Lecture(3:(January(22,(2013 -...

CHM(224(•(Organic(Chemistry(IISpring(2013,(Des(Plaines(•(Prof.(Chad(Landrie

•Reac&ons*of*Phenols*(17.9);*Review*of*

SE:Ar*(Ch.*16)*

•Ethers:*Naming*and*Proper&es*(18.1)

•Ether*Synthesis*(18.2)

•Epoxida&on*(18.5)

Lecture(3:(January(22,(2013


17.9;*You*should*review*Ch.*16

ReacIons(of(Phenols:(Electrophilic(AromaIc(

SubsItuIon

© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)

Slide Lecture 1: January 15

• very strong electrophiles attack the aromatic ring on phenols, not the oxygen

• hydroxyl group is a strongly activating group (electron donor)

• so strong, no catalyst is required for bromination even in a non-polar solvent such as 1,2-dichloroethan

• hydroxyl group is an ortho/para directing group

Reac-ons)of)Phenols:Electrophilic)Aroma-c)Subs-tu-on)(SEAr)

4



• arenium ion: carbocation formed from an aromatic ring; also called a σ-complex

• formation of arenium ions is slow since the ground state is so stable (loss of aromaticity)

• requires very reactive (high energy) electrophiles

Quick)Review:)SEAr

5



Quick)Review:)SEAr

6



CarbocationsR X AlCl3+

(R = 3º or 2º)

R+ AlCl4–+

Quick)Review:)SEAr

7



FriedelCCraDs)Alkyla-on

8



Acylium Ions

R C O R C O R Cl

O+ AlCl3 R C O + AlCl4–

FriedelCCraDs)Acyla-on

9



FriedelCCraDs)Acyla-on

10



• Friedel-Crafts acylation (C-acylation) is observed product when an acid catalyst is used (e.g., AlCl3)

• O-acylation is observed when the electrophile is solely an acid chloride.

O"#vs.#C"Acyla-on)of)Phenols

11



• Friedel-Crafts acylation (C-acylation) is observed product when an acid catalyst is used (e.g., AlCl3)

• O-acylation is observed when the electrophile is solely an acid chloride.

O"#vs.#C"Acyla-on)of)Phenols

12



morphine diacetylmorphine (heroin)

OCAcyla-on)of)Morphine

13



Kolbe-Schmidt Reaction

Synthesis)of)Aspirin

14



• oxanion substituent (phenoxide) is an even more powerful activating group than hydroxyl

• phenoxide undergoes SEAr with carbon dioxide under high pressure

• the process is in equilibrium• equilibrium processes are under

thermodynamic control, which means the more stable product is formed

• the more stable product is the weakest conjugate base

• ortho salicylate is the weakest conjugate base since the carboxylate is stabilized by H-bonding to the hydroxyl group

KolbeCSchmidt)Reac-on

15



morphine 3-methylmorphine (codeine)

OCAlkyla-on)of)Phenol

16



morphine 3-methylmorphine (codeine)

Why is this methylation chemoselective? In other words, why is the phenol methylated, but not the alcohol?

OCAlkyla-on)of)Phenol

17



oxidation

oxidation

hydroquinone p-benzoquinone

catechol o-benzoquinone

Oxida-on)of)Benzenediols

18



oxidation

hydroquinone p-benzoquinone

CoQ10 = Coenzyme Q 10• a.k.a. ubiquinone• involved in electron transport in cells

isoprene unit

Q = benzoquinone10 = # of isoprene units

Oxida-on)of)Benzenediols

19



• NADH is generated during metabolism as molecules (e.g., carbohydrates like glucose) are broken down into simpler molecules

• NADH is an electron carrier (stored energy in the form of a C-H bond in the nicotinamide)

• These electrons are released in the electron transport chain to an enzyme that pumps protons (H+)

• An high concentration of protons drive another enzyme to produce ATP (the stored energy used by living organisms)

+ H+ + 2 e–

nicotinamideadeninedinucleotide (NAD+)

oxidation

reduction

NADH

Benzoquinones)in)the)Electron)Transport)Chain

20



• After NADH transfers its two electrons to the first enzyme in the transport chain, CoQ (ubiquinone) transfers the electrons to another enzyme

• This transfer causes the next enzyme to release H+ into the intermembrane space

• The released H+ causes ATP synthase to make ATP

• Summary: ubiquinone (a benzoquinone) is an electron carrierH+

reduction

oxidation

*Note: Not the likely mechanism. Just easiest to keep track of electrons this way.

