ALDOL AND RELATED CONDENSATIONS AS A TOOL IN TEACHING ORGANIC CHEMISTRY HENKVPRICEH~wELLS, OKLAHOMA
AGRICULTURALAND MECHANICAL COLLEGE.
OKLAHOMA STILLWATER,
The large number of condensation reactions which must be studied in a course of organic chemistry are apt to burden the memory of the average student unless the instructor makes a serious attempt to correlate material in such a fashion as to simmer these condensations down to a mmparatively few types. Considerable effortin this direction has been put forth by our textbook authors, and perhaps they have resorted to speculation a t times to achieve a pedagogical end. In a similar manner here, i t is intended as a means to an end to point out possible analogies among certain reactions, and to crystallize them about "aldol condensation" as a type in order that the student may have a t least a helpful tool in his attempt to master these reactions. As in the formation of aldol from acetaldehyde, the reactions with which we are concerned appear to take place between two particular types of groups or functions, (1) a labile hydrogen atom, usually alpha to a double bonded linkage, as the so-called Vorlander hydrogen1 and (2) a more or less easily reduced unsaturated radical, usually a carbonyl group. These condensations may be considered as involving a compensating oxi-
H I H,C-C-I
0-H
H H
I I --C-C=O--+ I
H
H H H I l l H,C-C-C-C=O /
1
OH H ALDoL
It is the experience of the author that the use of the more impressive term ''Vorlander hydrogen" for an active alpha hydrogen atom is very stimulating to the student's interest in locating such atoms in particular structures. The "Vorltinder Rule" is quickly presented t o the student by writing the following series where E represents non-metallic 12 3 4 12 3 12345 elements, H.E.E:E; H.E:E; H.E.E.E:E and pointing out that the hydrogen atom in the first member has a greater reactivity than that in either the second or third members. I n the frrst ease the double bond between two E atoms lies in the 3 4 oosition t o the active hydrogen atom, just as the labile hydrogen in organic acids, phenols, imides, oximes, beta-ketonic esters, nitroparaffins, etc. If a more detailed discussion is needed here, see the original work of VorlGnder, Ber.. 34,1633 (1901). 597
598
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dation and reduction change, where group one (1) reduces group two (2) and the latter oxidizes the former. The compensating oxidation and reduction change giving rise to aldol may be represented by the mechanism illustrated by the reaction on page 597. The alpha or Vorlander hydrogen atom marked by (1) apparently reduces an aldehyde carbonyl to an alcoholic hydroxide group and the carbon atom marked by (2) is simultaneously oxidized in the sense of losing hydrogen. All aldol-like condensations may be divided here into three sub-groups; (1) the true aldol type, (2) the Claisen condensation type, (3) the Cannizzaro reaction type. True Aldol In the true aldol type the speed of reaction is often increased by a small concentration of hydroxide ion. However, a number of other catalysts may be a t times more advantageous, such as hydrogen ions, H~SOI;HCl; ZnC12; A1CI3; and Feel3. Acetone readily undergoes aldoling2 in the presence of calcium hydroxide which gives a small concentration of hydroxide ion. It is doubtful whether many of us ever have used pure acetone, since even a trace of ammonia from the air may cause some "aldoling." ACETONE
H I CH, \
-H,O
CH,
7 CH,
CH, H CH, \ I \ H C-C=C-C 3
II
When three molecules of acetone are condensed by means of concentrated HzSOa to give mesitylene, the third molecule of acetone might be considered as aldoling with an intermediate mesityl oxide molecule. a "Aldoling" is used throughout the paper far convenience only, and refers to a mechanism similar to that pictured for the compensating oxidation and reduction change giving rise to aldol on page 597. Thus the term will be used at times even when not referring to true aldol condensations.
