 95% of the reactants were accounted for in the competitive experiments where this method of analysis w a ~used.
51
REACTIVITIES OF ALDEHYDES AND KETONES
I n one experiment, where the mole ratio of phenylmagensium bromide t o benzaldehyde and cyclohexanone was about 1:3:3, an unusual reaction occurred. Instead of the expected condensation of the carbonyl compounds with the Grignard reagent, the aldehyde and ketone condemed with each other forming 2,6-dibenzylidenecyclohexanone (9). This condensation did not occur if the mole ratio of the Grignard reagent wm equal to or greater than 1G:lA:lK. Addition of phenylmagnesium bromide to a mixture of benzaldehyde and acetpne. The addition product was hydrolyzed with an equivalent quantity of 1 N acetic acid, and the mixture was treated with excess sodium carbonate to neutralize any excess acid. The mixture wsa then filtered, and the reeidue on the filter paper was washed several times with ether. The filtrate and washings were combined, extracted with ether, and the ether fraction dried with anhydrous sodium sulfate. After removal of the drying agent and distillation of the ether, there were left in the flask the products of the reaction plus unreacted benzaldehyde. The total residue waa weighed and then washed twice with saturated sodium bisulfite solution. The combined aqueous fraction and precipitate were washed with ether. The benzaldehyde thus recovered was determined by treating the precipitate and the aqueous fraction with excess 10% sodium carbonate solution, warming the mixture to 70-80°, extracting with ether, drying the ether extract, and finally weighing the residue after removal of the drying agent and distillation of the ether. TABLE VI1 REACTION OF BENZALDEHYDE AND ACETONE WITH PHENYLNAGNESIUM BROMIDE
~-
NOFXALITY
RUN NO
17 18
YIELD OF ALCOHOLS
OF GBIGNAABD
1
SOLUTION
% Secondary
1.69N 1.72 N 1.90N
21.6
I
% Tertiary
62.9 61.2 56.7
84.5 82.8 72.9
0.34 .35 .28
The combined ether washings and ether fraction from the bisulfite treatment were dried with sodium sulfate. After removal of the sodium sulfate, and distillation of the ether, the cooled residue waa weighed. It was then diluted with anhydrous ether to 50 cc., and 5-cc. aliquots of this solution were taken as samples t o be acetylated. Another 5-cc. portion was taken for the determination of the acid content of the solution. Finally one 5-cc. portion was taken t o determine the efficiency of the bisulfite treatment for removal of the benzaldehyde. This was tested by distilling the ether, dissolving the residue in methanol, and treating the aolution with 2,4-dinitrophenylhydrazine. No precipitate was formed. The yield of benzohydrol was calculated froin the acetylation determination, and the yield of phenyldimethylcarbinol was determined by difference. The results are given in Table VII. Addition of phenylmagnesium bromide to a mixture of benzaldehyde and pinacolone. The addition product was hydrolyzed by pouring the mixture into ice-water. The mixture waa allowed t o stand overnight, and was then decanted and filtered. The residue on the filter paper was washed several times with ether, and the combined filtrate and washings were extracted with ether. After drying the ether fraction, the drying agent was removed and the ether distilled. The cooled residue, which contained the products and the unchanged reactants, was first weighed and then diluted with dry ether t o 50 cc. Aliquots (2 cc.) of this solution were taken for acetylation and for acidity determination. This gave the yield of benzohydrol. The benzaldehyde waa: determined by the bisulfite method.8 The 8 This precaution is necessaxy to ensure tho precipitation of only the 2,4-dinitrophenylhydrmone of pinacolone in the succeeding determination. A part of the pinacolone is undoubtedly removed by the bisulfite treatment. This is not objectionable, since it is the combined weight of the recovered aldehyde and ketone which is ultimately sought.
52
M. S. KHARASCH AND J. H. COOPER
ether extract from the bisulfite treatment was dried. After removal of the drying agent and distillation of the ether, the residue was dissolved in methanol and diluted to 50 cc. Aliquots (2cc.) of this solution were diluted with methanol t o 10 cc., and the pinacolone determined by the 2,4-dinitrophenylhydrazinemethod previously described. In calculating the total recovered benzaldehyde and pinacol, a correction was made for that portion lost in the samples taken for acetylation. The yield of phenylmethyl-tert.-butylcarbinolwas calculated by difference. The results of these experiments are listed in Table VIII. IAddition of phenylmagnesium bromide to a mixture of acetaldehyde and acetone. Special precautions were taken in addition to avoid loss of the extremely volatile acetaldehyde. The addition was carried out in a 250-cc. Erlenmeyer flask immersed in ice. The flask was equipped with a trident adapter, the vertical arm of which was a mercury seal. The two side-arms accommodated a reflux condenser and a dropping-funnel. The solution of the carbonyl compounds in ether was introduced into the flask through the dropping-funnel, which was then washed with 10 cc. of ether, and the washings allowed t o run into the flask. TABLE VI11 REACTIONOF BENZALDEHYDE AND PINACOLONE WITH PHENPLMAGNESIUM BROMIDE YIELD OF ALCOHOLS
NORMALITY OF GEIGNARD SOLUTION
RUN NO.
