Silyl ether
Encyclopedia
Silyl ethers are a group of chemical compound
s which contain a silicon
atom covalently bonded
to an alkoxy group. The general structure is R1R2R3Si−O−R4 where R4 is an alkyl group or an aryl
group. Silyl ethers are usually used as protecting groups for alcohols in organic synthesis
. Since R1R2R3 can be combinations of differing groups which can be varied in order to provide a number of silyl ethers, this group of chemical compounds provides a wide spectrum of selectivity for protecting group chemistry. Common silyl ethers are: trimethylsilyl
(TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS/TBDMS) and triisopropylsilyl (TIPS), [2-(trimethylsilyl)ethoxy]methyl (SEM). They are particularly useful because they can be installed and removed very selectively under mild conditions.
at high concentration in DMF. If DMF is replaced by dichloromethane, the reaction is somewhat slower, but the purification of the compound is simplified. A common hindered base for use with silyl triflates is 2,6-lutidine
. Primary alcohols can be protected in less than one hour while some hindered alcohols may require days of reaction time.
When using a silyl chloride, no special precautions are usually required, except for the exclusion of large amounts of water. An excess of silyl chloride can be employed but is not necessary. If excess reagent is used, the product will require flash chromatography to remove excess silanol
and siloxane
. Silyl triflates are water sensitive and must be run under inert atmosphere conditions. Purification involves the addition of an aqueous acid such as saturated ammonium chloride
solution. This quenches remaining silyl reagent and protonates amine bases, removing them from the reaction mixture. Following extraction, the product can be purified by flash chromatography.
Silyl triflate is more reactive and also converts ketones to silyl enol ethers.
remove the silyl group when protection is no longer needed. Larger substituents increase resistance to hydrolysis
, but also make introduction of the silyl group more difficult.
In acidic media, the relative stability is (see above references):
In basic media, the relative stability is (see above references):
However, it turns out that this reaction is hard to repeat. If the reaction were controlled solely by thermodynamics then, statistically, if the dianion is of similar reactivity to the monoanion, then a corresponding statistical mixture of 1:2:1 disilylated:monosilylated:unsilylated diol will result. However, the reaction in THF is made selective by two factors kinetic deprotonation of the first anion AND the insolubility of the monoanion. At the initial addition of TBSCl, there is only a minor amount of monoanion in solution with the rest being in suspension. This small portion reacts and shifts the equilibrium of the monoanion to draw more into solution, thereby allowing for high yields of the mono-TBS compound to be obtained. Superior results in some cases may obtained with butyllithium
:
A third method uses a mixture of DMF
and DIPEA.
Alternatively, an excess (4 eq) of the diol can be used, forcing the reaction toward monoprotection.
Silyl ethers are mainly differentiated on the basis of sterics or electronics. In general, acidic deprotections deprotect less hindered silyl groups faster, with the steric bulk on silicon being more significant than the steric bulk on oxygen. Fluoride-based deprotections deprotect electron-poor silyl groups faster than electron-rich silyl groups. There is some evidence that some silyl deprotections proceed via hypervalent silicon species.
The selective deprotection of silyl ethers has been extensively reviewed. Although selective deprotections have been achieved under many different conditions, some procedures, outlined below, are more reliable. A selective deprotection will likely be successful if there is a substantial difference in sterics (e.g., primary TBS vs. secondary TBS or primary TES vs primary TBS) or electronics (e.g. primary TBDPS vs. primary TBS). Unfortunately, some optimization is inevitably required and it is often necessary to run deprotections partway and recycle material.
