# Acetonide
An **acetonide** is a cyclic acetal formed from acetone and a diol, usually a vicinal (adjacent) 1,2-diol, in which the two oxygen atoms of the diol are joined through a single carbon bearing two methyl groups, the isopropylidene carbon[1](https://goldbook.iupac.org/terms/view/A00064/pdf). The group is also called an isopropylidene ketal, and in carbohydrate notation the protected derivatives are named as 1,2-O- or 1,3-O-isopropylidene compounds[1](https://goldbook.iupac.org/terms/view/A00064/pdf) • [2](https://library.uniq.edu.iq/storage/books/file/Pharmacotherapy/1668427108Essentials%20of%20Organic%20Chemistry%20For%20Students%20of%20Pharmacy%2C%20Medicinal%20Chemistry%20and%20Biological%20Chemistry%20%28%20PDFDrive%20%29.pdf). Acetonides are among the standard protecting groups for 1,2- and 1,3-diols and are described as essential in carbohydrate and nucleoside chemistry[3](https://www.sigmaaldrich.com/US/en/technical-documents/technical-article/chemistry-and-synthesis/reaction-design-and-optimization/protecting-group-organic-synthesis).
| Key fact | Detail |
|---|---|
| Definition | Cyclic acetal derived from acetone and diols, usually [vicinal diols](https://www.edgepedia.org/vicinal-diol) or polyhydroxy compounds (IUPAC)[1](https://goldbook.iupac.org/terms/view/A00064/pdf) |
| Selectivity | Selective for 1,2- and 1,3-diols; in cyclic systems the two hydroxyls must be cis-oriented[3](https://www.sigmaaldrich.com/US/en/technical-documents/technical-article/chemistry-and-synthesis/reaction-design-and-optimization/protecting-group-organic-synthesis) • [2](https://library.uniq.edu.iq/storage/books/file/Pharmacotherapy/1668427108Essentials%20of%20Organic%20Chemistry%20For%20Students%20of%20Pharmacy%2C%20Medicinal%20Chemistry%20and%20Biological%20Chemistry%20%28%20PDFDrive%20%29.pdf) |
| Installation | Acetone, 2,2-dimethoxypropane (2 equiv.), or 2-methoxypropene, with catalytic p-toluenesulfonic acid or camphorsulfonic acid[3](https://www.sigmaaldrich.com/US/en/technical-documents/technical-article/chemistry-and-synthesis/reaction-design-and-optimization/protecting-group-organic-synthesis) • [4](https://www.chem.iitb.ac.in/~kpk/protectinggroups.pdf) |
| Removal | Acid hydrolysis: dilute aqueous HCl or p-TsOH in acetone/H2O; trifluoroacetic acid-water (9:1) is particularly effective[3](https://www.sigmaaldrich.com/US/en/technical-documents/technical-article/chemistry-and-synthesis/reaction-design-and-optimization/protecting-group-organic-synthesis) • [5](https://ndl.ethernet.edu.et/bitstream/123456789/3287/1/38.pdf.pdf) |
| Stability | Stable to base, nucleophiles, and reducing agents; acid- and Lewis-acid sensitive[3](https://www.sigmaaldrich.com/US/en/technical-documents/technical-article/chemistry-and-synthesis/reaction-design-and-optimization/protecting-group-organic-synthesis) • [6](https://www.researchgate.net/publication/326318347_A_Facile_One-pot_Procedure_for_Transformation_of_Acetonides_into_Diacetates_Catalyzed_with_BiOTf3) |
| Main use | Protection of diols in carbohydrate and nucleoside synthesis; the glycerol acetonide solketal is a named example[3](https://www.sigmaaldrich.com/US/en/technical-documents/technical-article/chemistry-and-synthesis/reaction-design-and-optimization/protecting-group-organic-synthesis) • [7](https://webbook.nist.gov/cgi/cbook.cgi?ID=C100798&Mask=28F&Units=SI) |
## Formation
Aldehydes and ketones react with 1,2- or 1,3-diols under acidic conditions to form cyclic acetals or ketals. In a cyclic diol the two hydroxyl groups must be cis-oriented so that a thermodynamically favorable fused-ring system can form; cis-cyclohexane-1,2-diol reacting with acetone gives the 1,2-O-isopropylidene derivative, termed for convenience an acetonide[2](https://library.uniq.edu.iq/storage/books/file/Pharmacotherapy/1668427108Essentials%20of%20Organic%20Chemistry%20For%20Students%20of%20Pharmacy%2C%20Medicinal%20Chemistry%20and%20Biological%20Chemistry%20%28%20PDFDrive%20%29.pdf). The reaction is an equilibrium, so effective formation requires an acid catalyst and removal of the water produced; the same mechanism operates in reverse during hydrolysis[8](https://www2.chemistry.msu.edu/faculty/reusch/virttxtjml/chapt17.htm).
