Williamson Ether Synthesis and Halodehydration

Williamson Ether Synthesis: Ether Synthesis

• This is a two-step reaction using an acid-base reaction between an alcohol and NaH, followed by a standard SN2 reaction mechanism.
• In step one, NaH, a base, deprotonates the alcohol to generate an alkoxide.
• The alkoxide generated in step one is the nucleophile.
• Only primary and secondary alcohols make for good nucleophiles.
• The electrophile is classically a primary or secondary alkyl halide, where the alpha-carbon is sp3 hybridized; alkyl tosylates work as well.
• The solvent needs to be polar aprotic, for example: DMSO, MeCN, THF, DMF, and/or acetone.
• This reaction follows all SN2 rules, therefore inversion of stereochemistry occurs, if the carbon bearing the leaving group is a stereocenter.
• There is no reaction on an sp2 carbon bearing a leaving group.
• There is no change of stereochemistry at the alpha-carbon of the alcohol.

Intramolecular Williamson Ether Synthesis of Halohydrins: Epoxide Synthesis

• A base, like NaH deprotonates an alcohol, followed by an SN2 reaction mechanism.
• The required backside-attack of an SN2 demands an anti-periplanar relationship between the hydroxyl group and the leaving group.
• In terms of reaction components, a base, like NaH deprotonates the alcohol to generate an alkoxide.
• The alkoxide generated in step one is the nucleophile; primary, secondary and tertiary alcohols all work fine.
• The electrophile is classically a primary or secondary alkyl halide, where alpha-carbon is sp3 hybridized; alkyl tosylates work as well.
• the solvent needs to be polar aprotic, for example: DMSO, MeCN, THF, DMF, and/or acetone.
• When considering the stereochemical outcome of the reaction, ensure that the starting material (halohydrin) is drawn in the correct conformation.
• The hydroxyl and leaving group must be anti-periplanar.

Halodehydration: Alkyl Halide Synthesis

• Predominantly SN1 for secondary alcohols, and exclusively SN1 for tertiary alcohols.
• SN2 for primary alcohols.
• Chlorodehydration of primary alcohols requires the use of ZnCl2 in HCl (Lucas' Reagent).
• For reaction components:
  • hydrogen halide acid (never HF) is required
• ZnCl2 is needed, if reacting a primary alcohol with HCl
• Electrophile: a primary, secondary, or tertiary alcohol, where alpha-carbon is sp3 hybridized.
• Consider the acid (HX) to be the solvent.
• This follows all SN1 rules for secondary and tertiary alcohols and allylic or benzylic primary alcohols, therefore racemization of stereochemistry occurs if the carbon bearing the hydroxyl group is a stereocenter.
• For non-allylic/benzylic primary alcohols, expect the mechanism to be SN2.
• Look-out for carbocation rearrangements, for reactions proceeding via a carbocation intermediate (secondary and tertiary alcohols, allylic and benzylic primary alcohols).
• Look-out for allylic rearrangements for reactions proceeding via allylic carbocation intermediates; alkene stability dictates the major product.

Chlorodehydration with SOCl2: Alkyl Chloride Synthesis

• This is typically an SN2 reaction not SN1, so there is no reaction with tertiary alcohols.
• Internal Nucleophilic Substitution results in retention of stereochemistry.
• SOCl2 (thionyl chloride) activates the alcohol, converting it to an electrophile, and supplies the nucleophilic chloride.
• Use of a weak base, typically a 3-amine: pyridine or trimethylamine is needed.
• An alcohol must be primary or secondary, and alpha-carbon must be sp3 hybridized.
• The amine base is often the solvent (polar and aprotic).
• This reaction follows all SN2 rules, therefore inversion of stereochemistry occurs if the carbon bearing the hydroxyl group is a stereocenter.

Bromodehydration with PBr3: Alkyl Bromide Synthesis

• This is exclusively an SN2 reaction; no reaction with tertiary alcohols.
• PBr3 (phosphorus tribromide) activates the alcohol, converting it to an electrophile, and supplies the nucleophilic bromide.
• Use a weak base, typically a 3°-amine: pyridine or trimethylamine.
• An alcohol: must be primary or secondary, and alpha-carbon must be sp3 hybridized.
• Amine base here is often the solvent (polar and aprotic.)
• This reaction follows all SN2 rules, therefore inversion of stereochemistry occurs if the carbon bearing the hydroxyl group is a stereocenter.

