Reactivity of Alcohols, Ethers, and Epoxides | Organic Chemistry 1

The reactivity of alcohols, ethers and epoxides are studied in this chapter: typical reactions of alcohols (deprotonation, substitution, elimination, oxidation), preparation of alkoxides, nucleophilic substitutions of alcohols, dehydration of alcohols, carbocation rearrangements, reactivity of ethers, epoxide opening

Typical Reactions of Alcohols

Preparation of Alkoxides

Deprotonation with a base:


Bronsted acid-base reaction. Strong bases are needed to deprotonate alcohols (pKa ~ 16-18). Butyl lithium (BuLi), sodium hydride (NaH) and potassium hydride (KH) are commonly used


Deprotonation with a metal:


Reduction with alkali metals

Nucleophilic Substitutions of Alcohols

Formation of alkyl halides:


SN2 reactions

  1. The OH group is converted into a good leaving group (OSOCl or HO+PBr2)
  2. Nucleophilic attack of X- and loss of the leaving group (SO2 / Cl- or HOPBr2)


Formation of alkyl halides with HX:

HO- is a bad leaving group and can be replaced with a better leaving group to favor SN reactions. HX is for example used:



CH3OH and primary alcohols: SN2 reactions

  1. Protonation of the OH group - Formation of a good leaving group H2O

  2. Nucleophilic attack of X-


Secondary and tertiary alcohols: SN1 reactions
Carbocations are intermediates and rearrangements can occur


Formation of alkyl tosylates:


This process converts the poor leaving group -OH into a good one -OTs
TsCl is called p-toluenesulfonyl chloride or tosyl chloride. The tosylate -OTs is a good leaving group because it is stabilized by resonance forms

Alkyl tosylates undergo either substitution or elimination, depending on the reagent: 

Substitution reaction:

Mechanism: SN2 reaction with strong nucleophile

Elimination reaction:

Mechanism: E2 reaction with strong base

Dehydration of Alcohols

Dehydration using strong acid:


Primary alcohols: E2 reaction

  1. Protonation of the oxygen atom - Formation of HSO4-

  2. β elimination using HSO4- as base


Secondary and tertiary alcohols: E1 reaction - carbocation rearrangements can occur

  1. Protonation of the oxygen atom - Formation of HSO4-
  2. Heterolytic cleavage of the C-O bond - Formation of a carbocation
  3. β elimination using HSO4- as base


Dehydration using POCl3:


E2 reaction - no carbocation rearrangements occurs

  1. Converting OH group into OPOCl2, a good leaving group
  2. β elimination using pyridine as base

Carbocation Rearrangements

Electron-donating groups, such as alkyl groups, stabilize a positive charge ⇒ stability of carbocations: tertiary > secondary > primary. A less stable carbocation can rearrange to a more stable carbocation. These rearrangements involve the migration of an alkyl group or a hydrogen atom from a carbon atom to an adjacent carbon atom. They are respectively called 1,2-alkyl shift and 1,2-hydride shift


  1. Loss of a good leaving group - Formation of a carbocation

  2. 1,2-shift of a hydrogen atom or an alkyl group - Formation of a more stable carbocation

  3. SN1 (nucleophilic attack to form the substitution product) or E1 (loss of a proton to form an alkene)

Reactivity of Ethers

Cleavage of C-O bonds with strong acids:


Methyl and primary alkyl groups: SN2 reaction

  1. Protonation of the oxygen atom - Formation of X-

  2. Nucleophilic attack of the carbocation by X - Formation of RX and R'OH (which will react with another equiv. of HX)


Secondary and tertiary alkyl groups: SN1 reaction

  1. Protonation of the oxygen atom - Formation of X-
  2. Cleavage of a C-O bond - Formation of a carbocation and R'OH (which will react with another equiv. of HX)
  3. Nucleophilic attack of the carbocation by X - Formation of RX

Reactivity of Epoxides

Epoxide opening with strong nucleophiles:

The nucleophile attacks the less hindered carbon atom


  1. SN2 reaction - backside attack

  2. Protonation of the alkoxide with water


Epoxide opening with acids:

The nucleophile attacks the more hindered carbon atom


  1. Protonation of the epoxide oxygen

  2. SN2 reaction - backside attack


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Alcohols typically undergo reactions such as nucleophilic substitution, elimination, oxidation, and esterification, each influenced by their structure. Primary alcohols readily participate in oxidation reactions to form aldehydes and carboxylic acids whereas secondary alcohols usually yield ketones. Tertiary alcohols are less prone to oxidation, but are more susceptible to nucleophilic substitution and elimination due to steric hindrance. The presence of the hydroxyl group (-OH) also allows alcohols to form alkoxides with strong bases, which are useful intermediates in various synthetic reactions.

Alkoxides are formed when alcohols react with a strong base, such as sodium hydride (NaH) or sodium metal (Na), resulting in the abstraction of the hydrogen atom from the hydroxyl group (-OH) to form an alkoxide ion.

