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Reactions >> Protecting Groups >> Stability

Dimethyl acetals

T. W. Green, P. G. M. Wuts,
Protective Groups in Organic Synthesis,
Wiley-Interscience, New York, 1999, 297-304, 724-727.

 

Stability

H2O: pH < 1, 100°C pH = 1, RT pH = 4, RT pH = 9, RT pH = 12, RT pH > 12, 100°C
Bases: LDA NEt3, Py t-BuOK Others: DCC SOCl2
Nucleophiles: RLi RMgX RCuLi Enolates NH3, RNH2 NaOCH3
Electrophiles: RCOCl RCHO CH3I Others: :CCl2 Bu3SnH
Reduction: H2 / Ni H2 / Rh Zn / HCl Na / NH3 LiAlH4 NaBH4
Oxidation: KMnO4 OsO4 CrO3 / Py RCOOOH I2, Br2, Cl2 MnO2 / CH2Cl2

General

Dimethyl acetals can be prepared from carbonyl compounds with excess methanol catalyzed by a Brønsted (i.e. protic) acid or Lewis acid (e.g. BF3) together with a dehydrating agent or other means of water removal that will drive the equilibrium in the following reaction to the right.

As an example of the use of a dehydrating agent, acetalization can be carried out by using methanol with trimethyl orthoformate or the orthoformate alone. Trimethyl orthoformate forms methyl formate and methanol on reaction with water and thus removes the water from the reaction mixture.

Deprotection is often performed by acid-catalyzed transacetalization in acetone (in excess or as solvent), or hydrolysis in wet solvents or in aqueous acid.

Acetals offer stability against all types of nucleophiles and bases and most oxidants, so long as the conditions do not lead to hydrolysis of the acetal. Hydride reductions in neutral and basic media will generally not affect acetal-protected carbonyls.

Up to now, various mild methods for acetalization and deacetalization have been developed to spare other acid-sensitive functionality, such as the use of catalysts such as ammonium nitrate, Amberlyst-15 or silica gel, and dehydrating agents such as P2O5.


Protection


 Perchloric acid adsorbed on silica gel is an extremely efficient, inexpensive, and reusable catalyst for the protection of aldehydes and ketones and the subsequent deprotection. Acetalization was mostly carried out under solvent-free conditions with trialkyl orthoformates, but weakly electrophilic carbonyl compounds and substrates that can coordinate with the catalyst, required the corresponding alcohol as solvent.
 R. Kumar, D. Kumar, A. K. Chakraborti, Synthesis, 2007, 299-303.


Acyclic and cyclic acetals of various carbonyl compounds were obtained in excellent yields in the presence of trialkyl orthoformate and a catalytic amount of tetrabutylammonium tribromide in absolute alcohol. This convenient, mild, chemoselective method allows acetalization of an aldehyde in the presence of ketone, unsymmetrical acetal formation, and tolerates acid-sensitive protecting groups.
R. Gopinath, Sk. J. Haque, B. K. Patel, J. Org. Chem., 2002, 67, 5842-5845.


Simple pyridinium salt derivatives unexpectedly catalyze highly efficient acetalizations of aldehydes at ambient temperature. The aprotic catalyst promotes the formation of benzaldehyde dimethyl acetal at low  loadings more efficiently than a protic Brønsted acid catalyst with a pKa of 2.2. The ionic catalyst can be readily recovered by precipitation and reused without loss of activity.
B. Procuranti, S. J. Connon, Org. Lett., 2008, 10, 4935-4938.


Acetals of diaryl ketones with nitro, halo and methoxy substituents are easily prepared in high yield by treatment with an alcohol and the corresponding trialkyl orthoformate in the presence of a catalytic amount of trifluoromethanesulfonic acid.
A. Thurkauf, A. E. Jacobson, K. C. Rice, Synthesis, 1988, 233-234.

Deprotection


Acetals and ketals are readily deprotected under neutral conditions in the presence of acetone and indium(III) trifluoromethanesulfonate as catalyst at room temperature or mild microwave heating conditions to give the corresponding aldehydes and ketones in good to excellent yields.
B. T. Gregg, K. C. Golden, J. F. Quinn, J. Org. Chem., 2007, 72, 5890-5893.


Deprotection of acetals and ketals can be achieved by using a catalytic amount of sodium tetrakis(3,5-trifluoromethylphenyl)borate (NaBArF4) in water at 30 °C. For example, a quantitative conversion of 2-phenyl-1,3-dioxolane into benzaldehyde was accomplished within five minutes.
C.-C. Chang, B.-S. Liao, S.-T. Liu, Synlett, 2007, 283-287.


Er(OTf)3 is a very gentle Lewis acid catalyst in the chemoselective cleavage of alkyl and cyclic acetals and ketals at room temperature in wet nitromethane.
R. Dalpozzo, A. De Nino, L. Maiuolo, M. Nardi, A. Procopio, A. Tagarelli, Synthesis, 2004, 496-498.


A chemoselective method for the cleavage of acetals and ketals at room temperature in wet nitromethane by using catalytic cerium(III) triflate at almost neutral pH is presented. High yields and selectivity make this procedure particularly attractive for multistep synthesis.
R. Dalpozzo, A. De Nino, L. Maiuolo, A. Procopio, A. Tagarelli, G. Sindona, G. Bartoli, J. Org. Chem., 2002, 67, 9093-9095.


A convenient deprotection of acyclic and cyclic O,O-acetals and O,O-ketals is achieved in excellent yields within minutes under neutral conditions in the presence of a catalytic amount of iodine. Double bonds, hydroxyl groups, acetate groups, and highly acid-sensitive groups such as furyl, tert-butyl ethers, and ketoximes are tolerated.
J. Sun, Y. Dong, L. Cao, X. Wang, S. Wang, Y. Hu, J. Org. Chem., 2004, 69, 8932-8934.


Perchloric acid adsorbed on silica gel is an extremely efficient, inexpensive, and reusable catalyst for the protection of aldehydes and ketones and the subsequent deprotection. Acetalization was mostly carried out under solvent-free conditions with trialkyl orthoformates, but weakly electrophilic carbonyl compounds and substrates that can coordinate with the catalyst, required the corresponding alcohol as solvent.
R. Kumar, D. Kumar, A. K. Chakraborti, Synthesis, 2007, 299-303.