**Reagents.** The common installation conditions are acetone, 2,2-dimethoxypropane, and p-toluenesulfonic acid or camphorsulfonic acid as catalyst[4](https://www.chem.iitb.ac.in/~kpk/protectinggroups.pdf). 2,2-Dimethoxypropane serves as a water scavenger: its reaction releases acetone and methanol, which drives the equilibrium toward the protected product. It is also used together with acetone and an acid catalyst to protect the 2,3-hydroxyl groups of purine and pyrimidine nucleosides[9](https://www.chemicalbook.cn/article/introduction-of-2-2-dimethoxypropane.htm).
## Behavior in sugars
Sugars are polyhydroxy compounds, and which hydroxyls react is not always easy to predict. [Ring size](https://www.edgepedia.org/ring-size) can change during acetonation: a more stable pyranose form may lack cis-oriented hydroxyls while a less favored furanose form has them, and pyranose-furanose equilibration allows the change[2](https://library.uniq.edu.iq/storage/books/file/Pharmacotherapy/1668427108Essentials%20of%20Organic%20Chemistry%20For%20Students%20of%20Pharmacy%2C%20Medicinal%20Chemistry%20and%20Biological%20Chemistry%20%28%20PDFDrive%20%29.pdf).
- **D-Galactose** reacts with acetone to give a diacetonide: the less-favored alpha form has two pairs of cis-oriented hydroxyls that can react, leaving only the primary alcohol group unprotected and available for further modification[2](https://library.uniq.edu.iq/storage/books/file/Pharmacotherapy/1668427108Essentials%20of%20Organic%20Chemistry%20For%20Students%20of%20Pharmacy%2C%20Medicinal%20Chemistry%20and%20Biological%20Chemistry%20%28%20PDFDrive%20%29.pdf).
- **D-Glucose** is more complicated. The pyranose alpha-anomer could yield only a mono-acetonide, but the furanose form has two sets of hydroxyls that can react, and the product obtained is a diacetonide of alpha-D-glucofuranose[2](https://library.uniq.edu.iq/storage/books/file/Pharmacotherapy/1668427108Essentials%20of%20Organic%20Chemistry%20For%20Students%20of%20Pharmacy%2C%20Medicinal%20Chemistry%20and%20Biological%20Chemistry%20%28%20PDFDrive%20%29.pdf).
- A six-membered ketal ring involving the 4- and 6-hydroxyls is not favored with acetone, because it would force one of the two methyl groups into an axial position; those two hydroxyls instead form a cyclic acetal readily with benzaldehyde, which prefers six-membered rings with the phenyl group equatorial[2](https://library.uniq.edu.iq/storage/books/file/Pharmacotherapy/1668427108Essentials%20of%20Organic%20Chemistry%20For%20Students%20of%20Pharmacy%2C%20Medicinal%20Chemistry%20and%20Biological%20Chemistry%20%28%20PDFDrive%20%29.pdf).
