Aldehydes and Ketones
Hydrates, Hemiacetals, and Acetals
Last updated: September 25th, 2022 |
Hydrates, Hemiacetals, and Acetals – Their Formation From Aldehydes/Ketones, And Mechanisms That Are As Easy As P-A-D-P-E-A-D
Hydrates, hemiacetals and acetals are the products of addition reactions of oxygen-based nucleophiles (water and alcohols) to aldehydes and ketones
- A hydrate contains a carbon with two single bonds to OH.
- A hemiacetal contains a carbon with a single bond to OH and a single bond to OR (where R is a carbon group)
- An acetal (sometimes called a ketal if originating from a ketone) contains a carbon with two single bonds to OR groups.
Hydrates and hemiacetals are in equilibrium with their respective aldehydes and ketones.
Unlike hydrates and hemiacetals, acetals are “locked”, and are not in equilibrium with their corresponding aldehyde/ketone. For this reason, acetals are useful protecting groups for aldehydes/ketones.
Thiols can be used in place of alcohols to make thioacetals. The most common reaction of thioacetals is their reduction with Raney nickel to give the corresponding alkanes.
Table of Contents
- Hydrates – Their Formation and Mechanism
- Hemiacetals – Formation and Mechanism
- What about Intramolecular Hemiacetal Formation?
- Formation of Acetals From Hemiacetals
- Formation of Acetals From Aldehydes and Ketones -As Easy As PADPEAD
- Cyclic Acetals
- Reactions of Acetals
- Acetals as Protecting Groups
- Thioacetals (and their Reactions)
- Quiz Yourself!
- (Advanced) References and Further Reading
Hydrates, hemiacetals, and acetals. What are they, how are they formed, what are their properties, and most importantly – why should you care?
Let’s start with hydrates, which are the simplest . They happen to be the one example of the three you should care the least about, but hey – they’re illustrative!
Note the carbon attached to two OH groups. In the reaction between the aldehyde and water, a new C-OH bond has formed and a C-O pi bond has been broken. Another way of saying this is that net addition of H2O has occurred across the C=O bond.
Hydrate formation is generally reversible, and in any solution containing a hydrate there will be an equilibrium between the starting aldehyde or ketone and the hydrate product. Equilibrium generally (but not always, Note 2) favors the starting aldehyde or ketone.
Hydrates are relatively stable in solution but are difficult to isolate in their pure form. Once solvent H2O is removed, equilibrium tends to favor reversion back to the starting aldehyde/ketone. [Note 3 – This is classic “Le Chatelier”]
Hydrates can be formed under neutral (H2O), basic (NaOH/H2O) or even acidic (H3O+) conditions.
The simplest mechanism for hydrate formation is under basic conditions (e.g. NaOH / H2O). It consists of
1) addition of the nucleophile (HO- ) to the carbonyl carbon [forming C-OH, breaking C-O (pi)] followed by
2) protonation of the oxygen (form O-H).
If this mechanism looks familiar, it should! Astute readers may note that this is exactly the same as the classic “2 step” mechanism we recently explored for aldehydes/ketones shared by at least 7 other prominent reactions (reduction, Grignard addition, cyanohydrin formation, etc) – addition followed by protonation.
Under acidic conditions the mechanism is slightly longer since we have to account for an extra proton transfer step. One way to draw it is to start with 1) protonation of the aldehyde/ketone oxygen with acid, followed by 2) addition of H2O, and then 3) deprotonation of H2O with mild base.
Basic conditions [RO– , ROH] provide another example of the classic “two-step” addition-protonation mechanism so common to these functional groups (addition of RO(-) followed by protonation).
As with hydrates, the mechanism under neutral or acidic conditions requires an extra proton transfer step.
One way to draw the mechanism for formation under acidic conditions is 1) protonation of the aldehyde / ketone oxygen with acid, followed by 2) addition of neutral alcohol, and then 3) deprotonation of the oxygen with weak base.
Equilibrium generally favors the starting aldehyde/ketone. Likewise, isolation of pure acyclic hemiacetals is often difficult since removal of solvent generally leads to loss of the alcohol and restoration of the starting aldehyde / ketone. On the other hand, cyclic hemiacetals tend to be considerably more stable. [See post: Ring-Chain Tautomerism]
We’re still forming C-O, breaking C-O (pi), and forming O-H. That’s it. All that’s different is that the OH and the carbonyl are connected through a carbon chain. It takes some getting used to, but as I often tell my students, it’s conceptually no more different than the loop that results when you put a “nucleophilic” belt-buckle pin through an “electrophilic” belt notch.
If they can combine to form a 5- or 6-membered ring (i.e. reasonably free of ring strain) equilibrium will generally favor the cyclic form. Most simple carbohydrates exist predominantly as cyclic hemiacetals. For example, in water at 25° C, a solution of glucose contains less than 1% of the open-chain form at any given time! Likewise, fructose and ribose (and many other sugars, besides) are usually drawn as cyclic hemiacetals.
