Alcohols, Phenols, Ethers and Oxiranes

1
Alcohols, Phenols, Ethers and Oxiranes
B1
alcohols
phenols (naphthols)
ethers
oxiranes
2
Alcohols Physical Properties
B2

• Polar
• Hydrogen Bonding

lone pairs of electrons (oxygen is
electronegative)
Evidenced by b.p. (vs alkanes) ethane b.p.
-88.6oC ethanol b.p. 78.3oC ethylene
glycol b.p. 197oC
increasing degree of hydrogen bonding
3
Alcohols Physical Properties
B3

• Solubility
• high in water
• the longer the (non-polar) alkyl chain, less
  soluble the alcohol becomes.
• hydrophilic -OH vs hydrophobic chain
• ethanol solubility, g/100 ml H2O
  n-octyl solubility, g/100 ml H2O

4
Alcohols Acidity Basicity
B4

• as a base ? accepting protons
• as an acid ? donating protons

..
..
O
R

alcohol
H
..
..

R
O
OH
H
5
Alcohols Properties
B5
H
Protonated alcohol
O
R
H
This unit represents a good leaving group in
reactions (H2O)
Deprotonated alcohol
R
O

• Whyarehydroxy anionsstrong bases?

Alkoxide ions strong bases
e.g.
O
6
Comparative Acidity of Alcohols
B6
..
..
H2O


R
O
R
O
OH
strong base
H
weak acid (alcohol)

• organic bases pka
• acetic acid (CH3COOH) 4.8
• phenol (Ph-OH) 10
• ethanol (CH3CH2OH) 17
• water 15.7

7
Reactions to Prepare Alcohols
B7
Hydration of Alkene electrophilic addition

• water is added across the double bond
• acid is a catalyst (can use H2SO4 or H3PO4)
• Why does the hydroxy group (-OH)
  add to the 2o carbon and not the 1o
  carbon?

8
Mechanism of Electrophilic Addition
B8
CH
OH
step1addition ofH(electrophile) formation
of morestable 2o carbocation

• step3loss of H

• step2addition ofwater

O
H
H

• Alkenes are regions of high electron density.
• The electrophile (H) can add to either C1 or C2.
  The more stableproduct will predominate.
• This mode of addition is known as Markovnikov
  addition

9
Markovnikov Addition
B9

• Experimental Observation
• In the addition of HX across a double bond, H
  adds to the least substituted carbon, and X- to
  the most substituted.

H, H-OH
10
Markovnikov Addition
B10

• Mechanistic Explanation
• The addition of HX across a double bond favours
  thereaction pathway involving the most highly
  substituted carbocation intermediate.

H
CH
OH
2o Carbocation
11
Hydration of Alkene
B11

• Problems associated with this reaction
• Suseptibility of other functional groups present
  to acid
• Rearrangment (isomerization) of alkenes in acid

CH
C
CH
C
HO
12
Mechanism of 1,2-alkyl Shift
B12
OH
C
C
H
H

• 1,2-alkyl shiftformation of morestable 3o
  carbocation
• Driving force of the reaction is
  the formation of this stable intermediate

C
C
C
C
H
H
formation of 2o carbocation
13
Reactions to form AlcoholsHydroboration of
Alkenes
B13
C

• Note Stepwise addition of reagents
• Hydrogen electrophile has attacked more highly
  substituted carbon
• Hydroxy nucleophile is attached to less
  substituted carbon

14
Hydroboration of Alkenes, Mechanistic Outline
B14
CH
C
C
H
OH
CH
C
CH
C
H
H
B
3
H
H
B

• Addition of the boron atom to the less sterically
  hindered carbon (disadvantage when there is
  little steric differentiation between the two
  carbons)

15
B15
Anti-Markovnikov Addition Example
Me
Me
H
H
HO
Hydroxylation of cholesterol
16
Reactions to make AlcoholsGrignard Synthesis
B16
anhydrous ether
?
?-
R-X Mg
R-Mg-X
Grignard Reagent
X Cl, Br, I

• Grignard Reagents are highly polarised
• They are synthetic equivalents of R as a
  nucleophile
• they attack aldehydes and ketones to produce
  alcohols
• (further reactions of Grignard reagents will be
  studied later)

17
Grignard Reactions with Formaldehyde
B17

• Reaction of Grignard reagents with formaldehyde
  (methanal)
• produces primary alcohols

General Example
H
R-Mg-X
C
O
H
Specific Example
H
MgBr
C
O

H
phenyl magnesiumbromide
formaldehyde
18
Grignard Reactions with other Aldehydes
B18

• Reaction of Grignard reagents with aldehydes
  produces secondary (2o) alcohols

General Example
O
OH
H
R-Mg-X
C
H
R'
R'
R
any aldehyde
2o alcohol
Specific Example
O
Me-Mg-X
H
methyl magesium bromide
Propanal
2o alcohol
19
Grignard Reactions with Ketones
B19

• Reaction of Grignard reagents with ketones
  produces tertiary (3o) alcohols

General Example
O
OH
R
R-Mg-X
C
R2
R1
R1
R2
any ketone
3o alcohol
Specific Example
O
Me-Mg-X
methyl magnesium bromide
3o alcohol
cyclohexanone
20
Mechanism of Grignard Reactions
B20
MgBr
O
MgBr
O
H

H

• Nucleophilic Grignard reagent attacks? carbonyl
  carbon
• arrow from the carbonyl double bond to O shows
  that the oxygen carries the negative charge on
  the intermediate
• Intermediate salt is quenched withacid/water
  mixture, producing thealcohol

OH
H
21
Properties of Grignards
B21

• Grignard reagents are susceptible to attack by
  water
• even weak bases will destroy Grignard
  reagents(includes any compound with a proton
  (H) attached to anelectronegative element e.g.
  oxygen, nitrogen, sulfur,triple bonded carbon)
• ? Grignard reactions must be performed in the
  complete absence of water (e.g. using anhydrous
  ether as a solvent)

H
MgBr
O
Mg(OH)Br

H
H
base
acid
22
Reactions to make AlcoholsAlkyl Halide Hydrolysis
B22

• hydroxyl (-OH) attacks on an alkyl
  halide
• What is the mechanism of this reaction?

