Charles D. Hurd
Northwestern University Evanston, lllinois
Hemiacetals, Aldals and Hemialdals
This paper deals with some important concepts of aldehyde chemistry that have been too frequently ignored or unappreciated. Three terms need defining: acetal, acylal, aldal. For convenience, let C represent carbon a t the alcohol state of oxidation, C' the aldehyde (or ketone) state, and C" the acid state. From this, an acetal contains C'-O--C in its structure, an acylal C'-O--C', and an aldal C'-GC'. The term "aldal" was derived (1) from aldehydealdehyde. If C' also holds a hydroxyl group, then the classification, respectively, becomes hemiacetal, hemiacylal, and hemialdal. Aldehyde chemistry is generally thought of in terms of the carbonyl group, yet in solution this group may have changed to a greater or lesser extent by addition of the solvent. I n this way, water may give rise to an aldehyde hydrate HO-CHR-OH, methanol to a hemiacetal CHI&CHR-OH. and acetic acid to a Since compounds hemiacylal CH;CO&CHR-OH. of these structures generally are not isolahle as such from the simple aldehydes, they are sometimes disregarded in chemical reactions, whereas in many instances they are the vital intermediates. Perhaps the best known, isolahle, acyclic examples are chloral hydrate and chloral ethanolate, both crystalline substances. A lesser known example is the crystalline hemiacetal, CnH23CH(OH)-OC~2H2s, that is made simply by mixing dodecanal and 1-dodecanol(2). The hydroxyl group in the above generalized structures may react further. For example, the aldehyde hydrate may add again to the aldehyde: HO--CHR--OH+RCH=O-HO-CHR-4-CHR-OH
Quite recently, Klass (5) demonstrated the formation of such compounds as crystalline entities from heptanal,
decanal, and dodecaual. Since the ratio of aldehyde to water is 2: 1 in 2RCHO. H 2 0 they were called "hernihydrates." I t is evident from the structure, however, that they are hemialdals. Since hydroxyls are attached to both aldehyde carbons, they might be regarded as bis-hemialdals. Aldehyde polymers such as paraformaldehyde, paraldehyde, and metaldehyde are common substances with repeating aldal units. "Delrin" has these units also, in spite of its unfortunate publicity as an "acetal resin." Delrin is made by polymerizing formaldehyde and endcapping the hemialdal hydroxyls. An acylal function results if such a hydroxyl is changed to OCOCH3, and an acetal function if it is changed to OCHs: acylal aldel acetal CHI-C04-CH4-CH~~O-CH~)n-O-CH~O-CH~
The pseudo base (I) related to N-alkylpyridinium hydroxide may be regarded as a hemiacetal in the "ammonia system." I t follows logically from their classification as hemiacetals that compounds of this
type react readily with alcohol to give an "acetal" (11) or th%tthey react with themselves to give the "aldal" 111. The a- or p-hydroxy aldehydes dimerize into cyclic hemialdals, dimer IV arising from glycolaldehyde and dimcr V from aldol (4). ~~
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527
methanol no more than traces of hemiacetal are formed with a k y l or aryl ketones, most aromatic aldehydes, and most cyclic ketones (cyclopentanone, Z-methylcyclohexanone, cyclopentadecauone). Exceptions were pnitrohenzaldehyde and other aromatic aldehydes with electron-attracting substituents. Exceptions also were cyclohexanone and its 3-alkyl or Calkyl homologs. The y-hydroxy aldehydes exist primarily as cyclic hemiacetals. One such is VI, from 4-hydroxyhutanal (5). Hydration of the double bond of dihydropyran yields tetrahydropyran-2-01 (VII), a hemiacetal that
VI
VII
structure resembles chloral alcoholate in that the aldehydic carbon of both is attached to an electronpoor carbon atom, that from chloral being caused by the strong inductive effect of chlorine, and that from I X by delocalization of electrons:
Most hemiacetals are not isolable. Their existence in solution in mixtures of aldehydes and alcohols has generally been taken for granted but solid confirmatory work, based on such physical evidence as refractive indices, heats of solution, ultraviolet and infrared spectra is fairly recent. I n au important study, Melchior (9) used ultraviolet absorption data and was the first to show that aromatic aldehydes deviated from this pattern, yielding no significant amount of hemiacetals with methanol. I n confirmation, Kubler and co-workers (10) concluded that for dilute solutions in
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Journal of Chemical Education