Even if equilibrium strongly favors the cyclic hemiacetal (often the case with 5- and 6-membered rings) there will always be a small concentration of the hemiacetal in its linear (“acyclic”) form with the parent aldehyde/ketone. This behavior goes by the fancy name of ring-chain tautomerism .
If you continue on to the chapter on carbohydrates later in Org 2, you will learn that this is also responsible for the property of mutarotation in sugars whereby the optical rotation of a solution of certain forms of glucose can change over time.
The reversibility of hemiacetal formation in solution also means that despite their appearances, cyclic hemiacetals have the same reactivity as the parent aldehyde/ketone since the two forms are interchanging rapidly in solution.
A carbon that is single-bonded to two OR groups is generally referred to as an acetal. (The term “ketal” also gets used to describe acetals originating from ketones, but we’ll stick with “acetal” here). [Note 4]
So how are they made?
If hydrates and hemiacetals are made through the net addition of H2O and ROH across a C-O pi bond, respectively, you might note a dilemma here.
There’s no C-O pi bond to add our second equivalent of ROH across!
The hemiacetal needs a kick in the pants!
Now, if we add (anhydrous) acid, we’ll end up protonating the OH group to give H2O+ . [Note 5 – why doesn’t OR get protonated here?] As we’ve seen many times before, the conjugate acid is a better leaving group. This sets up the second-most important mechanism of carbonyls, elimination of a leaving group to form a new C-O pi bond where the O bears a positive charge. [Note 6 ].
Now we have a C-O pi bond that we can add our second equivalent of ROH across.
Addition of ROH, followed by deprotonation, gives us our neutral acetal.
So how does that work?
- Conversion of an aldehyde/ketone to a hemiacetal (under acidic conditions),
- Conversion of a hemiacetal to an acetal
We’ve already covered both of these steps! So all we’re going to do here is put everything together into one extended sequence.
In the chemistry of carbonyls (like aldehydes and ketones) there’s a lot of repetition of just a handful of mechanistic steps. So you might find it helpful to abbreviate some of these steps as P (protonation) D (deprotonation) A (addition) and E for (elimination) because this will help you remember the mechanisms more easily.
Going from an acetal to a hemiacetal is P A D. The first step is protonation of the aldehyde, followed by addition of the alcohol nucleophile, and deprotonation of the oxygen to give the neutral hemiacetal.
Note that I drew in tosic acid (TsOH) as the acid catalyst here, but more often than not, a simple H+ will be sufficient here.
Going from the hemiacetal to the acetal is P E A D. The OH is protonated, followed by elimination of water, addition of the second equivalent of the alcohol, and then deprotonation to give the neutral hemiacetal.
So putting everything together we get P A D P E A D, which is a pretty easy mnemonic to remember.
[One note – one common shorthand term for Protonation-Deprotonation (or its converse D-P) is “proton transfer”. In upper level courses it’s not uncommon to omit drawing out the protonation-deprotonation steps and just wave The Magic Wand Of Proton Transfer. because, let’s face it, life is short]
One important thing to note about acetal formation is that every step is potentially reversible. This presents us with a small dilemma. If we want to make the acetal, for example, how can we drive the equilibrium towards the desired product?
The first consideration for driving the equilibrium forward is to use a large excess of ROH relative to the molar equivalents of H2O that are formed. The second consideration, which can be used in combination with the above, is to employ some kind of a drying agent (dessicant) that will react with any H2O is formed, or to sequester H2O in a Dean-Stark trap.
[H. Adkins and B. H. Nissen, Org Syn Coll. 1. Page 1. ]
There’s another wrinkle in acetal formation that deserves mention, especially as it seems to make its way on to a lot of exams.
In all of our examples up to this point, we’ve used “ROH” where it’s assumed that R is a short-chain alkyl group of some sort (e.g. CH3OH, CH3CH2OH).
So how does this work?
It’s really no different than the intermolecular case. The bonds that form and break are the same. The mechanism is the same. It’s still P A D P E A D. That said, here’s a link to the image if you need to see it for yourself.
BTW, there is a second possibility for making a cyclic acetal that is great exam question fodder. It requires a molecule that contains a ketone and two hydroxyl groups. Adding acid makes it wrap up into a tidy little bow. See Note 8 for details.
So what kinds of reactions do acetals undergo? As it turns out, not much.
Not so with acetals.
Once formed, acetals are “locked” into place and are not in equilibrium with their parent aldehyde/ketone. They’re solid as a rock under basic and neutral conditions. NaBH4, LiAlH4, Grignard reagents, organolithiums, PCC, you name it. Acetals are impregnable.
Like ethers – another contender for the “Most Boring Functional Group” award – acetals pretty much undergo only one reaction. When treated with aqueous acid, they can be hydrolyzed back to the starting aldehyde/ketone.
That’s it. You’ve seen all the reactions of acetals you need to see.
So how does this work? Let me spoil the suspense and tell you that it is some combination of P, D, E, and A.
