EXAM 6 REACTIONS OF ALCOHOLS, PHENOLS, ETHERS, EPOXIDES, THIOLS, AND SULFIDES

Preparation of alcohols: 1. To form a primary alcohol: - Primary alkyl halide SN2 reaction with strong nucleophile, NaOH

2. To form a tertiary alcohol: - Tertiary alkyl halide SN1 reaction with weak nucleophile, H2O

3. To form a secondary alcohol: - Secondary alkyl halide not as efficient! Better to use an alkene to prepare secondary alcohol - Alkene (3 ways) 1. Dilute H2SO4 (H2O, H2SO4) – acid catalyzed hydration2. (1) Hg(OAc)2, H2O (2) NaBH4 – oxymercuration demercuration no rearrangements3. (1) BH3, THF (2) H2O2, NaOH – hydroboration oxidation

4. Prep by reduction1. Catalytic Hydrogenation (H2, Pt/Pd/Ni) – reduces carbonyl groups & double bonds (not selective)

2. Sodium borohydride (NaBH4) (NaBH4, EtOH/MeOH/or H2O) – Selectively reduces only aldehydes to primary alcohols, and ketones to secondary alcohols

3. Lithium aluminum hydride (LiAlH4) (1. LAH (or LiAlH4), 2. H2O) – reduce aldehydes, ketones, carboxylic acids, and esters to alcohols. Aldehydes –> primary alcoholsCarboxylic acids –> primary alcohols Esters –> primary alcohols Ketones –> secondary alcohols

Selectivity of Reducing Agents

- NaBH4 – will not reduce alkene double bonds (very selective for only aldehydes + ketones)- LiAlH4 (LAH) – will not reduce alkene double bonds (selective for aldehydes, ketones, carboxylic acids, esters) - H2/Pt, Pd, or Ni – will reduce alkene double bonds (not selective- reduces all carbonyl and double bonds)

5. Reaction of carbonyl compounds with Grignard reagents to form Alcohols

- reaction of a carbonyl compound in a two-step reaction: 1. RMgX/ 2. H2Oto form alcohols and add an R group

- you may prepare a Grignard reagent with by using an alkyl halide and adding Mg:

Oxidation and ReductionOxidation: Loss of electron, loss of a C—H bond, formation of a C—O bond (or C—N, C—Cl) Reduction: Gain of electron, formation of a C—H bond, loss of a C—O bond (or C—N, C—Cl)

Diols: Preparation- 2 ways: 1. Starting with an alkene2. Starting with a ketone

1. Alkenea. 1. RCO3H, 2. H3O+ (anti-dihydroxylation)b. OsO4, NMO (syn-dihydroxylation)

2. Ketones

a. H2/Pdb. 1.LAH, 2. H2Oc. NaBH4, MeOH

Protection of Alcohols- When you have an alcohol with another substituent on it that you’d like to do a Grignard reaction with, you can protect the alcohol to ensure it is not affected. You can do so by using the following reagent:TMSCl, Et3N- this will convert the OH into OTMS as you complete your reaction. You can then deprotect the alcohol once you have your desired product by using: TBAF

Alcohol reactions- alcohols can undergo elimination and nucleophilic substitution- in order to do so, they must be converted into good leaving groups

1. SN1 reactions with alcohols - tertiary alcohols + HX (X= Cl, Br, I, F) - carbocation intermediate is formed - first, you protonate your alcohol!!

2. SN2 reactions with alcohols a. primary and secondary alcohols + HX (X= Br)

- IMPORTANT: HCl does not work as well with primary/secondary alcohols!! You must use ZnCl2 as a catalyst in order for this reaction to work!!

b. alcohol + TsCl/pyridine

- SN2, so stereochemistry inverts!c. Primary and secondary alcohols reacting with SOCl2/pyridine, and PBr3

- SOCl2 with Pyridine converts OH to Cl (stereochemistry inverts)

- PBr3 OH converts to Br (stereochemistry inverts)

3. E1 and E2 reactions with alcohols – Dehydration

a. alcohol + concentrated H2SO4 & heat – can undergo rearrangement!- primary alcohols in an E2 mechanism

- secondary alcohols in an E1 mechanism - tertiary alcohols in an E1 mechanism

b. alcohol + TsCl/Pyridine, then NaOEt – do not undergo rearrangements!