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ALDOL AND RELATED CONDENSATIONS
599
The formation of formose from six molecules of formaldehyde using a catalyst such as barium hydroxide is anothe$classical example of aldol condensation. A much longer series of aldol condensations than that FORMALDEHYDE
H H H H H H I I -H I I I I 0 H-C H-C H-C H-C H-C H-C !IJ/
ll//
II / /
II
0
0
0
0
A/'
0 "
n H H H H H I I I I I I H-C-C-C-C-C-C I I I I I I I OHOHOHOHOH 0 in the case just cited gives rise to complex molecules of very high molecular weight, such as in bakelite and similar resins. The complex bodies may possess the same percentage composition as that of the simpler molecules.
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MARCTI, 1930
It is rather common to have aldoling between two aldehyde groups as is essentially the case in the above formation of formose. Other familiar examples of this kind are found in the furfuroin and benzoin condensation.
H
A large number of reactions involve a reactive hydrogen alpha to a double or triple bonded nitrogen atom. An example of this kind is the formation of a-ally1 pyridine from or-picoline and' acetaldehyde, which is a step in the synthesis of y-coniine.
The less familiar instances of quinaldine condensing with acetaldehyde t~:~ive or-ally1 quinoline and with phthalic anhydride to yield quinoline yellow can be shown in a similar manner to the case just given. Many other more or less common and important reactions can be represented as following the simple, compensating oxidation and reduction mechanism which is being presented. The list would be too extensive to demonstrate here, but after studying several of the following reactions as true aldol types one should then recognize other cases readily as they appear in the literature. In this study the student is recommended to first locate the reactive hydrogen, keeping in mind the Vorlander rule and the ideas of Smiles3when dealing with hydrogen present in structures a
Smiles, Tmns. Chem. Soc., 77, 160 (1900).
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601
like that of formaldehyde, ammonia, and acetylene. Smiles believes the structure demanded by the Vorlander rule is merely a reinforcing influence upon the lability of the hydrogen which already exists owing to the presence of an adjoining atom capable of showing a rise in valence. It must also be recognized early that every hydrogen in the benzene nucleus may be considered as VorlSnder atoms.
Drill Suggestions on True Aldol (1) Perkin-Fittig synthesis of unsaturated acids. (2) Skraup synthesis of quinoline. (3) Benzal and dibenzal acetone from benzaldehyde and acetone. (4) Phorone from acetone. ( 5 ) Phenylhydrazones, osazones, oximes, and semi-carbazones from aldehydes and ketones. (6) Formation of lenco-bases of various diphenyl and tri-phenyl.methane dyes, including the phthaleins. (7) Formation of Schiff bases including intermediate products. (Basic catalysts favor usually the side chain for reactive hydrogen.) (8) Dimethyl fulvene from cyclo-pentadiene 1, 4, and acetone. (Include other fulvenes.) (9) Nitro alcohols and nitro olefines from nitro methane and aldehydes. (10) Ring closure of certain dialdebydes to form polymethylene derivatives. (11) Pseudo-ionone from citral and acetone. (12) Quinaldine from a-amino benzaldehyde and acetone. (13) Quinoline yellow from quinaldine and phthalic anhydride. (14) Hoesch synthesis of ketones from certain phenols and nitriles. (15) Furfuroin from furfural. (16) Resinification of aldehydes by alkalies (accounts partially for low yields in the synthesif, of phenolic aldehydes by the Reimer-Tiemann method). (17) Inactive fructose from glycerose. (18) In general as a working hypothesis to explain the synthesis of fats in the plant kingdom and the conversion of sugars into fats in the animal body. Claisen Condensation The Claisen condensation type is essentially the aldoling in non-aqueous media of certain substances, many of which would give rise to entirely different products were the conditions for true aldol employed. The non-aqueous catalysts usually depended upon to effect the change are, (1) alcoholic sodium ethylate, (2) alcohol-free sodium ethylate, (3) metallic sodium, and (4) sodamide (freshly prepared). Among the more common reactions in this grouping are those used for producing-(1) beta-ketonic esters, e. g., acetoacetic ester, (2) beta diketones, e. g., acetyl acetone, and benzoyl acetone, (3) cyclic beta-ketonic esters from certain diacid esters4 Since the preparation of substances in the first two of the three divisions are the most familiar examples, the following graphical illustrations should "-kin
and Titley, I. Chen. Sac., 122, 1562 (1922); McElvain,
Soc., 46. 1721 (1924).
