lecture(3:(january(22,(2013 -...
TRANSCRIPT
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
CHM(224(•(Organic(Chemistry(IISpring(2013,(Des(Plaines(•(Prof.(Chad(Landrie
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
• 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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
Quick)Review:)SEAr
6
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
CarbocationsR X AlCl3+
(R = 3º or 2º)
R+ AlCl4–+
Quick)Review:)SEAr
7
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
FriedelCCraDs)Alkyla-on
8
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
Acylium Ions
R C O R C O R Cl
O+ AlCl3 R C O + AlCl4–
FriedelCCraDs)Acyla-on
9
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
FriedelCCraDs)Acyla-on
10
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
• 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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
• 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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
morphine diacetylmorphine (heroin)
OCAcyla-on)of)Morphine
13
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
Kolbe-Schmidt Reaction
Synthesis)of)Aspirin
14
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
• 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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
morphine 3-methylmorphine (codeine)
OCAlkyla-on)of)Phenol
16
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
oxidation
oxidation
hydroquinone p-benzoquinone
catechol o-benzoquinone
Oxida-on)of)Benzenediols
18
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
• 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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
• 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
CHM(224(•(Organic(Chemistry(IISpring(2013,(Des(Plaines(•(Prof.(Chad(Landrie
Naming*and*Physical*Proper&es*(18.1)
Ethers
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
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.
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
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)
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
Nomenclature)of)Diethers
26
HO OH OHHO
ethylene glycol
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
Nomenclature)of)Sulfides
28
• -iirane: 3-membered ring• -etane: 4-membered ring• -olane: 5-membered ring• -ane: 6-membered ring
thietane thiolane thianethiirane
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
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.
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
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)
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
Physical)Proper-es)of)Ethers
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.
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
Physical)Proper-es)of)Ethers
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.
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
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.
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
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.
CHM(224(•(Organic(Chemistry(IISpring(2013,(Des(Plaines(•(Prof.(Chad(Landrie
18.3:18.5
PreparaIon(of(Ethers:(Review(and(New
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
Prepara-on)of)Ethers
43
1. Condensation of Alcohols
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
Prepara-on)of)Ethers:)Condensa-on
44
1. Condensation of Alcohols
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
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.
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
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.
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
Prepara-on)of)Ethers:)Williamson
48
4. Williamson Ether Synthesis
O Na+ Cl O
alkoxide alkyl halide ether
+ NaCl
Williamson Ether Synthesis
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
Prepara-on)of)Ethers:)Williamson
49
4. Williamson Ether Synthesis
O Na+ Cl O
alkoxide alkyl halide ether
+ NaCl
Williamson Ether Synthesis
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
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.
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
Prepara-on)of)Epoxides
55
2. Intramolecular Williamson Ether Synthesis of Vicinal Halohydrins
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
Prepara-on)of)Epoxides
58
2. Intramolecular Williamson Ether Synthesis of Vicinal Halohydrins
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
Prepara-on)of)Epoxides
59
2. Intramolecular Williamson Ether Synthesis of Vicinal Halohydrins
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
Intramolecular)Cycliza-on)of)Halohydrins)Can)Be)Stereospecifc
60
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 1: January 15
Synthe-c)Challenge
62
Design a synthesis for each epoxide.
Br ?O
H
H?
O
H
H
CHM(224(•(Organic(Chemistry(IISpring(2013,(Des(Plaines(•(Prof.(Chad(Landrie
Reac&ons*of*Ethers:*cleavage,*
hydrogena&on*of*benzyl*ethers,*Claisen*
rearrangement,*epoxide*ring*opening
Next(Lecture.(.(.