Conversion to acetals. One of the better known reactions of herniacetals is acetal formation, by continued reaction with alcohol under conditions of acid catalysis. Protonation of either oxygen of the hemiacetal is possible:
VIII
may be regarded as a carbohydrate model, namely,. 2,3,4-trideoxypentopyranose. On heating, it changes (6) into 2,2'-oxyhis(tetrahydropyran) (VIII). This is an interesting compound to classify, since the two ring oxygen6 are part of acetal systems whereas the middle oxygen is part of an aldal system. VIII, therefore, is an acetal-aldal. Sucrose is comparable, in that the oxygen atom connecting the two C8 moieties is part of a C-(r-C aldal grouping; in contrast, the common reducing disaccharides (maltose, lactose, cellobiose) have a connecting oxygen that is part of a C-(r-C acetal grouping. Pseudostropanthidm and aldosterone (7) are cyclic hemiacetals among the steroids. Glycoses are probably the best known cyclic hemiacetals. Crystalline hemiacetals related to quaternary heterocyclic carbaldehydes have been reported recently (S), one such being IX. This
528
Reactions of herniacetals
The ouium carbon-oxygen bond in either of these structures is weak, as is true for all sigma-bonded onium structures. Detachment of Hz0 from the first structure would lead to the resonance-stabilized hybrid
and then reaction with methanol would form the acetal RCH(OCH&. Detachment of CHaOH from the second of the two structures would lead to
and then reaction with water would produce the aldehyde hydrate RCH(OH)%or the aldehyde RCHO (11). Obviously then, if acetal formation is desired, water is maintained in as low a concentration as possible. Hemiacetal chlorides. If dry hydrogen chloride is passed into an aldehyde-alcohol mixture a t 0 ' to 5" the resultant product is a hemiacetal chloride (I??). As in acetal formation, a cation intermediate is formed but it now combines with C1- which is in excess:
Generally, in practice, it is well to use such compounds without purification by distillation in view of their tendency to decompose. Obviously, the classification of these compounds as a-chloro ethers tends to conceal this high reactivity and their aldehydic nature. The reactivity of hemiacetal chlorides is pronounced. A compound of this class will react with Grignard reagents, for example, to give good yields of ethers: Such a reaction succeeds even with carbohydrate hemiacetal halides, as in the conversion of tetra-0-acetyl-aD-glucopyr&nosyl chloride into 1-0-C-phenyl-1,s-Danhydroglucitol (IS) by reaction with an excess of phenylmagnesium bromide.
Simple hemiacetal chlorides absorb ketene in the presence of zinc chloride to yield an acyl chloride (14):
The zinc chloride assists in the removal of C1 and sets the stage for production of a carbonium ion:
Hemiacetal chlorides.undergo halogenation at position 2 in the same manner as aldehydes to which they are related:
As before, this dihalide is reactive toward Grignard reagents but only the halogen at position 1 reacts. The other halogen atom is quite unreactive. The If R = H, the product is RCHBF--CHR'-OCHp. above steps are the critical ones in the Swallen-Board synthesis (15) of or-olefins. The final step is eliminaBrZnOCH3. tion by zinc dust, yielding RCH=CHR1 In a variation of this theme, Lauer and Spielman (16) treated the 0-bromo ether, formed as above, with powdered KOH to produce unsaturated ethers:
+
RCHB-CHR'4CHa
+ KOH
-
RCH=CRU-OCHs
Although powdered KOH did effect elimination satisfactorily, this stringent requirement emphasizes the great difference in reactivities between the 0-halo ethers and the hemiacetal halides. Cannizzaro reaction. In this well known reaction, the anion of an aldehyde hydrate or the anion of a hemiacetal is the initiating species. This would in-OH, or CH30CH2 clude HOCH-0from CHFO -0- from CH30CH20H -OCHa, or HOCHPh-Ofrom PhCH=O -OH. Such an anion adds to another molecule of aldehyde, prior to shift of a hydride ion:
+
+
+
As usually performed, the aqueous medium promotes hydrolysis to methanol and formate ion. Oxidation of primary alcohols lo esters. The customary laboratory preparations of acetaldehyde and propionaldehyde (17) involve oxidation of ethanol or 1-propanol by aqueous chromic acid under conditions wherein the aldehyde is removed as formed. It is difficult to adapt this approach to the synthesis of higher aliphatic aldehydes since they cannot be distilled away without removing the reagent alcohol as well.
