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Short Topic: More ways to use reagents |
Hydrolysis of Thioacetals Using Oxidizing Reagents

Haruhiko Taguchi
Tokyo Chemical Industry, Co. Ltd.

In this issue of TCI MAIL, the highlighted topic of synthetic methods is dethioacetalization using oxidizing reagents. Professor Takeda has written of the attractive usages of thioacetals, in particular, the preparation of titanium-carbene complexes using thioacetals (see TCIMAIL No.157 Science “spring” seminar). However, there are some serious problems to the use of thioacetals for synthesis, even though they are very useful as building blocks. What are problems? Nasty smell! Of course smells are a problem, but there are other problems that are of greater consequence.
It is well known that thioacetals are used as formyl anion equivalents and Prof. Seebach originally introduced this concept of umpolung.1) This idea was very innovative because the carbonyl carbon has an electrophilic character and it acts as a carbocation. Using the concept of umpolung, if the carbonyl group is transformed to the corresponding thioacetal, the character of the carbon changes to a carbanion. And furthermore, treatment of the thioacetal with a strong base generates an anionic species, which reacts with various electrophiles. It is very easy to introduce various electrophiles into a carbonyl carbon after the transformation of the carbonyl group.
The concept of

The concept of "Umpolung" proposed by Prof. Seebach

Well now, the important question before us, is how to undo this transformation of the carbonyl to the thioacetal? According to Seebach’s umpolung strategy, the method for hydrolysis of thioacetals, has been the use of mercury salts. In 60’s and 70’s, mercury salts had been useful reagents in organic synthesis, but in recent years, environmental concerns have almost completely eliminated there use in the laboratory. Almost all laboratories do not use mercury salts in organic synthesis because chemists tend to avoid their use for environmental reasons.
To resolve the problems associated with the use of mercury, other methods for the hydrolysis of thioacetals have to be developed. Thioacetals are similar to acetals, so can they be hydrolyzed by the treatment with a strong acid? This strategy is effective for the hydrolysis of acetals; however, in the case of thioacetals, this method is not effective. The pKa value of alcohols are about 16, while that of thiols are between 10 and 11. Since, the pKa values of thiols are 5 units higher than those of alcohols, protonation of sulfur atom does not occur and dethioacetalizations does not proceed.
Why is mercury so effective in dethioacetalization? The reason why mercury salts have been so effective has to do with the chemical affinity of mercury and sulfur atoms. Why is their affinity for each other so good? It is based on the principle of hard and soft acids and bases, that is the HSAB theory, which provides the answer.
According to HSAB theory, sulfur atoms tends to form ion pairs with soft ions, and it turns out that mercury is a soft ion. The chemical affinity of sulfur and mercury ions is quite strong. This effect enables mercury to form a coordinate bond with sulfur, which activates the carbon-sulfur bond towards hydrolysis.2)
Can thioacetals be hydrolyzed by using some other soft substance? Another concept of hydrolysis is to form sulfonium salts. Sulfur compounds, such as sulfides and sulfoxides, react readily with methyl iodide to form methylsulfonium salts. This chemical property is specific to sulfur and oxygen does not react in this way. The formed sulfonium salts have a positive charge and this species can undergo various reactions. By using this technique, the hydrolysis of thioacetals can proceed. In some references, relatively strong alkylating reagents are used to form sulfonium salts, which on subsequent hydrolysis under alkaline conditions regenerate the carbonyl compound.3) Interestingly, this type of hydrolysis proceeds using cupper salts,4) which are soft ions.
These synthetic techniques provide alternate methods to hydrolyze thioacetals, avoiding the use of mercury salt. It should be noted, that there are problems associated with this method also. For one, it is often necessary to use a strong alkylating reagent, and because these reagents have cancer inducing properties, many chemists do not use them.
Another idea for thioacetal hydrolysis is to use oxidizing reagent. Hypervalent iodine compounds, such as Dess-Martin periodinane,5) [Bis(trifluoroacetoxy)iodo]benzene (PIFA)6) and 2-iodoxybenzoic acid (IBX)7), are used for thioacetal hydrolysis. These oxidizing reagents oxidize the thioacetals to sulfoxides or sulfones, and after oxidation, water-mediated hydrolysis is possible.8) If hydrolysis is performed in an alcohol base, the formed carbonyl compound reacts with alcohols to form corresponding acetals. Usually, acetals cannot be derived from thioacetals under acidic conditions, so this result is potentially useful.
Dethioacetalization by oxidation with IBX is quite structure specific. IBX oxidation of benzyl or allylthioacetals proceed rapidly, while IBX oxidation of other alkyl group thioacetals proceed slowly or not at all.
Examples of dethioacetalizations using oxidizing reagents

Examples of dethioacetalizations using oxidizing reagents

Why is the hydrolysis of thioacetals possible using hypervalent iodine? Iodine is a soft ion species, based on the HSAB theory, and thus it readily reacts with sulfur to cause oxidation.
Another unique dethioacetalization is presented. Through the use of chloramine T as an oxidizing reagent.9) the hydrolysis of a sensitive silyl thioacetal has been reported to yield a silyl ketone.10) Now various acylsilanes are synthesized by this method.
Synthesis of acylsilanes using Chloramine T

Synthesis of acylsilanes using Chloramine T

Chemical syntheses using thioacetals is a powerful tool for the construction of complex compounds. TCI has many thioacetals and related reagents for making thioacetals and removal of the thioacetal group. The Umpolung technique can be made possible by using a number of TCI reagents.


The HSAB theory, proposed by Pearson, helps to qualitatively understand the properties of elements. The HSAB theory describes the reactions of acids with bases and defines the chemical character of acids and bases as “Hard” or “Soft”.
Hard acids and bases generally have short atomic radius and low polarization while soft acids and soft bases generally have long atomic radius and high polarization. As to chemical properties, hard acids tend to bind with hard bases and soft acids tend to bind with soft bases.
The HSAB theory is a qualitative and experimental rule and it should be considered as one of several factors in understanding the chemical reactions. This rule is useful for approximating the nature of the chemical reaction. In particular, in considering electrostatic properties of elements, it is important to note that hard species tend to form ionic bonds, while soft species tend to form covalent bonds.
Iodine is a soft species having the properties that large molecule size, easily polarizable and low in electronegativity. Generally, iodine acts as a monovalent species to form a single bond with various elements.
It can have over eight electrons beyond the octet theory by readily extending its valence. In this expanded valence state, is called hypervalent iodinane. It is known that trivalent and pentavalent iodines are hypervalent iodinane, and each of their structure are pseudo trigonal bipyramidal molecular geometry and square pyramidal molecular geometry.
These hypervalent iodine compounds show strong oxidative action because the reduced monovalent iodines possess a more stable octet structure. These chemical properties are useful for oxidation in organic synthesis. Dess-Martin periodinane and [bis(trifluoroacetoxy)iodo]benzene (PIFA) are typical reagents for such purposes.

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