I. Am. Chcm.
602
JOURNAL OF CHEMICAL EDUCATION
MARCH,1930
be studied first, followed by a similar study of other cases found in the literature. It appears that metallic sodium or sodium ethylate might catalytically effect the aldoling of two molecules of ethyl acetate, with subsequent elimination of a molecule of alcohol.
Other esters of the aceto acetic ester type may be formed in the same manner by starting with other fatty esters, and eliminating a molecule of alcohol between the carbalkoxy group of one ester molecule and a hydrogen atom alpha to the carbonyl gtoup in the other ester molecule which is entering into the reaction. c Beta-diketones, the preparation for which Claisen's condensation was originally designed, may be formed in much the same manner as aceto acetic ester by aldoling a fatty ester with a fatty ketone, with subsequent splitting out of alcohol.
. .
-C,H,OH
r H,C-C=C-C-CH3
/ I', II OHH 0
-+
I H,C-C-C-C-CH, II I II 0 H 0
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603
Reversed Aldoling
It is interesting to note here the effect which concentrated alkali has upon aceto acetic ester types, and to interpret these well-known cases of " a c i d decomposition in the light of the present work. Usually this "acid" decomposition may be brought about by concentrated sodium hydroxide in alcohol. The mechanism of the change may be pictured as virtually "reversed ald~ling,"~ involving the addition first of a molecule of water t o the double bond or the carbonyl group depending upon whether the en01 or keto form is functioning. ACETOACETATE ETHYL
-
OHH 0 \ I II H~C-C=C-C-OC,H~
+HOH
OHH 0 \ I II H,C-C-C~C-O(C~H, / I OH'H
0 ACID C
In the acid hydrolysis of di-alkyl acetic esters the preliminaty addition of the molecule of water apparently takes place a t the carbonyl group since no en01 variety is possible.
-
DI-ALKYLAcmrc EsTEn
0 R
0
II I I1 H3C-C-C-C-OC,H, I R
+HOH
I
+HOH
OH \
H3C-C
II
+
OHR 0 \ I II ,,. H3C-C-C-C-O[C2H5 1 /I OH R
R 0 I II H-C-C-OH I
+ C2H,0H
If aldol condensation can be considered as compensating oxidation and reduction, "reversed aldol" could be looked upon perhaps as intrarnol~cularoxidationand reduction.
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MARCH,1930
"Reversed Aldoling" seems to be rather a general reaction and may be used as above in showing the decomposition of beta-diketones by alkali, as well as in explaining certain changes in terpene chemistry, such as the dealdoling of citral by refluxing i t with aqueous potassium carbonate. Illustrations of the two changes just mentioned are given below in order.
OHH 0
\ I II H,C-C-C-C-CH,/
OH H
OH 0 \ II H,C-C+ H,C-C-CH, II 0 ACETIC ACID
CITUL
ACETONE
on
There are certain cases where the "reversed aldoling" does not involve the preliminary addition of a molecule of water. An example of this kind is the splitting of lactic acid by dilute sulfuric acid into acetaldehyde and formic acid. The reaction resembles the reverse of the reaction of its formation from acetaldehyde through the cyanohydrin by aldol condensation.