Secondary alcohols are smoothly oxidized to ketones by Cr (VI). This chromic oxidation has been developed by Bordwell and Wellman (18) into a useful, qualitative means of distinguishing primary and secondary alcohols from tertiary alcohols. Discussions of these oxidations of primary alcohols in text books quite generally stipulate that the steps go from alcohol to aldehyde to acid. This is amazing for it is wrong, and evidence has been available to cast doubt on it for many years. Instead, the steps are alcohol to aldehyde to hemiacetal to ester. Milas (19) seems to have been the first to recognize the intermediacy of hemiacetals. In 1928 he observed that about the same yields of esters resulted by starting with the primary alcohol or with the appropriate acetal. He suggested that in the acid medium the acetal first hydrolyzed to the hemiacetal and then underwent oxidation to ester. . Powerful supportiug evidence came in 1932 from the carbohydrate field where it was established (20) that D-glucopyranose underwent oxidation by buffered (BaCOa) bromine water to produce 6-D-gluconolactone, a cyclic ester. The original 6-membered ring of the cyclic hemiacetal remained 6-membered in the lactone. If D-gluconic acid had been formed first the resulting lactone would have been y-~-gluconolactone. Unfortunately, the significance of this observation was not appreciated by organic chemists generally. A few years later, Schulz (%I)reported a 32% yield of decyl decanoate from 1-decanol and chromic acid. The most convincing evidence involving noncyclic compounds was supplied by W. Masher (22) in 1953. He treated 1-butanol in 70% acetic acid with chromium trioxide. Butyl butyrate was formed in 60% yield, without appreciable formation of butyl acetate. 111 contrast, a mixture of acetic and butyric acids caused esterification of 1-butanol to the two esters, butyl acetate and butyl butyrate, in 64 and 4% yields respectively. By rate studies it was demonstrated that primary aliphatic alcohols consume the oxidant as fast. as the corresponding aldehydes consume it, a result contrary to the generally prevailing opinion that aldehydes are the faster by far. The same type of evidence was offered in 1960 by Cymerman-Craig and Horning (23). It included the'observation that benzyl alcohoI is oxidized by Cr (VI) only to benzaldehyde hut no further. This is an interesting consequence of the fact that benzaldehyde does not form hemiacetals. Westheimer (64) has made a rigorous investigation of the mechanism of oxidation of isopropyl alcohol by Cr (VI). The initial, reversible step is production of a chromic ester. This is followed by a slow step wherein there is concurrent attack a t a proton held by the orcarbon by a base (water) and elimination of the anion -Cr08H a t the Cr (IV) level.
Then Cr (IV) disproportionates into Cr (111) and Cr (VC. The above treatment is for a secondary alcohol, hut it seems safe to assume that a primary alcohol would Volume 43, Number 10, October 1966
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change into an aldehyde by an identical mechanism. If the aldehyde can now change to its hemiacetal, it is reasonable for the same mechanism of continued oxide tion to hold: RCH,OH
- RCHO
.RCH--OH CrO, I +
Adaptation of the above reasoning provides an explanation for the report by Morrison (25) that Cr03 in aqueous sulfuric acid serves well as a means of distinguishing aldehydes (dissolved in acetone) from ketones, and also for distinguishing aliphatic aldehydes from aromatic aldehydes. Here it would be the aldehyde hydrate rather than the hemiacetal that would react initially with Cr03. The product would be a chromic hemiacylal rather than a chromic ester. Furthermore, since the aldehyde hydrate was the starting point, the final product would be the acid, not the ester.