Benzoquinones)in)the)Electron)Transport)Chain

21


Naming*and*Physical*Proper&es*(18.1)

Ethers



Nomenclature)of)Ethers

23

Substitutive (preferred):1.Number longest chain alkyl group (ether-C higher priority than alkyl

groups and halides; alcohol-C higher priority than ether-C).2.Name ether alkyl groups as alkyoxy groups.

Function class (common for small):1.List each alkyl group alphabetically and separated by a space.2. End with functional class name, ether.



Nomenclature)of)Ethers

24

Substitutive (preferred):1.Number longest chain alkyl group (ether-C higher priority than alkyl

groups and halides; alcohol-C higher priority than ether-C).2.Name ether alkyl groups as alkyoxy groups.

Function class (common for small):1.List each alkyl group alphabetically and separated by a space.2. End with functional class name, ether.

methane

methoxy

ethane

ethoxy

propane

propoxy

butane

butoxy



Nomenclature)of)Cyclic)Ethers

25

O

furan

H

H

H

H O

tetrahydrofuran

HHHH

HHHH

“hydro” nomenclature: hydro refers to the number of hydrogens that must be added to the unsaturated parent

(epoxide)



Nomenclature)of)Diethers

26

HO OH OHHO

ethylene glycol



Nomenclature)of)Sulfides

27

• Sulfur analogs (RS–) of alkoxy groups are alkylthio groups.• For IUPAC: Name by replacing parent -ane with -thio.• For substitutive: Name each alkyl substituent in alphabetical

order and end name with sulfide.

Thiane



Nomenclature)of)Sulfides

28

• -iirane: 3-membered ring• -etane: 4-membered ring• -olane: 5-membered ring• -ane: 6-membered ring

thietane thiolane thianethiirane



Structure)and)Bonding)in)Ethers)and)Epoxides

29

• Alkyl groups in alcohols and ethers increase Van der Waals strain (steric strain) compared to water.

• Increased steric strain = increased C–O–C bond angle in ethers.



Conforma-onal)Analysis)of)Oxanes)&)Thianes

31

X A-Value (-∆Gº) (kcal/mol)

S 1.42

CH2 1.74

O 2.86

A = –∆Gº = –(Gequatorial - Gaxial)

C-X bond length (pm)

182

154

143

• Oxanes have higher A-values for alkyl groups at position 2 compared to cyclohexane, whereas thianes have lower A-values.

• As bond strength increases, bond length decreases.

• Smaller C-X bond length = increased 1,3-diaxial steric repulsion and great preference for equatorial



Conforma-onal)Analysis)of)Oxanes)&)Thianes

32

X A-Value (-∆Gº) (kcal/mol)

S 1.40

CH2 1.74

O 1.43

C-X bond length (pm)

182

154

143

• Cyclohexanes have lower A-values for groups in position 3 than oxanes and thianes

• Oxanes & thianes replace one CH3/H 1,3-diaxial interaction with a lone-pair/H 1,3-diaxial

• lone-pair/H 1,3-diaxial has lower eclipsing strain than CH3/H

A = –∆Gº = –(Gequatorial - Gaxial)



Physical)Proper-es)of)Ethers

33

• Boiling points of ethers are similar to their alkane analogues.• London dispersion forces must be major contributing VWF over

dipole-dipole




34

• Because ethers are significantly more polar than their alkane analogues, they are useful as organic solvents.

• Ethers are relatively unreactive toward a variety of reagents.



Ethers)as)Solvents)in)Grignard)Reac-ons

35

Mg

Cl

O O

•ethers form Lewis acid-base complexes with Grignard reagents

•stabilize Grignard and protect from oxidation

•Mg then is tetrahedral in ethereal solvent

•solvent must be non-protic

H3CMg

Cl O+ 2

H3CMg

Cl

OOLewis acid Lewis base




36

•Ethers are able to hydrogen bond with water. Smaller ethers, such as diethyl ether, are significantly soluble in water.

•Ethers must be rigorously dried before use in water sensitive reactions such as Grignards.



Crown)Ethers

37

• Ethers are Lewis-bases: electron-pair donors

• Contain polar C–O bond and lone-pairs

• Crown Ethers are particularly strong Lewis bases

• Size of the interior of Crown ethers determine what ions they can sequester in a Lewis-acid base complex.

• Crown ethers increases solubility and nucleophilicity of some ionic compounds



Crown)Ethers

38

• Ethers are Lewis-bases: electron-pair donors

• Contain polar C–O bond and lone-pairs

• Crown Ethers are particularly strong Lewis bases

• Size of the interior of Crown ethers determine what ions they can sequester in a Lewis-acid base complex.

