Chapter 9: Further Reactions of Alcohols and the Chemistry of Ethers

Further Reactions of Alcohols and the Chemistry of Ethers

Oxidation of Alcohols to Aldehydes and Ketones

Alcohols can be oxidized to form aldehydes or ketones, depending on their structure and the oxidizing agent used. Pyridinium chlorochromate (PCC) is a common reagent for these transformations.

• Primary alcohols are oxidized to aldehydes:

• Secondary alcohols are oxidized to ketones:

Example Reactions:

• Primary alcohol + PCC → Aldehyde

• Secondary alcohol + PCC → Ketone

Equation:

• $\ce{RCH2OH} + [O] \rightarrow \ce{RCHO} + H2O$

• $\ce{R2CHOH} + [O] \rightarrow \ce{R2CO} + H2O$

SN1/SN2 Via Protonation

Alcohols can undergo substitution reactions via SN1 or SN2 mechanisms after protonation, which converts the poor leaving group (OH) into a better one (H2O).

• Primary alcohols react with HX to form alkyl halides via SN2 mechanism.

• Secondary and tertiary alcohols react via SN1 mechanism, forming carbocations and leading to mixtures of products (alkyl halides and alkenes).

• Protonation is required to activate the alcohol for substitution.

Equation:

• $\ce{R-OH} + HX \rightarrow R-X + H2O$

Example: Cyclohexanol reacts with HBr to form bromocyclohexane.

Carbocation Rearrangements

During SN1 reactions, carbocation intermediates may undergo rearrangements such as hydride or alkyl shifts to form more stable carbocations.

• Hydride shifts move a hydrogen atom with its bonding electron pair to an adjacent carbocation, increasing stability.

• Degenerate rearrangement occurs when a tertiary carbocation rearranges to another tertiary carbocation.

• Rearrangements are most favorable when they lead to a more substituted (more stable) carbocation.

Equation:

• $\ce{R-CH2-CH(OH)-R'} + H^+ \rightarrow [R-CH2-CH^+-R'] \rightarrow$ (hydride shift) $[R-CH^+-CH2-R']$

Example: Hydride shift in the reaction of 3° alcohol with HBr leads to a major rearranged product.

Mechanism of Carbocation Rearrangement

The mechanism involves four steps: protonation, loss of water, hydride shift, and trapping by nucleophile (e.g., bromide).

1. Protonation: Alcohol is protonated to form a better leaving group.

2. Loss of water: Water leaves, forming a carbocation.

3. Hydride shift: Hydride migrates to stabilize the carbocation.

4. Trapping: Nucleophile attacks the carbocation, forming the final product.

The Hydride Shift Transition State

Hydride shifts occur via a concerted process, with the migrating hydride and the carbocation on the same side. This process is facilitated by hyperconjugation and orbital overlap.

• Note: Hydride shift is a concerted process, not stepwise.

More Complications: Alkyl Shifts

Alkyl shifts can also occur during carbocation rearrangements, especially when hydride shifts are not possible. Alkyl shifts are slower than hydride shifts but can compete under certain conditions.

• Alkyl shift moves an alkyl group with its bonding electrons to an adjacent carbocation.

• Best when shifting from secondary to tertiary carbocation.

Example: Rearrangement by alkyl shift in SN1 reaction of 2° alcohol with HBr.

Turning ROH into RNu without the Use of Acid

Alcohols can be converted to alkyl halides using inorganic reagents such as PBr3 or ClSOCl, avoiding strong acids and carbocation rearrangements.

• PBr3 is used for converting alcohols to alkyl bromides.

• ClSOCl is used for converting alcohols to alkyl chlorides.

• These methods are milder and avoid carbocation formation.

Equation:

• $3\ce{ROH} + \ce{PBr3} \rightarrow 3\ce{RBr} + \ce{H3PO3}$

Mechanism of PBr3 Reaction with ROH

The reaction proceeds via two main steps: formation of a good leaving group and nucleophilic substitution (SN2).

1. Step 1: Alcohol reacts with PBr3 to form an intermediate with a good leaving group.

2. Step 2: Bromide ion attacks via SN2, displacing the leaving group and forming the alkyl bromide.

Example: 3-pentanol reacts with PBr3 to form 3-bromopentane and phosphorous acid.

Ethers: Structure and Properties

Ethers are compounds with an oxygen atom bonded to two alkyl or aryl groups. They lack acidic hydrogens and do not form hydrogen bonds, making them aprotic polar solvents with relatively low boiling points.

• Functional group: Alkoxyl (-OR)

• Examples: Diethyl ether, tetrahydrofuran (THF)

• Ethers are inert and commonly used as solvents in organic reactions.

The Williamson Ether Synthesis

The Williamson ether synthesis is a method for preparing ethers by reacting an alkoxide ion with a haloalkane via an SN2 mechanism.

• Best with unhindered primary alkyl halides and alkoxides.

• Polar aprotic solvents (e.g., DMSO) increase yield.

• Good leaving group (X) is required.

Equation:

• $\ce{R-X} + \ce{R'-O^-} \rightarrow \ce{R-O-R'} + X^-$

Example: Sodium alkoxide reacts with chloroalkane to form ether.

Synthesis of Cyclic Ethers

Cyclic ethers, such as epoxides, can be synthesized via intramolecular Williamson synthesis, where a haloalkane and alcohol are present in the same molecule.

• Deprotonation forms an alkoxide, which attacks the haloalkane intramolecularly.

• Results in ring closure and formation of cyclic ether.

Example: Formation of epoxide from 2-haloethanol.

Reaction of Strained Ethers (Epoxides)

Strained ethers such as epoxides react readily by ring opening, releasing ring strain. The reaction conditions determine the regioselectivity and mechanism.

• Basic conditions: Nucleophile attacks less hindered carbon via SN2 mechanism.

• Acidic conditions: Ether is activated, and nucleophile attacks more substituted carbon via SN1-like mechanism.

• Regioselectivity is determined by steric and electronic effects.

Equation:

• $\ce{Epoxide} + Nu^- \rightarrow \ce{Ring-opened product}$

Example: Methanol opens epoxide ring in the presence of acid to form 1-methoxy-2-ethanol.

Regioselectivity in Epoxide Ring Opening

For unsymmetrical epoxides, the site of nucleophilic attack depends on the reaction conditions:

• Basic conditions: Attack at less hindered (less substituted) carbon.

• Acidic conditions: Attack at more substituted carbon due to better stabilization of positive charge.

• Electronic effects favor nucleophilic attack at the carbon bearing greater partial positive charge ($\delta^+$).

Example: Acid-catalyzed ring opening of 2-methyl-oxirane leads to nucleophilic attack at the more substituted carbon.

Table: Comparison of Alcohol and Ether Properties

Compound	Functional Group	Hydrogen Bonding	Boiling Point	Solvent Properties
Alcohol	Hydroxyl (-OH)	Yes	High	Protic, polar
Ether	Alkoxyl (-OR)	No	Low	Aprotic, polar

Additional info: The notes cover advanced aspects of alcohol and ether chemistry, including mechanisms, rearrangements, and synthetic applications, suitable for college-level organic chemistry.