RCHO
-
H-OH, RCH-OH
I
OH
1 7 r
+
R-C--0-Cr0,H
I
-
OH
Benzaldehyde should be sluggish toward any addition of water, in line with its almost nonreaction with methanol. It should be much delayed, therefore, in forming any chromic hemiacylal. This explains the very slow oxidation rate of benzaldehyde that was observed. Since p-nitrobenzaldehyde forms a hemiacetal readily with methanol, it should also form the aldehyde hydrate readily. Hence, one may predict that this aromatic aldehyde should respond to the test about as fast as the aliphatic aldehydes. In passing, it is pertinent to mention that the pseudo base (I) is readily oxidized to a lactam
This formation of an amide from a hemiacetal in the LLarnrnonia system" is quite analogous to the formation of an ester from a conventional hemiacetal. Synll~esisof pyridine from aldehydes. Chichihabin (26) discovered that pyridine and 3-picoline could be made, although in poor yields, by passing a mixture of acrolein, acetaldehyde, and ammonia over an alumina catalyst at 370°, or by passing formaldehyde diethyl acetal, acetaldehyde, and ammonia over the same catalyst. Cislak and Wheeler (227) showed that industrially satisfactory yields of pyridine (35% yield) plus 3picoline (27% yield) were obtainable by passing a mixture of 45% aqueous formaldehyde, acetaldehyde (or acetylene), methanol, and ammonia in molar ratios, 530
/
respectively, of 1, 1.5, 1, 2.4 a t 500" over a fluid bed, aluminscsilica catalyst. Without methanol as a reagent, the yields of pyridine and picoline were low. All of the pyridine presently sold by Reilly Tar and Chemical Corp. is obtained in this way rather than from coal tar fractions. Cislak and Wheeler recognized in their patent that the methanol gave rise to formaldehyde methyl hemiacetal, but they mentioned that they were unable to explain why this should cause such a major improvement in yields. There does seem to be a logical explanation for the increased yield, and this will be given later on; but first, let us consider the steps without the methanol that lead to pyridine and 3-picolime. Essentially, an acid-catalyzed condensation of the aldehydes is involved, aluminesilica being the acid. I t was C. L. Thomas (28) who first pointed out that alumina-silica was quite acidic for vapor phase reactions. Pines and co-workers (29) have greatly extended the concept that acid sites exist on alumina catalysts. In the following presentation this "acid" will be simply shown as a proton, H+. I n Step 1, vinyl alcohol is obtained through protonation of acetaldehyde, then deprotonation.
Journol of Chemical Education
In Step 2, formaldehyde is protonated to form a reactive carbonium complex. The position of equilibrium may he far on the neutral aldehyde side in view of the weakly-bound proton to the onium oxygen as well as the high temperature of the operation.
The same conclusion is reached if formaldehyde hydrate is taken as the substance to be protonated (Step 2a). Here the weak oxonium-carbon bond is broken a t the high temperature, yielding again the car-
+ bonium residue CHzOH that deprotonates into CHI= 0.
In Step 3, acrolein is formed by condensation of the products of Steps 1 and 2.
In Step 4, acrolein undergoes protonation. This carbonium complex may condense with either scrolein (Step 4a) or with vinyl alcohol (Step 4b). On reaction with ammonia the former yields 3-picoline and the latter yields pyridine.
viously given. Since the carbonium ion from Step 2b is essential for the successful continuation in Steps 3 and 4 it is evident that the hemiacetal has made this possible. CH,
S t e p 4a.
-I
CHi-CH-CHL
I CH=CHs I I CHO CHO CH,
CH,
-
+
I
-H+
CHO
I
CHO
CH2-C=CHs
I
I
Literature Cited (1) Hum, C. D., (1938).