Temperature shifts the outcome. In the classic study by Makoto Kiso and [Akira Hasegawa](https://www.edgepedia.org/akira-hasegawa), acetonation of D-glucose with 2,2-dimethoxypropane in N,N-dimethylformamide containing a trace of p-toluenesulfonic acid at room temperature gave 4,6-O-isopropylidene-D-glucopyranose almost exclusively, while at 95 degrees the major products were 5,6-O-isopropylidene-D-glucofuranose, 1,2:5,6-di-O-isopropylidene-alpha-D-glucofuranose, and an acyclic di-O-isopropylidene derivative. The variation reflects pyranose-furanose equilibria, with D-glucose mainly pyranose at room temperature but furanose and acyclic at 95 degrees, and the reaction is kinetically controlled with favored attack at the primary hydroxyl[10](https://www.sciencedirect.com/science/article/pii/S0008621500859492).
## Deprotection
The original diol is regenerated by acid hydrolysis, effectively reversing the acetal-forming reaction[2](https://library.uniq.edu.iq/storage/books/file/Pharmacotherapy/1668427108Essentials%20of%20Organic%20Chemistry%20For%20Students%20of%20Pharmacy%2C%20Medicinal%20Chemistry%20and%20Biological%20Chemistry%20%28%20PDFDrive%20%29.pdf). Representative conditions are dilute aqueous HCl or p-TsOH in acetone/H2O[3](https://www.sigmaaldrich.com/US/en/technical-documents/technical-article/chemistry-and-synthesis/reaction-design-and-optimization/protecting-group-organic-synthesis). For carbohydrate derivatives, removal of the isopropylidene group generally offers few problems: trifluoroacetic acid-water (9:1) is particularly effective, and other occasions may warrant iodine in methanol, a Lewis acid, or cerium(IV) ammonium nitrate[5](https://ndl.ethernet.edu.et/bitstream/123456789/3287/1/38.pdf.pdf). Selective removal of just one acetal from some di-O-isopropylidene derivatives is possible[5](https://ndl.ethernet.edu.et/bitstream/123456789/3287/1/38.pdf.pdf).
The group's lability pattern is what makes it useful in orthogonal schemes. Acetonides survive strongly basic conditions but are sensitive to acid and Lewis acids[6](https://www.researchgate.net/publication/326318347_A_Facile_One-pot_Procedure_for_Transformation_of_Acetonides_into_Diacetates_Catalyzed_with_BiOTf3), and they are stable to base, nucleophiles, and reducing agents[3](https://www.sigmaaldrich.com/US/en/technical-documents/technical-article/chemistry-and-synthesis/reaction-design-and-optimization/protecting-group-organic-synthesis). An acetonide (acid-labile) can therefore be used alongside a benzyl ether (removed by [hydrogenolysis](https://www.edgepedia.org/hydrogenolysis)) and a silyl ether (removed by fluoride ions), allowing selective deprotection of each group in turn[11](https://pdf.benchchem.com/42/stability_of_acetonide_protecting_group_to_different_reaction_conditions.pdf).
## Applications
Acetonides protect diols across synthetic chemistry, with their largest role in carbohydrates, where two of a sugar's hydroxyl groups can be bound up while other reactions are carried out[2](https://library.uniq.edu.iq/storage/books/file/Pharmacotherapy/1668427108Essentials%20of%20Organic%20Chemistry%20For%20Students%20of%20Pharmacy%2C%20Medicinal%20Chemistry%20and%20Biological%20Chemistry%20%28%20PDFDrive%20%29.pdf). In total synthesis they serve the same purpose for acyclic 1,2- and 1,3-diols; 1,3-polyol fragments of natural products such as polyene macrolide antibiotics are often protected as polyacetonides, and the hydrolysis behavior of anti-1,3-diol acetonides has been used to differentiate 1,3-anti from 1,3-syn diols[12](https://www.sciencedirect.com/science/article/pii/S0040403905025864).
