Goals for the day:

1) Grignard Reaction

2) Ethers (Naming and reactions)

3) Epoxides (naming and reactions)

4) Thiols & sufides (reactions)

Alkyl, aryl, and vinylic halides react with magnesium in ether or tetrahydrofuran to generate Grignard reagents, RMgX

Grignard reagents react with carbonyl compounds to yield alcohols

17.5 Alcohols from Carbonyl Compounds: Grignard Reagents

Grignard reagents act as nucleophilic carbon anions (carbanions = : R) in adding to a carbonyl group

The intermediate alkoxide is then protonated to produce the alcohol

Mechanism of the Addition of a Grignard Reagent

Try to predict the products…

OCH3 MgBr

MgBrOH

Possible depictions are…

OCH3 MgBr

MgBrOH

OH

CH3

O

H H

Try to fill in the mechanism…

OCH3 MgHBr

OH

CH3

1)

2) H3O +

O

CH3O

CH3 MgHBr

H O

H

H

Reactions of Grignard Reagents with Carbonyl Compounds

Yields tertiary alcohols in which two of the carbon substituents come from the Grignard reagent

Grignard reagents do not add to carboxylic acids – they undergo an acid-base reaction, generating the hydrocarbon of the Grignard reagent

Reactions of Esters and Grignard Reagents

Cannot be prepared if there are reactive functional groups in the same molecule, including proton donors

Grignard Reagents and Other Functional Groups in the Same Molecule

Predict the product…

O

OCH3

CH3 MgBr

Remember it goes all the

way to the alcohol &two CH3 groups

are added…

O

OCH3

CH3 MgBr

O

OCH3

CH3

O

CH3

O

CH3

CH3

OH

CH3

CH3

OH

CH3

CH3

Naming Ethers

Ethers contain the R-O-R bond. Basically, you name the two groups

attached to the oxygen (alphabetically) and add the term ether.

O

The smallest ether is dimethyl ether

Ethers as attachments

Methoxy

Ethoxy

isopropoxy

O

CH3

O

O

Pick one to try to name & panel submit

O O

Pick one to try to name & panel submit

O O

Isopropyl pheny ether

Or

Isopropoxy benzene

Secbutyl vinyl ether

Or

1-secbutoxy ethene

R–O–R ~ tetrahedral bond angle Oxygen is sp3-hybridized Oxygen atom gives ethers a slight dipole momentNot very reactive, so they make good solvents (diethyl

ether is the “ether” we use in lab all the time). Not water soluble (although diethyl ether is slightly…

see diagram on the following page)…

Properties of Ethers

This is why you have to “dry” the organic layer in your reactions!

ether layer

water layer

water layer ether layer

add MgSO4

ether layerether layer(dried)

f ilter

Diethyl ether prepared industrially by sulfuric acid–catalyzed dehydration of ethanol – also with other primary alcohols

18.2 Synthesis of Ethers

OH

H+

O2

Works really only if the ether that you want is symmetric….otherwise you can get mixed results..

18.2 Synthesis of Ethers

OH

OH

O

Problem is.....propanol reacts with itself and ethanol reacts with itself…

Need for an unsymmetric ether synthesis

OH

OH

O

O

O

Mechanism of ether formation from alcohols…

Reaction of metal alkoxides and primary alkyl halides and tosylates

Best method for the preparation of unsymmetric ethers

Alkoxides prepared by reaction of an alcohol with a strong base such as sodium hydride, NaH

The Williamson Ether Synthesis

Predict the product...

OH

Na Br

The carbons of the alkyl halide become the “second” group of the ether...

OH

Na BrO

An SN2 process…

OH

Na BrO

O Na + Br

SN2

th

Note that the second step of the reaction is an SN2 process, soworks best for primary alkyl halides (or methyl bromide)

Which is better?(you get phenyl propyl ether either way)…

OH

Na Br

O

BrOH

Na

a)

b)

Path “a” is better because the alkyl halide is primary and will react faster in the SN2 reaction

OH

Na Br

O

BrOH

Na

a)

b)

Cyclic ethers behave like acyclic ethers, except if ring is 3-membered

Two common structures are ethylene oxide and THF

Cyclic Ethers

O

Also called epoxidesEpoxides (Oxiranes)

Treat an alkene with a peroxyacidAbbreviation for this reagent is MCPBA…

Preparation of Epoxides Using a Peroxyacid

What’s the product?

MCPBA

Answer…

MCPBA

O

Addition of HO-X to an alkene gives a halohydrinTreatment of a halohydrin with base gives an epoxide Intramolecular Williamson ether synthesis

Epoxides from Halohydrins

Water adds to epoxides with dilute acid at room temperature

Product is a 1,2-diol (on adjacent C’s: vicinal)Mechanism: acid protonates oxygen and water

adds to opposite side (trans addition)

18.6 Reactions of Epoxides: Ring-Opening

Anhydrous HF, HBr, HCl, or HI combines with an epoxide

Gives trans product

Halohydrins from Epoxides

Regiochemistry of Acid-Catalyzed Opening of Epoxides 1) Nucleophile preferably adds to less hindered site if

primary and secondary C’s 2) Nucleophile adds to a tertiary carbon because of

carbocation character

1)

2)

Steps of Acid-Catalyzed Opening of Epoxides

1) Protonation

2) Attack of the nucleophile from the backside

Note: check for degree of substitution

Strain of the three-membered ring is relieved on ring-opening

Hydroxide cleaves epoxides at elevated temperatures to give trans 1,2-diols

Base-Catalyzed Epoxide Opening

Adds –CH2CH2OH to the Grignard reagent’s hydrocarbon chain

Acyclic and other larger ring ethers do not react

Addition of Grignards to Ethylene Oxide

Large rings consisting of repeating (-OCH2CH2-) or similar unitsNamed as x-crown-y

x is the total number of atoms in the ringy is the number of oxygen atoms18-crown-6 ether: 18-membered ring containing 6 oxygen

atomsCentral cavity is electronegative and attracts cations

18.7 Crown Ethers

Thiols (RSH), are sulfur analogues of alcoholsNamed with the suffix -thiol SH group is called “mercapto group” (“capturer

of mercury”)

18.8 Thiols and Sulfides

From alkyl halides by displacement with a sulfur nucleophile such as –SH The alkylthiol product can undergo further

reaction with the alkyl halide to give a symmetrical sulfide, giving a poorer yield of the thiol

Thiols: Formation and Reaction

Sulfides (RSR), are sulfur analogues of ethersNamed by rules used for ethers, with sulfide in

place of ether for simple compounds and alkylthio in place of alkoxy

Sulfides

Reaction of an alkyl thiol (RSH) with bromine or iodine gives a disulfide (RSSR)

The thiol is oxidized in the process and the halogen is reduced

Cysteine amino acid forms cystine bonds

Oxidation of Thiols to Disulfides

Thiolates (RS) are formed by the reaction of a thiol with a base

Thiolates react with primary or secondary alkyl halide to give sulfides (RSR’)

Thiolates are excellent nucleophiles and react with many electrophiles

Sulfides

Have a wonderful day!

An ether has two organic groups (alkyl, aryl, or vinyl) bonded to the same oxygen atom, R–O–R

Diethyl ether is used industrially as a solventTetrahydrofuran (THF) is a solvent that is a cyclic ether

Thiols (R–S–H) and sulfides (R–S–R) are sulfur (for oxygen) analogues of alcohols and ethers

Ethers and Their Relatives