Ch 11- Alcohols and Ethers

Alcohols

• Alcohols are compounds whose molecules have a hydroxyl group attached to a saturated carbon atom

• The saturated carbon may be that of a simple alkyl group

• Examples• Or the saturated carbon may be connected to

an alkenyl, alkynyl, or benzene ring

Alcohols and Ethers

• Compounds that have a hydroxyl group attached directly to a benzene ring are called phenols

• Ethers differ from alcohols in that the oxygen atom is bonded to 2 carbons

Nomenclature of Alcohol

• See section 4.3f

• Remember that the hydroxyl group has priority over halogens, double bonds, triple bonds, and alkyl groups in numbering and naming.

Nomenclature of Ethers

• Common Name:• List the two alkyl groups in alphabetical order,

followed with ether– example

• IUPAC Name:• IUPAC names are used for more complex ethers or

compounds with more than one ether linkage• In IUPAC, ethers are named as Alkoxy substitutes

Physical Properties

• Ethers have BP that are roughly comparable with alkanes of similar molecular weight

• Alcohols on the other hand have much higher BP’s due to hydrogen bonding

• Ethers can hydrogen bond with water, just not other ether molecules

• Because of this, both have increased water solubility.

Synthesis of Alcohols from Alkenes• We have already covered 3 ways:

1) Acid-Catalyzed Hydration Alkenes:-Markovnikov addition-rearrangement possible due to carbocation

2) Oxymercuration-Demercuration-Markovnikov addition-no carbocation, no rearrangement

3) Hydroboration-Oxidation-Anti-Markovnikov product-no carbocation, no rearrangement- Stereoselective: gives syn-addition product

Reactions of Alcohols

1) Alcohols as Acids- The hydrogen of the hydroxyl group can

be abstracted in the presence of bases stronger than the Alkoxide product

-ex.-The equilibrium when mixed with

hydroxide favors the alcohol!

Reactions of Alcohols

2) Conversion of Alcohols into Alkyl HalidesA) Via substitution with HX

example:-primary and methyl via Sn2-secondary and tertiary via Sn1

-Because Chlorine is a weaker nucleophile, must add ZnCl2 must be added for primary and secondary alcohols.

Reactions of Alcohols

• B) Alkyl Bromides using phosphorus tribromide– Example and Mechanism

– Usually occurs without presence of carbocation– Preferred method of synthesis of Alkyl Bromide from

alcohol

Reactions of Alcohols

• C) Alkyl Chlorides using Thionyl Chloride– Example and Mechanism

– Usually done with a tertiary Amine present to consume HCl

Reactions of Alcohols

3) Tosylates, Mesylates, and TriflatesLeaving Groups/Protecting Groups of Alcohols

The Hydroxyl group of an alcohol can be converted to a super group or protected by converting it to a sulfonate ester derivative

Why protect?

• Prevents unwanted reactions

• Differentiates and selectively react certain alcohols in organic synthesis

Most Common Sulfonate Esters

• The mesyl group, methane sulfonate esters, (mesylates)

• The tosyl group, p-toluene sulfonate esters, (tosylates)

• The trifyl group, trifluoromethane sulfonate esters, (triflates)

Synthesis of Sulfonate Esters

• The desired sulfonate ester is prepared by reacting the appropriate alcohol with the desired sulfonyl chloride

• Examples:

Reactions of Sulfonate Esters

• Mesylates, tosylates, and triflates are frequently used to promote nucleophilic substitution reactions because they are great leaving groups.

• example

Reactions of Sulfonate Esters

• They are great leaving groups because the sulfonate anions are very weak bases and nucleophiles

• The triflate anion is one of the best of all known leaving groups.

• Triflates can actually leave to form vinylic carbocations, which are the least stable of all carbocations

Reactions of Sulfonate Esters

• Stereochemistry is not affected in the formation of the sulfonate ester because the C-O bond is unchanged.

• Example

• For the substitution steps, typical protocol is followed: Sn2=inverted

Sn1= loss

Mechanism for Sulfonate Ester

• Very straight forward

Synthesis of Ethers

• 1) Intermolecular Dehydration of Alcohols– Already seen dehydration of alcohol to form

alkenes– Primary alcohols can dehydrate to form ethers– Usually occurs at lower temperatures than

required to form alkene– Promoted by distilling off the ether as it forms– The process is acid catalyzed:

Synthesis of Ethers

• This method only works with primary alcohols

• Secondary and tertiary alcohols dehydrate to the alkene before ethers can form.

Synthesis of Ethers

• 2) The Williamson Ether Synthesis– An important reaction to synthesized

unsymmetrical ethers– It is an Sn2 reaction with a sodium alkoxide as the

nucleophile and an alkyl halide, sulfonate, or sulfate as the leaving group

– ExampleNote: Since this is an Sn2 reaction, the LG must be either a methyl, primary or secondary LG!