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ALDOL AND RELATED CONDENSATIONS
H 0 I II H,C-C-C-OH 1 f OH'
H I
0 I1
-H,C-C+H-C-OH II . 0
LACTIC Acm
ACETALDBHYDEFORMIC Acm
The Cannizzaro Reaction The Cannizzaro reaction involves a very special type of aldoliug where two aldehyde groups mutually undergo a compensating oxidation and reduction change. The reactive hydrogen joins to the carbon of the reduced carbonyl group rather than to the oxygen atom. This reaction almost invariably runs parallel with true aldol condensations and vice versa. Some factors such as a rise in temperature of the reaction mixture and high concentration of the hydroxide ion often favor the Cannizzaro type of change. The best-known cases of this important reaction are perhaps the formation of benzyl alcohol and benzoic acid by heating benzaldehyde in the presence of a high concentration of the hydroxide ion, and the production in a similar manner of furane a-carboxylic acid and furfuralcohol from furfural. The ultimate result in the former reaction is an intermolecular oxidation and reduction, i. e., the reduction of the second molecule of benzaldehyde by the first molecule and the oxidation of the latter by the second molecule to give benzyl alcohol and benzoic acid, respectively. C
BENZALDEHYDE
-.
BHNZYL BENZOATE
H
HOH
, ,
H,C6-C-OH II 0
BENZOICAcm
Claisen,' a
I + HO-Cr-C6H, I H
BENZYLALCOHOL
Kohn and Tranton,? and Lachmann8 have demonstrated
Claisen, Be?., 20, 646 (1887). Kohn and Tranton, I. Chem. Soc., 75,1155 (1899). hchmann, I. Am. Chem. Soc., 46, 708 (1924).
006
JOURNAL OF CHEMICAL EDUCATION
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beyond doubt that benzyl benzoate is an intermediate product in the above reaction. It is possible to extract the intermediate ester by carrying the reaction out under a layer of ether. It is also possible to stop the subsequent hydrolysis and obtain benzal benzoate as the main product by using absolute alcohol and sodium ethylate. The polymerization of acetaldehyde in the presence of concentrated sulfuric acid to give paraldehyde may be shown to follow the Cannizzaro mechanism as follows.
C-H
\
o=.c
/'
\-
The depolymerization of paraldehyde may be regarded as "reversed aldoling." This particular change is brought about usually by heating with dilute sulfuric acid. I n "aldoling" and "dealdoling" it'is rather common to use essentially the same chemical catalyst, which one m i s t expect on a theoretical basis since the equilibrium of the reaction can be approached from either side. The synthesis of methyl heptenone by the method of Barbier and Bouveaults affords a unique drill exercise on the last three main points presented. The Claisen type of change is used in obtaining one of the starting materials, namely acetyl acetone which is condensed with gem-dimethyl trimethylene bromide to give an unsaturated diketoue, which on being heated with aqueous potassium carbonate takes up a molecule of water and undergoes "reversed aldoling" to give methyl heptenone and acetaldehyde. The latter substance yields acetic acid as a by-product through the Cannizzaro reaction. Further Suggestions on the More Complex Reactions
A few examples will be taken up next from the more complex chapters of general organic chemistry and analyzed in view of improving the method of presentation. First, a typical synthesis of a leuco base in the triphenyl methane group of dyes as i t appears in most textbooks on the subject is reproduced here. Barbier and Bauveault, Comfit, rend., 122, 393 (1896).
