Ethers and Epoxides: ochem2 week 7 part 2
Ether Nomenclature
Common Naming (More Popular for Simplicity)
Identify the two carbon chains (R groups) attached to the ether oxygen.
Name these R groups as substituents (e.g., methyl, ethyl, isopropyl, phenyl, benzyl).
List them in alphabetical order.
Add the word "ether" at the end.
Examples:
Isopropyl methyl ether: For a structure with an isopropyl group and a methyl group on either side of the oxygen.
Ethyl phenyl ether: For a structure with an ethyl group and a phenyl group (benzene directly bonded to oxygen) on either side.
Note on Benzene Derivatives:
Phenyl: Benzene ring directly bonded to the oxygen (C6H5-O-R).
Benzyl: Benzene ring separated from the oxygen by a carbon (C6H5-CH_2-O-R).
IUPAC Naming (Systematic Naming)
Ethers are not priority groups; they are treated as substituents.
They do not necessitate the lowest possible numbering on their own unless part of a tie-breaker.
Steps:
Identify the Parent Chain:
For linear structures, this is the longest continuous carbon chain.
For rings, the ring itself is the parent chain.
Identify the Alkoxy Group: One side of the ether oxygen (the shorter R group) combined with the oxygen forms an "alkoxy" substituent.
To name it, drop the "-yl" from the alkyl name and add "-oxy" (e.g., methyl becomes methoxy, ethyl becomes ethoxy, propyl becomes propoxy).
Number the Parent Chain: Assign numbers to the parent chain, giving the lowest possible number to the alkoxy substituent according to standard IUPAC rules.
Construct the Name: Prepend the number and the alkoxy substituent name to the parent chain name.
Examples:
Two ethoxy pentane: For a pentane chain with an ethoxy group on the second carbon. (The side that is not part of the parent chain forms the substituent name).
Ethoxybenzene: For a benzene ring with an ethoxy group attached.
Two methoxy propane: For a propane chain with a methoxy group on the second carbon.
Para dimethoxy benzene: For a benzene ring with two methoxy groups in a para relationship. (This replaces common names like "anisole" when there are multiple substituents; benzene is treated as the parent).
Ether Synthesis Reactions
1. Acid-Catalyzed Ether Synthesis (SN2 Mechanism)
Conditions: Acidic conditions (e.g., H2SO4) with an alcohol.
Purpose of Acid: Alcohols are poor leaving groups. The acid protonates the alcohol, converting the hydroxyl group ($-OH$) into a good leaving group (water, -OH_2^+). This also makes the alcohol a better electrophile.
Mechanism (SN2):
Protonation: One equivalent of alcohol is protonated by the acid.
Nucleophilic Attack: Another equivalent of alcohol (acting as a nucleophile) attacks the alpha carbon of the protonated alcohol (which is now a good electrophile). The water molecule leaves.
Deprotonation: The resulting protonated ether is deprotonated (often by water, which is formed as a byproduct, or another alcohol molecule) to yield the neutral ether.
Requirements: Favors primary or methyl groups for the electrophilic carbon to ensure SN2 reaction.
2. Williamson Ether Synthesis (Basic Conditions, SN2 Mechanism)
A two-step process, typically carried out in basic conditions.
Step 1: Alkoxide Formation (Preparation of Nucleophile)
An alcohol is reacted with a strong base (e.g., sodium hydride, NaH).
The base deprotonates the alcohol, forming an alkoxide (an alcohol with a negative charge on the oxygen, R-O^-).
Alkoxides are powerful nucleophiles.
Step 2: SN2 Reaction
The alkoxide nucleophile attacks a primary or methyl alkyl halide (the electrophile).
The halide leaving group departs, forming the ether.
Key Limitations (Due to SN2 Nature):
Alkyl Halide Substitution: The alkyl halide must be primary or methyl.
Using secondary or tertiary alkyl halides will lead to elimination (E2) as the dominant reaction, rather than substitution.
Steric Hindrance: Cannot use aryl or vinyl halides (e.g., phenyl bromide).
The sp^2 hybridized carbons in these halides are planar, preventing the backside attack required for an SN2 mechanism.
Asymmetric Ethers: When synthesizing unsymmetric ethers, it is crucial to choose the reactants carefully:
The more sterically hindered group (secondary/tertiary) should be part of the alcohol component.
The less sterically hindered group (primary/methyl) should be part of the alkyl halide component.
Example: To make tert-butyl methyl ether, use tert-butanol as the alcohol and methyl bromide as the alkyl halide. Reversing this (methanol and tert-butyl bromide) would lead to elimination.
3. Williamson Ether Synthesis Modification (One-Step with Silver Oxide, Ag_2O)
A modified, one-step version of Williamson ether synthesis.
Reagents: Alcohol and alkyl halide reacted in the presence of silver oxide (Ag_2O).
Mechanism: Silver oxide facilitates the reaction without separate deprotonation or leaving group activation steps, acting as both a base and a leaving group scavenger.