A named small-molecule example is **solketal**, the acetonide of glycerol, systematically 2,2-dimethyl-1,3-dioxolane-4-methanol and also listed as 1,2-O-isopropylideneglycerol or glycerol acetonide[7](https://webbook.nist.gov/cgi/cbook.cgi?ID=C100798&Mask=28F&Units=SI). Cyclic acetal formation is also exploited industrially: an acid-catalyzed tandem sequence on renewable 1,2-diols such as propylene glycol with isopropenyl acetate releases acetone, which then promotes acetalization on a second molecule of the glycol[13](https://arts.units.it/handle/11368/2979581).
## References
1. [IUPAC Gold Book: acetonides](https://goldbook.iupac.org/terms/view/A00064/pdf)
2. [Essentials of Organic Chemistry for Students of Pharmacy, Medicinal Chemistry and Biological Chemistry, section on cyclic acetals and ketals](https://library.uniq.edu.iq/storage/books/file/Pharmacotherapy/1668427108Essentials%20of%20Organic%20Chemistry%20For%20Students%20of%20Pharmacy%2C%20Medicinal%20Chemistry%20and%20Biological%20Chemistry%20%28%20PDFDrive%20%29.pdf)
3. [Protecting Groups in Organic Synthesis, Sigma-Aldrich technical article](https://www.sigmaaldrich.com/US/en/technical-documents/technical-article/chemistry-and-synthesis/reaction-design-and-optimization/protecting-group-organic-synthesis)
4. [Protecting Groups: 1,2 & 1,3-Diols, course notes, IIT Bombay](https://www.chem.iitb.ac.in/~kpk/protectinggroups.pdf)
5. [Protecting group manipulations in carbohydrate synthesis (book chapter)](https://ndl.ethernet.edu.et/bitstream/123456789/3287/1/38.pdf.pdf)
6. [A Facile One-pot Procedure for Transformation of Acetonides into Diacetates Catalyzed with Bi(OTf)3](https://www.researchgate.net/publication/326318347_A_Facile_One-pot_Procedure_for_Transformation_of_Acetonides_into_Diacetates_Catalyzed_with_BiOTf3)
7. [NIST Chemistry WebBook: 1,3-Dioxolane-4-methanol, 2,2-dimethyl- (solketal)](https://webbook.nist.gov/cgi/cbook.cgi?ID=C100798&Mask=28F&Units=SI)
8. [Carbonyl Reactivity, Virtual Textbook of Organic Chemistry, Michigan State University](https://www2.chemistry.msu.edu/faculty/reusch/virttxtjml/chapt17.htm)
9. [Introduction of 2,2-Dimethoxypropane, ChemicalBook](https://www.chemicalbook.cn/article/introduction-of-2-2-dimethoxypropane.htm)
10. [Kiso, M. and Hasegawa, A. (1976). Acetonation of D-glucose with 2,2-dimethoxypropane-N,N-dimethylformamide-p-toluenesulfonic acid. Carbohydrate Research 52, 87-94](https://www.sciencedirect.com/science/article/pii/S0008621500859492)
11. [Stability of acetonide protecting group to different reaction conditions, BenchChem troubleshooting](https://pdf.benchchem.com/42/stability_of_acetonide_protecting_group_to_different_reaction_conditions.pdf)
12. [Selective hydrolysis of anti-1,3-diol-acetonides for the differentiation of 1,3-anti and 1,3-syn diols, Tetrahedron Letters](https://www.sciencedirect.com/science/article/pii/S0040403905025864)
13. [Acid-Catalyzed Reactions of Isopropenyl Esters and Renewable Diols, ACS Sustainable Chemistry & Engineering](https://arts.units.it/handle/11368/2979581)
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*Topic: Encyclopedia › Physical world and mathematics › Chemistry › Organic substances › Alcohols, ethers, and organooxygen groups › Alcohols and polyols › Alcohol reactions (oxidation, dehydration, substitution) › Diol and polyol reactivity*
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