Some Common Acidic Conditions:
Some Common Basic Conditions:
Chemical compound
A chemical compound is a pure chemical substance consisting of two or more different chemical elements that can be separated into simpler substances by chemical reactions. Chemical compounds have a unique and defined chemical structure; they consist of a fixed ratio of atoms that are held together...
s which contain a silicon
Silicon
Silicon is a chemical element with the symbol Si and atomic number 14. A tetravalent metalloid, it is less reactive than its chemical analog carbon, the nonmetal directly above it in the periodic table, but more reactive than germanium, the metalloid directly below it in the table...
atom covalently bonded
Covalent bond
A covalent bond is a form of chemical bonding that is characterized by the sharing of pairs of electrons between atoms. The stable balance of attractive and repulsive forces between atoms when they share electrons is known as covalent bonding....
to an alkoxy group. The general structure is R1R2R3Si−O−R4 where R4 is an alkyl group or an aryl
Aryl
In the context of organic molecules, aryl refers to any functional group or substituent derived from an aromatic ring, be it phenyl, naphthyl, thienyl, indolyl, etc....
group. Silyl ethers are usually used as protecting groups for alcohols in organic synthesis
Organic synthesis
Organic synthesis is a special branch of chemical synthesis and is concerned with the construction of organic compounds via organic reactions. Organic molecules can often contain a higher level of complexity compared to purely inorganic compounds, so the synthesis of organic compounds has...
. Since R1R2R3 can be combinations of differing groups which can be varied in order to provide a number of silyl ethers, this group of chemical compounds provides a wide spectrum of selectivity for protecting group chemistry. Common silyl ethers are: trimethylsilyl
Trimethylsilyl
A trimethylsilyl group is a functional group in organic chemistry. This group consists of three methyl groups bonded to a silicon atom [−Si3], which is in turn bonded to the rest of a molecule...
(TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS/TBDMS) and triisopropylsilyl (TIPS), [2-(trimethylsilyl)ethoxy]methyl (SEM). They are particularly useful because they can be installed and removed very selectively under mild conditions.
Formation
Although many methods are available for forming silyl ethers, there are two common strategies: reaction of the alcohol with a silyl chloride with an amine base at room temperature and reaction of the alcohol with a silyl triflate with a hindered amine base at low temperature. Silyl triflates are more reactive than their corresponding chlorides, so they can be used to install silyl groups onto hindered positions. One extremely reliable and rapid procedure is the Corey protocol in which the alcohol is reacted with a silyl chloride and imidazoleImidazole
Imidazole is an organic compound with the formula C3H4N2. This aromatic heterocyclic is a diazole and is classified as an alkaloid. Imidazole refers to the parent compound, whereas imidazoles are a class of heterocycles with similar ring structure, but varying substituents...
at high concentration in DMF. If DMF is replaced by dichloromethane, the reaction is somewhat slower, but the purification of the compound is simplified. A common hindered base for use with silyl triflates is 2,6-lutidine
2,6-Lutidine
2,6-Lutidine is a natural heterocyclic aromatic organic compound. It has been isolated from the basic fraction of coal tar and from bone oil. It is a dimethyl substituted derivative of pyridine. It has been detected in waste water from oil shale processing sites and former creosoting facilities...
. Primary alcohols can be protected in less than one hour while some hindered alcohols may require days of reaction time.
When using a silyl chloride, no special precautions are usually required, except for the exclusion of large amounts of water. An excess of silyl chloride can be employed but is not necessary. If excess reagent is used, the product will require flash chromatography to remove excess silanol
Silanol
Silanol, also known as silyl alcohol, is a chemical with formula SiH3OH. It is the simplest silicon alcohol, and is a heavy, volatile, colorless, flammable liquid. At room temperature it is a polar liquid...
and siloxane
Siloxane
A siloxane is any chemical compound composed of units of the form R2SiO, where R is a hydrogen atom or a hydrocarbon group. They belong to the wider class of organosilicon compounds....
. Silyl triflates are water sensitive and must be run under inert atmosphere conditions. Purification involves the addition of an aqueous acid such as saturated ammonium chloride
Ammonium chloride
Ammonium chloride NH4Cl is an inorganic compound with the formula NH4Cl. It is a white crystalline salt that is highly soluble in water. Solutions of ammonium chloride are mildly acidic. Sal ammoniac is a name of natural, mineralogical form of ammonium chloride...
solution. This quenches remaining silyl reagent and protonates amine bases, removing them from the reaction mixture. Following extraction, the product can be purified by flash chromatography.
Silyl triflate is more reactive and also converts ketones to silyl enol ethers.
