CM1501 – Alcohols and phenols (part II)

Dr. Hoang T. Giang

chmhoan@nus.edu.sg

Office: S5-05-08

Reference: McMurry’s Organic Chemistry 8th ed. chapter 17

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3.2 Alcohols to halides

a. Conversion of alcohols into alkyl halides Tertiary alcohol + HBr alkyl bromide + HCl alkyl chloride Mechanism: SN1 (carbocation formation) Examples: Primary and secondary alcohols reaction with SOCl2 alkyl chloride reaction with PBr3 alkyl bromide Mechanism: SN2

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3.2 Alcohols to halides

- What is the stereochemistry for the SN2 product?

- Can we use HCl or HBr with primary and secondary alcohols?

- Can we use SOCl2 or PBr3 with tertiary alcohols?

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3.2 Alcohols to tosylates

b. Conversion of alcohols into tosylate Alcohols react with p-toluenesulfonyl chloride (p-TosCl) to yield alkyl tosylates - OTos (can be written as OTs) is an excellent leaving group, alkyl tosylates behave much like alkyl halides in SN1 and SN2 reactions

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3.2 Alcohols to tosylates

Substitution reaction with tosylates

why we need R-OTos if we can use bromide or chloride?

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3.2 Alcohols to tosylates

Stereochemistry: In the formation of alkyl tosylate, only the O-H bond is broken, the C-O bond remains intact

From the same alcohol Either R or S product can be made

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3.2 Alcohols to tosylates

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3.3 Acidity and protecting group

a. Alcohols are weak acids Alcohols do not react with weak bases, such as NaHCO3, amine and very limited extent with NaOH Strong bases: NaNH2, Grignard reagent deprotonate alcohols

Reactions with alkali metals - Phenol is stronger acid than alcohol, phenol can react with NaOH

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3.3 Acidity and protecting group

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3.3 Acidity and protecting group

Implications of alcohol acidity: 1. Grignard reagents cannot be used in the presence of

alcohol -OH group R-MgBr + R’-O-H R-H + R’O-MgBr (strong base) (weak acid) 2. Deprotonation of alcohols gives alkoxide, which is much

stronger nucleophile than the alcohol (for SN2 reaction)

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3.3 Acidity and protecting group

b. Protection of alcohols: Conversion of alcohols into trimethylsilyl ether - Trimethylsilyl ethers (TMS ethers) do NOT react with oxidizing agents (PCC, Dess-Martin, Jone oxidation), reducing agents (LiAlH4)or Grignard reagents (RMgBr)

- Trimethylsilyl ethers react with aqueous acid or fluoride ion (F-) to regenerate the alcohol (deprotection)

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3.3 Acidity and protecting group

Example of using protecting groups:

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3.3 Acidity and protecting group

Example of using protecting groups:

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3.3 Acidity and protecting group

a. Williamson’s ether synthesis - The most generally useful method in preparing ethers - alkoxide ion (formed from reaction between alcohol and NaH) reacts with a primary (or secondary) halide/tosylate

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3.3 Other reactions of alcohols

What is the product?

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3.3 Other reactions of alcohols

b. Esterification - Alcohols react with carboxylic acids to give esters, a strong acid such as sulfuric acid is used as catalyst

- Esterification reaction under acidic catalyst is equilibrium: large amount of alcohols (or carboxylic acids) is needed to drive the reaction toward product

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3.3 Other reactions of alcohols

b. Esterification A more practical method to synthesize ester is by reacting alcohol with acid chloride (more reactive than carboxylic acid) 1 eq of organic base, such as pyridine is typically added to remove the HCl formed

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3.3 Other reactions of alcohols