Aldehydes and Ketones
On Acetals and Hemiacetals
Last updated: February 3rd, 2021 |
(Part VI on a series of posts on the reactions of neutral nucleophiles with carbonyl compounds)
When I started this series on reaction mechanisms of carbonyl compounds, it was in an effort to justify a little statement I made on the side of this summary sheet. I said that by understanding just 6 mechanistic steps in detail, you can understand greater than 95% of the 110 reactions on the sheet. Today, in the penultimate post in this series, I’m actually not going to introduce any new concepts, because all the reactions have been talked about before. The only thing that is changing here is the identity of the nucleophile and the electrophile.
On the left is what is probably the most well-known hemiacetal there is: glucose. Glucose can also be drawn as a straight-chain aldehyde, but the reaction between the C-5 hydroxyl and the C1-aldehyde to form the 6-membered ring is so favorable that there is only a miniscule (~0.003%) amount of the aldehyde is actually present in solution. Still, the aldehyde is present in a high enough concentration that treatment of glucose with a reducing agent like NaBH4 will eventually completely reduce it to the alcohol,
hence its classification as a reducing sugar. Now, when you treat a hemiacetal with an alcohol in the presence of acid, the effect is to exchange OH for OR. The group on the right there is called an acetal (sometimes you’ll also see it called a ketal).
Let’s start with a discussion on how hemiacetals form. It’s essentially just a [1,2]-addition of an alcohol to an aldehyde or ketone. The C=O π bond breaks, and we’re left with a tetrahedral compound. Like all [1,2]-additions to carbonyls with neutral nucleophiles, the reaction is faster in the presence of an acid, but it’s not an absolute requirement here: hemiacetals form quite nicely under neutral conditions. Thus, you can draw it via the neutral pathway or through the acid-catalyzed pathway:
However, in order for a hemiacetal to reach full acetal-hood, there is no getting around the requirement for a painful initiation ritual: it must be subjected to treatment with acid to undergo further reaction. As we’ve seen before in imine formation and in the Fischer esterification, protonation of the hydroxyl group of the hemiacetal transforms a poor leaving group (hydroxyl – the conjugate base of water, pKa = 15.7) to an excellent leaving group (water – the conjugate base of hydronium ion, pKa = -1.7). This 17-orders of magnitude increase in the leaving group ability allows for the lone pair of oxygen to expel water from the carbonyl carbon in a 1,2-elimination reaction, leading to the formation of the highly reactive oxonium ion. [note again – positively charged species tend to end with -ium]. Just like with protonated carbonyls, the oxygen of the oxonium ion is positively charged, meaning that the C=O π bond is significantly weaker than in a neutral carbonyl. Thus, the highly electrophilic carbon is able to combine rapidly even with weak nucleophiles like alcohols, leading to a highly facile 1,2 addition.
Now since we’re interested in isolating the neutral product, not its protonated version, the final step is simply a deprotonation.
So to summarize, the 6 steps (5 if you make the hemiacetal through the neutral pathway) are: protonation, 1,2-addition, proton transfer, 1,2-elimination, 1,2-addition, and a final deprotonation. 6 steps – but if you’ve been following this series, it’s just the same old reactions, over and over. The lyrics change, there are subtle differences in tone, but it’s essentially the same song.
Again, this is an equilibrium reaction, so all the steps are reversible. To go from the acetal back to the aldehyde or ketone, one simply heats the acetal in aqueous acid. As with all equilibrium reactions, Le Chatelier is king: you get out of it what you (don’t) put into it.
In the next (and last) installment of this series, I’ll talk about the reaction that is probably the most involved you will ever be asked to draw: the acid-catalyzed aldol condensation. A 7-step beast that actually includes some (kind of) new reactions! And then I can put this series to rest.
- Darstellung der Acetale
Emil Fischer and Georg Giebe
Ber. 1897, 30 (3), 3053
One of the earliest references in the chemical literature on acetalization reactions, by the legendary chemist Emil Fischer.
- —The direct acetalisation of aldehydes
Robert Downs Haworth and Arthur Lapworth
J. Chem. Soc., Trans., 1922, 121, 76-85
Haworth and Lapworth are both great chemists in their own right, and in this paper they describe the synthesis of acetals of a variety of common aldehydes (e.g. cinnamaldehyde, anisaldehyde, citral, and others). This chemistry is of significance in the fragrance industry – a lot of aliphatic aldehydes have pleasant odors, but are not stable in either acid or base. The development of methods to protect aldehydes that can maintain their odor and structure is therefore commercially significant.
- Methods for the Preparation of Acetals from Alcohols or Oxiranes and Carbonyl Compounds
Frans A. J. Meskens
Synthesis 1981; 1981(7): 501-522
Review on acetal-forming reactions with a variety of references.
Homer Adkins and B. H. Nissen
Organic Syntheses, Vol. 1, p.1 (1941); Vol. 3, p.1 (1923)
An early procedure in Organic Syntheses for the preparation of acetaldehyde diethyl acetal. This reagent can be used as a convenient, easier-to-handle, less volatile source of in situ acetaldehyde.Acetal Hydrolysis:
- Mechanism and catalysis for hydrolysis of acetals, ketals, and ortho esters
G. H. Cordes and H. G. Bull
Chemical Reviews 1974, 74 (5), 581-603
A review on the work that had been done up to that point on determining the mechanism of acetal hydrolysis. Several studies point to carbocation formation as the rate-determining step.
- Acid-catalyzed Hydrolysis of Acetal and Chloroacetal
Maurice M. Kreevoy and Robert W. Taft Jr.
Journal of the American Chemical Society 1955, 77 (11), 3146-3148
This paper demonstrates the relationship between the rate of hydrolysis and the Hammett acidity (Ho) of the solvent, a general acidity function. This gives further support for the hypothesis that carbocation formation is the rate-determining step.
- Trapping of the oxocarbonium ion intermediate in the hydrolysis of acetophenone dimethyl ketals
P. R. Young and W. P. Jencks
Journal of the American Chemical Society 1977, 99 (25), 8238-8248
In this paper, the oxocarbonium ion formed during acetal hydrolysis is trapped with bisulfite ion, establishing that it is indeed an intermediate in the reaction.
- Effect of Alkyl Group Size on the Mechanism of Acid Hydrolyses of Benzaldehyde Acetals
Alexanders T. N. Belarmino, Sandro Froehner, Dino Zanette, João P. S. Farah, Clifford A. Bunton, and Laurence S. Romsted
The Journal of Organic Chemistry 2003, 68 (3), 706-717
This paper suggests that the mechanism of hydrolysis changes from specific-acid catalyzed (by H+) to general-acid catalyzed depending on the acetal structure.
- General acid catalysis in the hydrolysis of 1,3-dioxolanes and 1,3-oxathiolanes. The hydrolysis of acetals and thioacetals of p-(dimethylamino)benzaldehyde
Thomas H. Fife and R. Natarajan
Journal of the American Chemical Society 1986, 108 (9), 2425-2430
- General acid catalyzed acetal hydrolysis. The hydrolysis of acetals and ketals of cis- and trans-1,2-cyclohexanediol. Changes in rate-determining step and mechanism as a function of pH
Thomas H. Fife and R. Natarajan
Journal of the American Chemical Society 1986, 108 (25), 8050-8056
These two papers demonstrate that as expected, the mechanism of acetal hydrolysis varies with pH.
- General acid catalysis of acetal, ketal, and ortho ester hydrolysis
Thomas H. Fife
Accounts of Chemical Research 1972, 5 (8), 264-272
An account by Prof. Fife on his work relating to the mechanisms of acetal hydrolysis.