[Actually if you know that 1) aldehyde → acetal is PADPEAD, and 2) P and D are inverse reactions, as are A and E, then you can figure out in advance what the mechanism for acetal → aldehyde is. Note 9. ]
OK. We start with an acetal and add aqueous acid. The first step is Protonation. This gives us the good leaving group ROH, which is displaced by an Elimination to give a new C-O pi bond. The C-O pi bond undergoes Addition of water, and the oxygen is converted to its neutral form through Deprotonation. Then, Protonation of the other OR group gives us ROH, which undergoes Elimination to give the protonated aldehyde. Deprotonation gives us the neutral aldehyde.
Although an aldehyde is depicted here, it also works for ketones.
To get the reaction to go to completion, it’s necessary to use a large excess of water, which drives the equilibrium towards the final product.
As we saw with alcohols, it provides us with a way of putting the chemical equivalent of “painter’s tape” over a reactive functional group while we fiddle around with a different functional group on the other side of the molecule, content in the knowledge that it won’t interfere with our machinations.
For example, trying to make a Grignard reagent on a molecule that has an aldehyde or ketone is a no-go. As soon as the Grignard is formed, it will react with the aldehyde or ketone, giving us a big “BFM” to write in our lab notebook.
However, if we first protect the ketone as an acetal, then convert it into a Grignard reagent, we can Grignard it up as much as we want without fear that the ketone will be destroyed. After we’re finished Grignarding, it’s a simple matter to then treat the resulting product with aqueous acid, liberating the ketone, unscathed.
As is often the case, many reactions of OH groups translate pretty well when you move down the periodic table to SH, only things get a lot smellier.
By treating an aldehyde or ketone with 1,2-ethanedithiol (the di-thiol equivalent of ethylene glycol) and a Lewis acid like BF3 (plain old H+ doesn’t work as well when sulfur is involved) one can make a thioacetal.
Thioacetals are perfectly serviceable protecting groups. However, they have one interesting feature that ordinary acetals lack.
By treating a thioacetal with Raney Nickel, one can effectively “delete” the thioacetal, replacing the C-S bonds with C-H bonds (Raney nickel is a finely divided nickel-aluminum alloy that contains adsorbed hydrogen).
Along with the Wolff-Kishner and Clemmensen, it’s a nifty trick for getting rid of troublesome carbonyl groups and converting them to alkanes, a key component of the great Friedel-Crafts Workaround, by the way.
So what have we learned?
- Water and alcohols can add to aldehydes and ketones to give hydrates and hemiacetals. The equilibrium generally favors the aldehydes/ketones but cyclic hemiacetals are pretty stable.
- Still, cyclic hemiacetals behave like aldehydes/ketones as far as reactivity is concerned, since they’re in equilibrium
- Treating a hemiacetal with acid and an alcohol will convert it to an acetal
- Treating an aldehyde or ketone with an alcohol (or a diol) plus acid will convert it to an acetal, via P A D P E A D.
- Acetals only undergo one significant reaction – hydrolysis with aqueous acid, which occurs via P E A D P E D.
- Acetals are useful protecting groups for aldehydes/ketones
- Thioacetals are also useful, but mostly because they allow conversion to an alkane via Raney Ni.
This post was extensively re-written in Feb 2022, replacing an older post called “On Acetals and Hemiacetals”
Note 1 – Another term for hydrates is “geminal diols” (gem-diols). Geminal refers to two groups bonded to the same carbons. We encountered gem-dihalides in the addition of HCl and HBr to alkynes, for example.
Chloral hydrate was the earliest hydrate to be isolated (in 1832) and saw early use as an anaesthetic. It is probably the most famous hydrate of all, playing a prominent role in numerous spy and detective films as a “Mickey Finn” or “knockout drug”.
From The Living Daylights, 1987
Note 3 – Le Chatelier’s principle, roughly stated, says that changing the concentration of a chemical will shift the equilibrium to the side that would counter that change in concentration. So if we reduce the concentration of CH3OH in the reaction below (i.e. by removing solvent) the reaction would undergo a shift to the left (production of more CH3OH) and thus loss of the hemiacetal.
Note 4 – Attempting to convert carbonyl group of an ester RCO2R into an “acetal” through using ROH / H+ to make RC(OR)3 does not work. However, these species, known as “ortho-esters” have been made through other means (e.g. basic hydrolysis of chloroform).
Note 5 – we could also protonate the OR group to give ROH(+), which could be eliminated to give a protonated carbonyl.
But now ask, “what happens next?”. If the concentration of ROH >> the concentration of H2O [normally the case in these situations] then the protonated carbonyl is just a dead end. Sequestering the H2O as it is eliminated will result in driving the equilibrium towards the final acetal product.
Note 6 – This species is known as an “oxocarbenium ion“.
Each mechanism has two P steps and two D steps (no net change in charge – they cancel)
Acetal formation (left to right) has two addition steps and one elimination step.
Aldehyde formation (right to left) has one addition step and two elimination steps.
- 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.