Tosylation with TsCl: Alkyl Tosylate Synthesis

• There is no substitution at the alpha-carbon, but rather at the hydroxyl oxygen.
• Tosylation retains the stereochemical configuration of a chiral alpha-carbon.
• TsCl (p-toluenesulfonyl chloride, tosyl chloride) activates the alcohol.
• Use a weak base: typically a tertiary amine: pyridine or trimethylamine.
• Alcohol can be any degree of substitution, and hybridization of alpha-carbon is not relevant.
• Phenols can be tosylated, but they cannot participate in SN2 reactions.
• This reaction uses a polar and aprotic solvent.
• Stereochemical considerations are particularly relevant when considering synthesizing chiral molecules.

Alcohol Dehydration: Alkene Synthesis

• E1 reactions occur for secondary and tertiary alcohols.
• E2 reactions occur only for primary alcohols.
• The acid must have a non-nucleophilic conjugate base, otherwise competitive SN1 is possible.
• The alcohol can be any degree of substitution, and alpha-carbon must be sp3 hybridized.
• Consider the acid to be the solvent.
• Any stereochemistry at the alpha-carbon is irrelevant since the reaction proceeds through carbocation at that position, which destroys the stereochemistry of the carbon.
• The trans-alkene product (or products) form preferentially to the cis-isomers.
• Multiple alkene products are often possible; the most substituted alkene will often be the major product – Zaitsev's Rule.
• Look-out for carbocation rearrangements.

POCl3 Mediated Alcohol Dehydration: Alkene Synthesis

• This is always an E2 reaction; primary, secondary, and tertiary alcohols are all reactive.
• Given the E2 mechanism, an anti-periplanar beta-hydrogen is required for elimination of the activated alcohol.
• POCl3 (phosphorus oxychloride) activates the alcohol.
• Use of a weak base, typically a tertiary amine like pyridine or trimethylamine is needed.
• The alcohol can be any degree of substitution, but alpha-carbon must be sp3 hybridized for elimination to occur.
• Consider the pyridine to be the solvent.
• Stereochemistry at the alpha-carbon is relevant since the reaction proceeds through an E2 mechanism, which requires an anti-periplanar beta-hydrogen.
• The trans-alkene product (or products) form preferentially to the cis-isomers.
• Multiple alkene products are often possible; the most substituted alkene will often be the major product – Zaitsev's Rule.

Nucleophilic Epoxide Opening: β-Substituted Alcohol Synthesis

• This is always an SN2 reaction, sterics are important.
• The least substituted carbon of the epoxide will be selectively attacked resulting in a regioselective reaction.
• The nucleophile is variable, but typically a strong anionic species.
• The less sterically hindered carbon, of the epoxide, is preferentially attacked.
• Water is added to quench the reaction, which protonates the alkoxide that forms after the epoxide is opened.
• This reaction uses a polar aprotic solvent.
• This is always SN2, therefore stereochemical inversion occurs if the nucleophile attacks a chiral carbon.
• Keep in mind the regioselectivity of this reaction.

Acid-Catalyzed Epoxide Opening: β-Substituted Alcohol Synthesis

• This performs a "SN2-like" reaction by protonating the epoxide oxygen, partly cleaving the C-O bond to the more substituted carbon.
• This results in significant partial positive charge buildup on that carbon.
• This reaction is highly regioselective with nucleophilic attack occurring at the more substituted carbon, similar to SN1.
• 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.
• The more sterically hindered carbon, of the epoxide, is preferentially attacked.
• Water is added to quench the reaction, which protonates the alkoxide that forms after the epoxide is opened.
• Consider the acid (or other nucleophile as the solvent).
• If the carbon being attacked is a stereocenter, then inversion occurs.
• However, unlike a typically SN2 reaction, the more substituted carbon is attacked due to the partial positive charge buildup, thus mimicking SN1.
• Keep in mind the regioselectivity of this reaction.

Explore the Williamson ether synthesis, including solvent preferences, nucleophile suitability, and typical bases. Understand the reaction mechanism and stereochemical outcomes. Also, examine halodehydration reactions of alcohols, focusing on stereochemistry and mechanisms for primary and tertiary alcohols.