Synthesis of Ethers

• Typically, Sodium Hydride is used to prepare the sodium alkoxide

• Example:

• The usual limitations of Sn2 apply:– Best results with methyl/primary LG– Tertiary LG only yields elimination– Substitution favored at low temperature

Synthesis of Ethers

• When synthesizing an ether using this method, look at the two ether bonds to decide which is better to make via Sn2

• Example 1- Synthesize 2-methoxypentane using Williamson Ether synthesis.

Synthesis of Ethers

• Example 2- Synthesize 1-ethoxy-4-methylbenzene

Synthesis of Ethers

• YOUR TURN!!• Example 3- synthesize t-butyl ethyl ether

Synthesis of Ethers

• 3) Synthesis of Ethers by Alkoxymercuration-demercuration– It is the reaction of an alkene with an alcohol in

the presence of a mercury salt, such as mercuric acetate, Hg(OAc)2 , mercuric trifluoroacetate, Hg (OCOCF3)2

– When the alcohol is the solvent, it is called a Solvomercuration-Demercuration.

Synthesis of Ethers

• This method parallels hydration by oxymercuration-demercuration we covered last semester, but instead of water attacking the merconium bridge, the alcohol does.

• Reaction and Mechanism:

• examples

Problem

• Say you wanted to make 2-t-butoxy-2-methylbutane. Which would be the best way, williamson or mercuration? Evaluate all the possible ways and give an explanation on why you chose the one you think is best.

Synthesis of Ethers

• 4) t-butyl ethers by alkylation of alcohols– Also used as protecting groups– T-butyl ethers can be made from primary alcohols

by mixing them first with strong acid (H2SO4) then with 2-methylpropane

– Ex. – The tbutyl ether, can be hydrolyzed easily with

dilute acid to reform the primary alcohol and tbutyl alcohol

Use of a Protecting Group

• Example:

Synthesis of Ethers• 5) Silyl Ether Protecting Group– Alcohol can also be protected as silyl ethers– One of the most common is t-butyl dimethyl silyl ether

group (TBDMS)

– TBDMS groups are stable in a pH range of ~4-12– They are synthesized by mixing the alcohol with tbutyl

chloro dimethyl silane in the presence of an aromatic amine such as:

– Usually done in aprotic solvent.

Synthesis of Ethers

• Examples:

• The TBDMS group can be removed using the fluoride ion.– Tetrabutyl ammonium fluoride (TBAF) or aqueous

HF usually provides the fluoride ion.• Example:

Reactions of Ethers

• Dialkyl ethers react with very few reagents other than acids

• This lack of reactivity coupled with the ability to solvate cations makes ethers especially useful as solvents

• The Oxygen of the ether linkage makes the ether basic

• They can accept protons from strong acids to form oxonium salts

• Example:

Reactions of Ethers

• Heating dialkyl ethers with very strong acids (HI, HBr, H2SO4) causes a reaction in which the carbon-oxygen bond breaks.

• Reaction:• Mechanism:

Epoxides

• Epoxides- are cyclic ethers with a 3 membered ring

• In IUPAC nomenclature, epoxides are named as Oxiranes.

• Examples:

Synthesis of Epoxides

• Epoxides are made from reacting alkenes with an organic peroxy acid (peracid)

• This process is called epoxidation

• Example:

• Possible Mechanism:

Synthesis of Epoxides

• Some peracids are unstable, therefore dangerous to use.

• Because of its stability, the peracid magnesium monoperoxy phthalate (MMPP)

• Examples:

Stereochemistry

• Note the stereochemistry!• Because it’s a 3 member ring, formation of the

epoxide must be syn-addition • With straight chain alkenes, the reaction is

stereospecific as well• The resulting oxirane will have the same

configuration as the alkene had!• Examples:

Reactions of Epoxides

• The highly strained 3 membered ring of epoxides make them much more reactive towards nucleophilic substitution

• The opening of the epoxide can either be acid catalyzed or base catalyzed with different regiochemistry results.

Acid Catalyzed Mechanism

• Seen with weak nucleophiles:

Base Catalyzed Mechanism

• Seen with strong nucleophiles:

Regioselectivity

• The opening of unsymmetrical epoxides is regioselective

• In the base catalyzed mechanism, attack by the strong nucleophile is on the less substituted carbon

• Ex• This is expected because it is an Sn2-like

attack!

Regioselectivity

• In the acid catalyzed opening, with the weak nucleophiles, the nucleophiles attack the More substituted carbon

• Ex.• Rationale: In the protonated epoxide, the additional

positive charge on the oxygen adds to the ring strain already present.

• As a result, bonds start to break leaving a partial positive charge on the more substituted carbon, which is where the nucleophile attacks

Regioselectivity

• This is the same reasoning used when the water attacked the Bromonium or merconium bridges!!

Problems

Anti 1,2-dihydroxylation of Alkene via epoxides

• Anti 1,2-diols can be synthesized from alkenes by first forming the epoxide, then doing an acid catalyzed opening.

• Example:

• NOTE: This is opposite of the Osmium reaction we saw in chapter 8 that produced the syn diols