- E2 mechanism since alcohol is turned into a better leaving group (OH –> OTs)

4. Reactions with oxidating agents Primary alcohols: a. Na2Cr2O7/H2SO4, H2O (chromic acid) converts primary alcohol to carboxylic acid

b. PCC (pyridinium chlorochromate)/CH2Cl2 (solvent) converts primary alcohol to aldehyde

Secondary alcohols: a. Na2Cr2O7/H2SO4, H2O (chromic acid) converts secondary alcohol to ketone

b. PCC (pyridinium chlorochromate)/CH2Cl2 converts secondary alcohol to ketone

Oxidation of Phenols- using Na2Cr2O7/H2SO4, H2O phenol is oxidized to form benzoquinone

Ethers and Epoxides; Thiols and Sulfides

Crown Ethers- 12-crown-4: solvates Li+- 15-crown-5: solvates Na+- 18-crown-6: solvates K+

Preparation of Ethers1. Industrial preparation of diethyl ether – 2 alcohols + acid (H2SO4 or H3O+) diethyl ether - SN2 process- only works well for primary alcohols

2. Williamson Ether synthesis - 2 step process- 1st step: hydride ion acts as a base and deprotonates the alcohols- 2nd step: the alkoxide ion acts as a nucleophile and attacks the alkyl halide in an SN2 process - steric considerations!! (methyl and primary alkyl halides work best for an SN2 mechanism)

3. Alkoxymercuration-Demercuration - markovnikov addition of RO and OH across the alkene

Ether Reactions

1. Acidic cleavage - ether is converted into two alkyl halides - Excess HX, heat (X= Br, I)

2. Phenyl ether cleaved under acidic conditions

Epoxide Preparation

1. Alkene converted into halohydrin with Br2/H2O, and treated with a strong base to form an epoxide (NaOH)

- remember: Br to the less substituted side, OH to the more substituted side.- form racemic mixtures

2. Alkene + MCPBA

- form racemic mixtures

3. Enantioselective epoxidation

- using (+)-DET and (-)-DET (+)-DET: adds above the plane (-)-DET: adds below the plane

Ring-opening reactions of epoxides

1. With strong nucleophiles (basic conditions) - using RONa/H2O, NaCN/H2O, NaSH/H2O, RMgBr/H2O, LAH/H2O- must consider regiochemistry and stereochemistry!!a. Regiochemistry- when the epoxide is unsymmetrical, the nucleophile will attack the less substituted position b. Stereochemistry- when the attack takes place at a chiral center, inversion of configuration occurs (ONLY AT THE CARBON ATTACKED)

2. With acidic conditions - HX (X= HCl, HBr, HI), [H+]/H2O, [H+]/ROH a. Regiochemistry: attack at the more substituted sideb. Stereochemistry: inversion at the carbon attacked

Thiol preparation

1. alkyl halide + NaSH - SN2 reaction – inversion of stereochemistry- can occur well with primary and secondary alkyl halides because SH is a strong nucleophile, but a weak base

Thiol Reactions1. oxidation of thiols - produce disulfides - using NaOH/H2O, Br2

Sulfide preparations

1. from oxidation of thiols (as seen above)

2. Thiol + (1) NaOH/(2) RX (RX= alkyl halide)- SN2 mechanism - works with methyl, primary, and secondary alkyl halides - does not work with tertiary alkyl halides

Sulfide Reactions 1. Reduction of disulfide- Disulfide + HCl, Zn produces 2 thiols

2. Oxidation of sulfides a. NaIO4- produces sulfoxides

b. 2 H2O2- produces sulfone