AND CAMPBELL, C. R., J. Am. Chem. Sac., 76, 4472 (1954). (3) KLLSS,D. L., et al., J. 0 ~Chem., . 28, 3029 (1963). (4) H u m , C. D., Ann. Reu. Bioehem., 14, 107 (1945). W. H., JR., J. Am. Chem. Soc., (5) H u m , C. D., AND SAUNDERS,
(2) ERICKSON, J. L. E.,
-
CH, CHO
I
CHQ
CANTOR, S., J. Am. Chem. Sac., 60, 2678
AND
74. . 7 5214 ---- 11Q52)~ (6) PAUL,R., Bull. Soe. Chim., [5] 1,971 (1934). (7) KWOTA,T., AND EHRENSTEIN, M., J. Org. Chrm., 29, 342 (1964); BARTON,D. H. R., AND BEATON, J. M., J. Am. C h m . Soc., 83, 4083 (1961). STEINBERG. G.. POZIOMEK. E. J.. AND HACKLEY, B. E., JR., (81 , J. 079.them'., 26,368 (1961). (9) MELCHIOR, N. C., J. Am. Chem. Soc., 71, 3651 (1949). (10) KUBLER,D. G., ~ L N DSWEENEY, L. E., J . 079. Chem., 25, 1437 (1960); BELL,J. M., KWLER, D. G., SARTWELL, P., AND ZEPP,R. G., J. 079.Chem., 30,4284 (1965). (11) O'GORMAN, J. M., AND LUCAS,H. J., J. Am. ChWll. Soe., 72, 5489 (1950); SEIPP, K. G., AND HILL, M. E., J . 079. Chem., 31, 853 (1966). (12) SHOEMAKER, B. H., AND Boom, C. E., J. Am. Chem. Sac., 53, 1505 (1931); H u m , C. D., AND GREEN,F. O., J. Am. Chem. Sac., 63, 2201 (1941). W. A,, J. Am. C h m . Soe., 67, (13) H u m , C. D., AND BONNER, 1972 (1945); HURD,C. D., AND MILES, H. T., J. Org. Chem., 29, 2976 (1964). (14) BLOMQUIST, A. T., HOLLEY,R. W., AND SWEETING, 0 . J., J. Am. Chem. Soc., 69, 2356 (1947); HURD,C. D., AND KIMBR~UGH. R. D. JR., J . Am. Chem. Soc., 82, 1373 (1960). (15) SWALLEN, L. C., AND BOORD,C. E., J. Am. Chem. Sue., 52, 651 (1930); DYKSTRA, H. B., LEWIS,J. F., AND BOORD, C. E., J. Am. Chem. Sue., 52,3396 (1930). (16) LAUER,W. M., AND SPIELMAN,M. A,, J. Am. C h m . Sac., 53. 1533 (1931). . . (17) "Organio Syntheses," John Wiley & Sans, New York, 1943, CON.Vol. 11, p. 541. F. G., AND WELLMAN, K. M., J. CHEM.EDUC., (18) . . BORDWELL. 39,318 (i962). (19) MILLS,N. A,, J. Am. Chem. Soc., 50, 493 (1928). (20) ISBELL,H. S., J. Res. Nail. Bur. Std., 8, 615 (1932). (21) SCKULZ, L., Ann. Rept. E s s a . Oils, Synthetic Perfumes, Inc., Schimmel and Co., 119 (1938). \----,-
.
'
CH,--CH,
CH=C
I
I
SCH
CH, CHO
\\CH-N %// + 2 H f i + 2 H
I
&HO
With these steps in mind, now it is pertinent to ask why the yields of pyridine and 3-picoline are increased so markedly if methanol is included as a reagent. It is suggested that the methanol functions in Step 2, with the methyl hemiacetal available for protonation (Step 2b). Step 2b.
H*
HOCH,OCH,
+
HD,--CH?OCH3
-
-H1O
+
CH20CHa
t
This step gives rise to a resonance-stabilized methylated
+ oxonium ion, CH---=CHb that should have considerably greater thermal stability than its hydrogen
+
counterpart, CHzO-H, of Step 2a. For the cation of 2b to decompose into formaldehyde, it would require scission into a methyl carhonium ion, and this seems relatively improbable. Hence step 2b provides a much
+
higher concentration of the carbonium ion CHzOCHs
+ than appears for CH,OH in step 2a. Acrolein is produced in Step 3 as before, but with the elimination of methanol:
+
Step 3. CHnOCH,
+ CHdHOH
f CHZ-CHZ-CHOH
AmI
-
-CHsOH
-----t
-Hi
CHe=CH-CHO
Steps 4a and 4b would be identical to the ones pre-
(22) MOSHEB,W. A,,
AND
PREISS,D. M., J . A n . Chem. Soc.,
75, 5605 (1953). (23) C-ERMAN, CRAIGJ., AND HORNING, E. C., J. Org. Chem., 25, 2098 (1960). (24) WATANABE, W., AND WESTHEIMER, F. H., J. Chem. Phys., 17, 61 (1949); WESTHEIMER, F. I