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M7
Would it not be more instructive to point out that the formation of the above leuco base involves a compensating oxidation and reduction of the true aldol type brought about usually by certain catalytic reagents? Every hydrogen in the benzene nucleus is a Vorlander atom and is particularly sensitive to labilization by acid catalysts such as H2S04,HC1, ZnCL, AICla, and FeCls. Often the para hydrogen atom in benzene derivatives seems to function more like an active alpha hydrogen than those in other positions in the ring. In dimethyl aniline i t is this para hydrogen which reduces the carbonyl group by aldoling with it. In the preparation
n
H
i------_A OH + HLC H~(cnj, 6 4
Lsuco BASEor MALACHITE GREEN
of the triphenyl methane dye, phenolphthalein, the formation of the intermediate carbinol may be represented as follows:
0-OH PHENOL
0 11
4--
+
H-
OH \
/YH40H C II
0
C II 0
I n the synthetic drug chapter one of the most important local anesthetics is 8-eucaine which is made from vinyl di-acetone amine. The reaction for the preparation of the latter substance as taken from one of the popular texts is shown as follows:
It is believed that the above reactions can be presented in a more understandable manner when interpreted as involving aldoling. Diacetonamine can be shown as forming from the action of ammonia upon mesityl oxide which is formed by aldoling two molecules of acetone as illustrated on page 598. The next step is the aldoling of acetaldehyde with diacetonamine, which is followed by a dehydration, closing the chain to a piperidone ring structure called vinyl diacetone' amine. DIACETONE ANILINE ACETALDEHYDE
*
H I
O II
H I
(nC) : c-c-c-c-H = / I NH, H
I
H
H
+ A-cn3 II
'\
*0
-
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609
No doubt, due to the use of speculation in many of the foregoing derivations, discrepancies will appear as the mechanism of certain of the discussed reactions are studied further in the light of exact research. But it is doubtful that the facts revealed in such research could be incorporated into the teaching of organic chemistry and thus serve the student to the extent that the above correlations would in minimizing his memory requirements. Artificial Atmosphere Found Better than RealVariety. Helium, the gas that makes the American non-inllamabe airships possible, may prove of value in helping submarine crews to work more efficiently, if a suggestion made recently by D. J. Willard Hershey, of McPhersan College, is adopted. Speaking before the chemists attending the recent meeting of the American Association for the Advancement of Science, be told of his study of artificial atmospheres. Some mixtures of gases, quite different from the mixture that forms the air we breathe, supported life of mice and guinea pigs even better than ordinary air, he discovered. Natural air contains 21 per cent oxygen, 78 per cent nitrogen, and 1 per cent of a mixture of gases including carbon dioxide, helium, argon, I;rypton, neon, audxenon. One series of experiments on white mice showed that a mixture of nitrogen and oxygen, in the same proportion as in air, but without the other gases, only supported life for a few days. This demonstrated that the rare gases are necessary for life. said Dr. Hershey. I n pure oxygen, the animals lived only two to five days, while a similar group of animals, also kept in a large bottle with n o d food supply, but supplied with ordinary air, suffered no ill effects whatever. With a mixture of 60 per cent oxygen and 40 per cent nitrogen, however, the animals lived as well as normally, if not better. A mixture of 79 per cent helium and 21 per cent df-ygen, practically ordinary air with the nitrogen replaced by helium, supported the life of mice in a normal manner. Using argon instead of helium and in the same proportion, the mice did not survive. Dr. Hershey pointed out that the argon mixture does not diffuse through the living cells as rapidly as natural air, while helium diffuses more rapidly. . As the heliumoxygen atmosphere is considerably lighter than air, i t would doubtless he possible for a person to live inside the gas hag of an airship containing it. However, Dr. Hershey found that a mixture of 25 per cent oxygen and 75 per cent argon supported the life of mice, and that a t the end of ten days in it, they appeared better than a t the start. "In the field of practical application of prepared atmospheres there is a wide range of commercial uses and values," said Dr. Hershey. "Medical men have a fair knowledge of the action of oxygen in the air, hut nothing is understood by them concerning the other gases. I t is quite possible that a knowledge of atmospheres may aid in the control of diseases. "In deep-sea diving, mines, and in submarines, foul air is encountered and is not sufficient in amount to sustain life. A prepared atmosphere far such activities would broaden their respective range of usefulness. An artificial atmosphere in a submarine that sustained life even more effectively than the normal air would hring about a safer and more efficient submarine. A prepared atmosphere would be of great advantage to the high altitude flyer.'' Dr. Hershey believes that the widest field of prepared atmospheres will he in the treatment of disease.-Science Snvice
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