% Secondary
1.83 N 2.00 N 1.65 N
21 22 23 (*I
I
'IELD
28.6 44.2 42.1
32.7 29.2 47.3
REACTIVITY
%
BAT10
% Tertiary
61.3 83.4 89.4
1
I
(A/K)
1.14 0.89 1.12
TABLE IX REACTION OF ACETALDEHYDE AND ACETONE WITH PHENYLMAQNESIUM BROMIDE RUN NO.
25 26 27
(*I
1
NORMALITY OF GBIGNARD SoLUT1oN
1.70 N 1.53 N 1.63 N
1
YIELD OF ALCOHOLS
o/o Secondary
29.3 33.6 30.0
1
% Tertiary
I
42.3 48.0 46.0
1
71.6 81.6 76.0
0.69 .70 .65
53.
REACTIVITI@S OF ALDICHYPES AND KETONES
from these results, the yield of phenylbenzylcarbinol was calculated. The remainder of the ether solution was then treated with sodium bisulfite in the manner previously described. Both the benzaldehyde and cyclohexanone were efficiently removed by this method, as was shown by the application of i,he 2,4-dinitrophenylhydrazinetest t o a portion of the ether fraction remaining after the bisulfite treatment. The combined weight of recovered benzaldehyde and cyclohexanone was thus determined, and the correction was applied t o the fraction used in the acetylation and acidity determinations. The yield of benzyl cyclohexanol was calculated by difference. The results are given in Table X. Sensitivity of the color test (6) f o r reactive (:rignard reagent. To each of a series of test tubes were added 0.5GC. of a 1% solution of Michler’s ketone in dry benzene plus a definite amount of a 1% solution of pure benzaldehyde in dry benzene; 0.5 cc. of phenylmagnesium TABLE X EEACTION OF BENZALDEHYDE AND CYCLOHEXANONE WITH BBNZYLMAGNESIUM CHLORIDE
-__
1
RUN NO.
NORMALITY OF GRIGNARD
I
1 1
YIELD OF ALCOHOLS
% Secondary
%b Tertiary
47.0 56.7
33.1 41.3
I
1.61 N 0.909 N
32 33
i
TOTAL YIELD
%
I
l
BEACTIVITY BATIO ( A / K )
I
1
80.1 98.0
1
1.45 1.37
TABLE X I M
5
’
S KETONE (CRAUS)
COLOR TEST
BENZALDEEYDE ( ~ ~ 4 1 1 3 ) ~
_____
~-
50:l 25:1 10:1 5:1 5:2 5:3 1:1 1:2 1:3 1:4 1:5 1:10 1:20 1:50
+ + + + + + + + (faint) -
bromide solution (about 1.5 N ) in dry ether was added. The contents were then treated with 1 cc. of water, and finally with 5 drops of :t 0.2% solution of iodine in glacial acetic acid. The appearance of a green color was considered a positive test. The results are listed in Table XI. The results given indicate that, if the mole ratio of benzaldehyde t o Michler’s ketone is 5:l or greater (corresponding t o a weight ratio of aldehyde t o ketone of 2:l or more), then the color test gives negative results, when active Grignard reagent is actually present. This failure is undoubtedly due to the fact that benzaldehyde reacts with the Grignard reagent much more rapidly than does Michler’s ketone. Hence, if the concentration of the aldehyde is sufficient, this substance may react with the Grignard reagent t o the complete exclusion of the Michler’s ketone. These considerations are of importance when the color test is applied t o a sample containing some other compound which may condense
54
M. 5. KHAFUSCH AND J. H. COOPER
with the Grignard reagent. In all such cases, the efficiency of the test must be previously checked by some other method, e.g., treatment with an ether solution of mercuric chloride. As has been demonstrated, the latter test may be positive where the color test is negative. Where the competing substance is one which reacts with the Grignard reagent at the same rate as does Michler’s ketone, or at a slower rate, then the color test is usually valid. SUMiVL4RY
1. The literature on the relative reactivities of carbonyl compounds has been reviewed and the validity of the results discussed. 2. The relative reactivities of a series of aldehydes and ketones toward the Grignard reagent have been studied. 3. The scope of the acetylation method for the determination of secondary alcohols in the presence of tertiary alcohols has been extended. 4. Satisfactory methods for the gravimetric determination of benzaldehyde and pinacolone as 2,4-dinitrophenylhydrazoneshave been developed. 5. The limitations of the Gilman color test for reactive Grignard reagents are discussed. CHICAGO,ILL.
REFEREKCES (1) For references to representative investigations see (a) MICHAEL, J . Am. Chem. Soc., 41, 393 (1919); (b) CONANT AND BARTLETT, J . Am. Chem. Soc., 64, 2881 (1932). (2) WESTHEIMER, J . Am. Chem. Soc., 66, 1962 (1934). (3) HIBBERT,J . Chem. Soc., 101, 341 (1912). (4) KHARASCH AND WEINHOUSE, J . Org. Chem., 1, 209 (1936). (5) GILMANAND SHULZE, J . Ant. Chem. Soc., 47, 2002 (1925). (6) GILXAN,ZOELLNER, AND DICKEY,J . Am. Chem. SOC., 61, 1577 (1929). (7) FREED AND WYNNE, Ind. Eng. Chem., Anal. Ed., 8, 278 (1936). AND BLOOM, Am. J . Pharm., 106,381 (1933). (8) FERRANTE (9) WALLACH, Chem. Zentr., 1, 638 (1908). (10) ALLEN,J . Am. Chem. SOC.,62,2958 (1930).