Removal of silyl ether protecting groups
Reaction with acids or fluorides such as tetra-n-butylammonium fluorideTetra-n-butylammonium fluoride
Tetra-n-butylammonium fluoride or TBAF is a quaternary ammonium salt with the chemical formula 4N+F-. It is commercially available as the trihydrate and as a solution in tetrahydrofuran....
remove the silyl group when protection is no longer needed. Larger substituents increase resistance to hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
, but also make introduction of the silyl group more difficult.
In acidic media, the relative stability is (see above references):
- TMS (1) < TES (64) < TBS (20 000) < TIPS (700 000) < TBDPS (5 000 000)
In basic media, the relative stability is (see above references):
- TMS (1) < TES (10-100) < TBS~TBDPS (20 000) < TIPS (100 000)
Monoprotection of symmetrical diols
It is possible to monosilylate a symmetrical diol, although this is known to be problematic occasionally. For example, the following monosilylation was reported:However, it turns out that this reaction is hard to repeat. If the reaction were controlled solely by thermodynamics then, statistically, if the dianion is of similar reactivity to the monoanion, then a corresponding statistical mixture of 1:2:1 disilylated:monosilylated:unsilylated diol will result. However, the reaction in THF is made selective by two factors kinetic deprotonation of the first anion AND the insolubility of the monoanion. At the initial addition of TBSCl, there is only a minor amount of monoanion in solution with the rest being in suspension. This small portion reacts and shifts the equilibrium of the monoanion to draw more into solution, thereby allowing for high yields of the mono-TBS compound to be obtained. Superior results in some cases may obtained with butyllithium
N-Butyllithium
n-Butyllithium is an organolithium reagent. It is widely used as a polymerization initiator in the production of elastomers such as polybutadiene or styrene-butadiene-styrene...
:
A third method uses a mixture of DMF
Dimethylformamide
Dimethylformamide is an organic compound with the formula 2NCH. Commonly abbreviated as DMF , this colourless liquid is miscible with water and the majority of organic liquids. DMF is a common solvent for chemical reactions...
and DIPEA.
Alternatively, an excess (4 eq) of the diol can be used, forcing the reaction toward monoprotection.
Selective deprotection
Selective deprotection of silyl groups is possible in many instances. For example:Silyl ethers are mainly differentiated on the basis of sterics or electronics. In general, acidic deprotections deprotect less hindered silyl groups faster, with the steric bulk on silicon being more significant than the steric bulk on oxygen. Fluoride-based deprotections deprotect electron-poor silyl groups faster than electron-rich silyl groups. There is some evidence that some silyl deprotections proceed via hypervalent silicon species.
The selective deprotection of silyl ethers has been extensively reviewed. Although selective deprotections have been achieved under many different conditions, some procedures, outlined below, are more reliable. A selective deprotection will likely be successful if there is a substantial difference in sterics (e.g., primary TBS vs. secondary TBS or primary TES vs primary TBS) or electronics (e.g. primary TBDPS vs. primary TBS). Unfortunately, some optimization is inevitably required and it is often necessary to run deprotections partway and recycle material.
Some Common Acidic Conditions:
- 100 mol% 10-CSA (camphorsulfonic acidCamphorsulfonic acidCamphorsulfonic acid, sometimes abbreviated CSA or 10-CSA is a organosulfur compound. Like typical sulfonic acids, it is a relatively strong acid that exists as a colourless solid that is soluble in organic solvents....
) in MeOH, room temperature; a "blast" of acid, deprotects primary TBS groups within ten minutes. - 10 mol% 10-CSA, 1:1 MeOH:DCM, −20 or 0 °C; deprotects a primary TBS group within two hours at 0; if CSA is replaced by PPTS, the rate is approximately ten times slower; with pTsOH, approximately ten times faster; solvent mixture is crucial.
- 4:1:1 v/v/v AcOH:THF:water, room temp.; this is very slow, but can be very selective.
Some Common Basic Conditions:
- HF-pyridine, 10:1 THF:pyridine, 0 °C; an excellent deprotection; removes primary TBS groups within eight hours; reactions using HF must be run in plastic containers.
- TBAF, THF or 1:1 TBAF/AcOH, THF; TBDPS and TBS groups can be deprotected in the presence of one another under different conditions.