Williamson Ether Synthesis

Williamson Ether Synthesis

• A method for synthesizing ethers.

• Consists of an acid-base reaction between an alcohol and NaH, followed by a standard SN2 reaction mechanism.

• General transformation: R-OH + R'-X -> R-O-R'

• NaH deprotonates alcohol to generate alkoxide.

• Alkoxide (generated in step 1) acts as the nucleophile.

• Classically a 1° or 2° alkyl halide is the electrophile.

• α-carbon is sp³; alkyl tosylates also work.

• Polar aprotic solvents are used: DMSO, MeCN, THF, DMF, acetone.

• Follows SN2 rules, leading to inversion of stereochemistry if the carbon bearing the leaving group is a stereocenter.

• No reaction occurs on an sp² carbon bearing a leaving group.

• There is no change to the stereochemistry at the α-carbon of the alcohol.

Intramolecular Ether Synthesis of Halohydrins

• AKA Epoxide Synthesis

• Acid-base reaction between alcohol and NaH, followed by standard SN2 reaction mechanism.

• Required backside-attack of an SN2 demands an anti-periplanar relationship between hydroxyl group and leaving group.

• NaH deprotonates alcohol to generate alkoxide.

• Electrophile is classically a 1° or 2° alkyl halide, where α-carbon is sp³. Alkyl tosylates also work.

• 1°, 2°, and 3º alcohols work fine.

• Polar aprotic solvents: DMSO, MeCN, THF, DMF, acetone.

• During reaction, consider the stereochemical outcome, make sure the starting material halohydrin is in the correct conformation.

• The hydroxyl and leaving group must be anti-periplanar.

Halodehydration

• Used for Alkyl Halide Synthesis
• Predominantly SN1 for 2º alcohols
• Exclusively SN1 for 3º alcohols.
• SN2 for 1° alcohols.
• Chlorodehydration of 1° alcohols requires the use of ZnCl2 in HCl (Lucas' Reagent).
• Hydrogen halide acid (never HF) is a reaction component
• Electrophile: a 1º, 2º, or 3º alcohol, where α-carbon is sp3
• The acid (HX) is solvent
• Follows SN1 rules for 2º and 3º alcohols and allylic or benzylic 1º alcohols.
• Racemization of stereochemistry occurs if the carbon bearing the hydroxyl group is a stereocenter.
• For non-allylic/benzylic 1° alcohols, anticipate the SN2 mechanism to be predominant
• Look out for carbocation rearrangements for reactions proceeding via a carbocation intermediate: 2° and 3° alcohols, allylic and benzylic 1º alcohols
• Also look out for allylic rearrangements for reactions proceeding via allylic carbocation intermediates.
• Alkene stability dictates the major product.

Chlorodehydration with SOCl2

• Used for Alkyl Chloride Synthesis

• Generally an SN2 mechanism, not SN1.

• No reaction occurs with 3º alcohols.

• SOCl2 (thionyl chloride) activates the alcohol, converting it to an electrophile, and supplies the nucleophilic chloride.

• Typically, a weak base such as a 3°-amine (pyridine or trimethylamine) is used.

• Alcohol must be 1° or 2°, and α-carbon must be sp³.

• Amine base is often the solvent (polar and aprotic).

• Follows SN2 rules, therefore inversion of streochemistry, if the hydroxyl group is a stereocenter.

Bromodehydration with PBr3

• Used for Alkyl Bromide Synthesis

• Exclusively SN2; no reaction with 3º alcohols.

• PBr3 (phosphorus tribromide) activates the alcohol, converting it to an electrophile, and supplies nucleophilic bromide.

• Weak base: typically a 3°-amine: pyridine or trimethylamine.

• Alcohol must be 1° or 2°, and α-carbon must be sp³.

• Amine base is often the solvent (polar and aprotic).

• Follows SN2 rules, therefore inversion of stereochemistry if the carbon bearing the hydroxyl group is a stereocenter.

Tosylation with TsCl

• Used for Alkyl Tosylate Synthesis

R-OH + TsCl --> R-O-Ts

• Does involve substitution at the α-carbon, it happens at the hydroxyl oxygen.
• Tosylation retains the stereochemical configuration of a chiral α-carbon. TsCl (p-toluenesulfonyl chloride, tosyl chloride) activates the alcohol.
• Weak base: typically a 3°-amine: pyridine or trimethylamine.
• Alcohol: can be any degree of substitution.
• Hybridization of α-carbon is not relevant.
• Phenols can be tosylated, but they cannot participate in SN2 reactions.

Alcohol Dehydration

• Results in Alkene Synthesis
• E1 for 2º and 3° alcohols.
• E2 only for 1º alcohols.
• Acid must have a non-nucleophilic conjugate base, otherwise competitive SN1 is possible.
• Alcohol can be any degree of substitution, and α-carbon must be sp³.
• Consider the acid the solvent.
• Any stereochemistry at the α-carbon is irrelevant since carbocation destroys the stereochemistry of the carbon at that position.
• The trans-alkene product (or products) form preferentially to the cis-isomers.
• Multiple alkene products are possible; the most substituted alkene will often be the major product – Zaitsev's Rule.
• Look-out for carbocation RAR.

POCl3 Mediated Alcohol Dehydration

• Results in Alkene Synthesis
• Always E2; 1º, 2º, and 3º alcohols are all reactive.
• Anti-periplanar β-hydrogen is required for elimination of the activated alcohol.
• POCl3 (phosphorus oxychloride) activates the alcohol.
• Weak base: typically a 3º-amine: pyridine or trimethylamine.
• Alcohol: can be any degree of substitution, but α-carbon must be sp³ for elimination to occur.
• Pyridine is the solvent
• Stereochemistry at the α-carbon is relevant since the reaction proceeds through an E2 mechanism, which requires an anti-periplanar β-hydrogen.
• The trans-alkene product (or products) form preferentially to the cis-isomers.
• Multiple alkene products are possible; the most substituted alkene will often be the major product – Zaitsev's Rule.

Nucleophilic Epoxide Opening

• Results in β-Substituted Alcohol Synthesis
• Always SN2 - sterics are important; the least substituted carbon of the epoxide will be selectively attacked resulting in a regioselective reaction.
• Nucleophile: variable, but typically a strong anionic species.
• Epoxide: the less sterically hindered carbon is preferentially attacked.
• Water: protonates the alkoxide that forms after the epoxide is opened
• Solvents are polar aprotic
• Always SN2, therefore stereochemical inversion occurs if the nucleophile attacks a chiral carbon.

Acid-Catalyzed Epoxide Opening

• SN2-like – protonation of the epoxide oxygen results in partial cleavage of the C-O bond to the more substituted carbon.
• Reaction is highly regioselective.
• Nucleophilic attack occurs at the more substituted carbon similar to SN1.
• Nucleophile: variable. If using HCl, HBr, or HI, then the halide is the nucleophile
• If H2SO4 or TsOH is used then a protic nucleophile can be used, typically alcohols or thiols
• Epoxide: the more sterically hindered carbon is preferentially attacked.
• Water quenches reaction protonates the alkoxide that forms after the epoxide is opened
• Consider either the acid as solvent, or the solvent component of the acid used.
• If the carbon being attacked is a stereocenter, then inversion occurs.
• The more substituted carbon experiences attack because of the partial positive charge buildup, thus mimicking SN1.

Explore the Williamson ether synthesis, covering topics such as the reaction between alcohol and NaH, the preferred solvents, and the stereochemical outcomes. Understand the roles of different reaction components and the use of thionyl chloride. Learn about the requirements for effective chlorodehydration of primary alcohols.