Alkoxides are good nucleophiles and strong bases, making them key intermediates in a variety of organic reactions such as the Williamson ether synthesis or as nucleophilic substitution reactions. They can also be used as bases to deprotonate other compounds in organic synthesis to facilitate further chemical transformations.

The rate of nucleophilic substitutions in alcohols is influenced by several key factors: 

  • The nature of the leaving group ⇒ a good leaving group, such as a water molecule generated from an alcohol protonation, will facilitate the reaction.
  • The structure of the alcohol ⇒ primary alcohols undergo substitutions more slowly than secondary and tertiary alcohols due to the lower stability of the carbocation intermediate.
  • The strength and solvation of the nucleophile ⇒ stronger, less hindered nucleophiles tend to react faster, and polar aprotic solvents generally increase the rate by better solvating the cations without stabilizing anions, thus enhancing nucleophilicity.
  • Primary alcohols preferentially undergo SN2 reactions because their central carbon atom is less sterically hindered, allowing the nucleophile to attack directly and displace the leaving group in one concerted step.
  • Secondary and tertiary alcohols, on the other hand, are more hindered, making it difficult for nucleophiles to approach. Therefore, they tend to undergo SN1 reactions where the alcohol leaves first, forming a more stable carbocation intermediate, and then the nucleophile attacks in a separate step.

The general mechanism involves protonation of the alcohol followed by loss of water to form a carbocation intermediate. The final step is deprotonation to yield the alkene product.

The dehydration of alcohols to form alkenes is influenced by several factors, including the type of alcohol, the acid catalyst used, and the reaction conditions.

  • Primary alcohols generally require harsher conditions for dehydration than secondary and tertiary alcohols, which can undergo the reaction more readily due to the increased stability of the resulting carbocations.
  • Strong acid catalysts, such as sulfuric or phosphoric acid, are often used to facilitate the reaction by protonating the alcohol, making it a better leaving group.
  • The reaction temperature and duration also play a significant role: higher temperatures tend to favor alkene formation and increase the reaction rate.

Carbocation rearrangements are structural reorganizations in which a carbocation (a positively charged carbon species) shifts its position within a molecule to form a more stable carbocation. These rearrangements typically occur during reactions such as the dehydration of alcohols or in certain substitution reactions when an intermediate carbocation is formed. They are driven by the tendency of molecules to reach a lower energy state; therefore, a carbocation will rearrange if it can form a more stable secondary or tertiary carbocation.

Carbocation rearrangements in alcohol reactions typically occur under conditions of dehydration, where an alcohol is converted to an alkene. The rearrangement involves the migration of a hydride or alkyl group to a neighboring carbon, resulting in the formation of a more stable carbocation intermediate.

  • E1 reactions involve a two-step process where the leaving group departs first to form a carbocation intermediate, which may undergo rearrangements to form a more stable carbocation before the elimination step occurs.
  • In contrast, E2 reactions proceed through a single concerted step where the base removes a proton from the substrate while the leaving group departs simultaneously. Because there is no intermediate carbocation formed in an E2 reaction, there is no opportunity for carbocation rearrangements to occur.

Ethers are less reactive than alcohols primarily due to the absence of the hydroxyl group, which is a reactive site in alcohols. In ethers, the oxygen is attached to two alkyl or aryl groups instead of a hydrogen atom, leading to a more stable molecular structure with no acidic hydrogens. Furthermore, ethers lack the ability to hydrogen bond with other molecules, which means they do not readily participate in reactions such as nucleophilic substitutions or dehydration that are typical for alcohols. The lone pairs of electrons on the ether oxygen are also less available for forming bonds with other atoms due to the lower electron density around the oxygen atom caused by its bonding with two carbon atoms.

Ethers typically undergo cleavage reactions when treated with strong acids like hydroiodic (HI) or hydrobromic (HBr) acids. In these acid-catalyzed reactions, the ether oxygen is protonated, making the ether more susceptible to nucleophilic attack, resulting in the cleavage of the C-O bond. The cleavage results in the formation of alkyl halides and alcohols or two alkyl halides if excess acid is used.

Epoxides are significantly more reactive than other ethers due to the strain in their three-membered ring structure. This ring strain increases chemical reactivity, making epoxides more susceptible to nucleophilic attack. Unlike other ethers which are generally quite stable and unreactive toward nucleophiles, epoxides can readily open their ring structure in the presence of nucleophiles under either acidic or basic conditions.


The regioselectivity in the opening of asymmetric epoxides depends on the reaction conditions.:

  • Under basic conditions, nucleophilic attack occurs at the less hindered carbon of the epoxide ring, driven by steric factors, resulting in the formation of the more substituted alcohol.
  • Under acidic conditions, the epoxide undergoes protonation, forming a positively charged oxygen atom. The nucleophile attacks the carbon bearing the positive charge, leading to the formation of the less substituted alcohol.