• Crown ethers increases solubility and nucleophilicity of some ionic compounds



Crown)Ethers

39

• Potassium cation sequestered inside crown ether.• Hydrophobic exterior of crown ether makes the complex soluble in the

hydrocarbon solvent• Fluoride anion is relatively unsolvated without potassium cation.• Fluoride anion is now “more anionic” and more nucleophilic.



Crown)Ethers

40

• Potassium cation sequestered inside crown ether.• Hydrophobic exterior of crown ether makes the complex soluble in the

hydrocarbon solvent• Fluoride anion is relatively unsolvated without potassium cation.• Fluoride anion is now “more anionic” and more nucleophilic.

In the absence of 18-Crown-6, KF is insoluble in benzene and unreactive toward alkyl halides.


18.3:18.5

PreparaIon(of(Ethers:(Review(and(New



Prepara-on)of)Ethers

43

1. Condensation of Alcohols



Prepara-on)of)Ethers:)Condensa-on

44

1. Condensation of Alcohols



Prepara-on)of)Ethers:)Alkene)Addi-on

45

2. Addition to Alkenes

• Reaction proceeds through a carbocation intermediate.

• Regioselective: Markovnikoff addition predominates.

• Most substituted ethers are formed.



Prepara-on)of)Ethers:)Haloetherifica-on

46

3. Haloetherification

• Reaction proceeds through a halonium ion intermediate.

• Regioselective: Addition to most δ+ charged carbon.

• Addition of alcohol to most substituted carbon.



Prepara-on)of)Ethers:)Williamson

47

4. Williamson Ether Synthesis

O Na+ Cl O

alkoxide alkyl halide ether

+ NaCl

Williamson Ether Synthesis

• Only works with 1º and methyl halides.• Higher substituted halides favor elimination over substitutution




48


O Na+ Cl O


+ NaCl





49


O Na+ Cl O


+ NaCl




Williamson)Ether)Synthe-c)Strategy

50

1º

2º

2º or 3º C O 1º or methyl C

1º or methyl C

2º or 3º CHO

X

Since alkoxides are stronger bases than hydroxide, only 1º or methyl halides will favor substitution over elimination since they are least sterically hindered.



Prepera-on)of)Ethers:)Epoxida-on

52

H3C

O

OHacetic acid

H3C

O

Operoxyacetic acid

O H

• peroxyacids are source of electrophilic oxygen atoms• addition of a single oxygen atom across double bond• similar to formation of bromonium ion intermediate• don’t worry about mechanism; for curious see textbook page 259



Epoxida-on)Can)be)Stereospecific

53

+

+

• Epoxidation can be stereospecific if a stereochemistry of the product is specific to the stereochemistry of the reactant.

• Without a chiral catalyst, epoxidation is not enantioselective.• Both enantiomers are formed from addition to both faces of the alkene.

X not stereospecific

√ stereospecific



Enan-oselec-ve)Epoxida-on

54

• A chiral catalyst or reactant may lower the T.S. energy leading to one enantiomer over the other. (We won’t discuss why! Phew!)

• This method only works with allylic alcohols.• The enantiopure forms of diethyl tartrate catalyze the epoxidations.• Either epoxide enantiomer may be prepared by selecting either enantiomer of diethyl tartrate

Reagents

epoxidizing agent chiral catalysts

Sharpless, K.B. The first practical method for asymmetric epoxidation. J. Am. Chem. Soc. 1980, 102, 5974-5976



Prepara-on)of)Epoxides

55

2. Intramolecular Williamson Ether Synthesis of Vicinal Halohydrins



Review:)Forma-on)of)Halohydrins

56

• if the solvent for the reaction is changed to water, halohydrins are formed

• since water is much more concentrated, it will add to halonium ion intermediate faster than the halide

bromohydrin



Review:)Forma-on)of)Halohydrins

57

H3C H

Br Br

H3C H

Br

OH2HH3C

H3CH3C

HH

Br

OH

HH3C H

Br H3CH3C

HH

Br

HOOH2

• product is most substituted alcohol; least substituted halide

• most substituted carbon is most partially positively charged in transition state = strongest electrophile = water most attracted to that carbon




58





59




Intramolecular)Cycliza-on)of)Halohydrins)Can)Be)Stereospecifc

60



Synthe-c)Challenge

62

Design a synthesis for each epoxide.

Br ?O

H

H?

O

H

H


Reac&ons*of*Ethers:*cleavage,*

hydrogena&on*of*benzyl*ethers,*Claisen*

rearrangement,*epoxide*ring*opening

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