Application: Can be useful for polyalcohols (like glucose) where multiple hydroxyl groups may react. While selectivity can be predicted (primary alcohols react faster than secondary, which react faster than tertiary), this is often considered advanced for this level.
Ether Synthesis via Modified Oxymercuration-Demercuration
A variation of the oxymercuration-demercuration reaction, typically used to form alcohols (using H_2O as the nucleophile).
Modification: Instead of using water (H_2O) as the nucleophile in the first step, an alcohol (R'OH) is used.
Mechanism: Follows Markovnikov's rule (hydroxyl from the alcohol adds to the more substituted carbon) and proceeds without carbocation rearrangements.
Alkene reacts with mercuric acetate (Hg(OAc)_2) to form a mercurinium ion (similar to a bromonium ion).
The added alcohol (R'OH) acts as a nucleophile, attacking the more substituted carbon of the mercurinium ion.
A demercuration step (using NaBH_4) reduces the mercury group.
Product: Results in an ether with the alkoxy group (-OR') on the more substituted carbon.
Example: If methanol (CH3OH) is used as the alcohol reagent, a methoxy group ($-OCH3$) will be added to the alkene (Markovnikov addition).
Reactivity of Ethers
Ethers as Solvents
Ethers are generally very stable and unreactive functional groups.
Their stability makes them excellent and common solvents in organic reactions.
They are also considered more environmentally friendly than some other solvents.
Cleavage of Ethers (Destruction/Cutting Ethers)
Ethers can be cleaved (cut in half) under strong acidic conditions.
Typically, hydrohalic acids (e.g., HBr, HI) are used, often due to the useful halide byproducts formed.
The mechanism of cleavage ($\text{SN1}$ or $\text{SN2}$) depends on the substitution pattern of the carbon chains attached to the ether oxygen.
Common First Step: Protonation of the ether oxygen by the strong acid, making the ether a better leaving group (similar to how an alcohol is protonated to make water a good leaving group).
SN2 Pathway (Favored by Less Substituted Carbons):
If one of the R groups in the ether is primary or methyl (or sometimes secondary).
After protonation, the halide ion (Br^-, I^-, etc., from the acid) acts as a nucleophile and attacks the less sterically hindered (less substituted) carbon directly bonded to the oxygen.
The bond breaks, and the more substituted side is released as an alcohol, while the less substituted side forms an alkyl halide.
Result: Less substituted side becomes alkyl halide, more substituted side becomes alcohol.
SN1 Pathway (Favored by More Substituted Carbons):
If one of the R groups in the ether is tertiary or can form a stable carbocation (e.g., benzylic).
After protonation, the bond between the oxygen and the more substituted carbon breaks, leading to the formation of a carbocation and an alcohol leaving group.
The halide ion then attacks the carbocation.
Result: More substituted side becomes alkyl halide, less substituted side becomes alcohol.
Competition: The SN1 pathway often competes with the E1 elimination reaction, especially at higher temperatures. To favor SN1 over E1, reactions are often run at cold temperatures.
Epoxides (Cyclic Ethers)
Structure and Reactivity
Definition: Epoxides are cyclic ethers consisting of a three-membered ring containing one oxygen atom and two carbon atoms.
Reactivity: Unlike linear ethers, epoxides are highly reactive due to significant ring strain.
Angle Strain: Bond angles in a three-membered ring are forced to be approximately 60^ ext{o}, which is much smaller than the ideal 109.5^ ext{o} for sp^3 carbons, leading to considerable instability.
Torsional Strain: All hydrogens on the ring are in an eclipsing conformation, contributing additional torsional strain.
This high reactivity makes epoxides excellent starting materials for other reactions.
Synthesis of Epoxides
Industrial Method: Oxidation of alkenes at high temperatures (e.g., 300^ ext{o}C).
Laboratory Method (via Peroxyacids):
Alkenes react with peroxyacids to form epoxides.
Peroxyacid Structure: Characterized by a -CO_3H group, containing an extra oxygen atom compared to a carboxylic acid. The active oxygen for epoxide formation is the one bonded to hydrogen.
Common Peroxyacid: meta-Chloroperoxybenzoic acid (m-CPBA) is widely used due to its relative stability.
m-CPBA Structure: Consists of a benzene ring with a chloro group in the meta position and a peroxyacid group ($-CO_3H$).
Stereochemistry: This reaction is a syn addition.
The oxygen from the peroxyacid is added to one face of the alkene, creating the three-membered ring on that same side.
The reaction is both stereoselective (favors one stereoisomer) and stereospecific (the stereochemistry of the starting alkene determines the stereochemistry of the epoxide product).
Reactions of Epoxides
Epoxides are primarily known for their ring-opening reactions.
One important reaction is hydrolysis, which opens the epoxide ring to form anti-diols (two hydroxyl groups on opposite faces of the former alkene carbons).
This mechanism will be reviewed in upcoming lectures.