General Example
Specific Example
Note benzylic position is always v.
reactive. This reaction operates under mild
conditions
23
Reactions to make AlcoholsAlkyl Halide Hydrolysis
B23

• These are Sn1 or Sn2 reactions (depending on
  conditions)
• Revise lecture notes from 1st Year (102/105) and
  the relevant textbooks (e.g. Ege chapter 7)
• Make sure you are familiar with the mechanism of
  reaction and the reactions uses limitations

??
??

OH
24
Reactions of Alcohols
B24

• Dehydration Reactions

OH
90
protonation of alcohol
O
H
H
H
H
loss of water (water is a good leaving group
- OH is not)
loss of H water is the base
25
Reactions of Alcohols
B25

• Dehydration reactions
• all reactions are reversible ? must remove
  product by distillation
• use a dehydrating acid e.g. H3PO4 or conc H2SO4
• Reactivity of alcohol (R-OH)
• (consistant with nucleophilic substitution
  mechanisms)

26
Reactions of Alcohols
B26

• Dehydration Reactions
• rearrangements are possible

major
minor
27
Reactions of Alcohols
B27

• Conversion to Alkyl Halides (nuclephilic
  substitution)
• important to convert OH into a good leaving
  group(? can be displaced by X)
• avoid formation of carbocation intermediates
  (which can lead to rearrangements)

28
Reactions of Alcohols
B28

• Gaseous HXreactivity HI gt HBr gt HCl
  reactivity

water a good leaving group
29
Reactions of Alcohols
B29

• via the tosylate

Cl
S
O
O

TsCl
OH
NaBr
OTs
Br
30
Reactions of Alcohols
B30

• using thionyl chloride
• using phosphorus trihalides

x
31
Reactions of AlcoholsOxidations Reductions
B31

• Primary Alcohols
• Secondary Alcohols
• Tertiary Alcohols

32
Reactions of Alcohols Oxidations
B32

• Reagents
• Potassium Permanganate (strong oxidising agent)
• Dichromate (strong oxidising agent)

33
Reactions of Alcohols Oxidations
B33

• Selective Oxidations
• With such strong oxidation reactions, often
  there are unwanted side reactions. ? milder more
  selective reagents are commanly used
• e.g. pyridinium chlorochromate

34
Reactions of Alcohols Oxidations
B34

• Selective Oxidation Reaction Examples

35
Reactions of Alcohols Oxidations
B35

• Swern Oxidation
• 2o alcohols will yield ketones

ii) triethylamine
1-decanal
1-decanol
O
Cl
Cl
O
36
Ethers Epoxides
B36

• NomenclatureSymmetrical - diethyl
  ether Et-O-Et
• - diphenyl ether Ph-O-Ph
• Unsymmetrical - phenyl vinyl ether
• Note methoxy phenoxy benzyloxy

37
Ethers Epoxides
B37

• Examples
• methoxybenzene (anisole)
• 1,2,3-trimethoxypropane
• 4-benzyloxy-1-butene

38
Ethers Epoxides
B38

• Physical Properties
• NOT 180o two dipole moments dont cancel
  each other out ? weak polarity
• Cyclic Ethers

39
Preparation of Ethers
B39

• Williams Synthesis
• alkoxide ion
• (generated with Na suitable for symmetrical
• or K or NaH) or unsymmetrical ethers
• Note Generation of alkoxides, generally requires
  Na
• Generation of phenoxides, NaOH is usually
  sufficient

40
Ether Synthesis Examples
B40

• Williams Synthesis is an Sn2 reaction
• limitation aryl halides have insufficient
  reactivity

Na
C
O
C
O
Br
X
41
Ether Synthesis Examples
B41
OH
Br
aq. NaOH

• Phenoxy anion generated with sodium hydroxide
• Phenoxy nucleophile attacks alkyl halide
• Note name benzyl phenyl ether

42
Ether Synthesis Examples
B42

• Intramolecular Example

NaOH
OH
Cl
4-chloropentan-1-ol
43
Reactions of Ethers
B43

• Comparatively unreactive
• cleavage by acids vigourous conditions required
• reactivity HI gt HBr gt HCl

phenol isolated due to low reactivity
44
Mechanism of Ether Cleavage
B44
45
Epoxides Synthesis
B45
a)
b)
46
Epoxides Synthesis
B46
c) peroxybenzoic acids
peroxybenzoic acid
Selectivity from multiple double bonds comes from
the more electron rich
COOOH
Cl
47
Epoxides Reactions
B47

• Sn2 attack by a nucleophile on a protonated
  epoxide
• Easily ring opened by either electrophilic or
  nucleophilic reagents, due to the strained nature
  of the 3-membered ring
• The driving force is the relief of that strain.

48
Epoxides Reactions
B48

• Examples

H
O
H
49
Epoxides Reactions
B49

• Other nucleophiles can be used

50
Epoxides Reactions
B50

• In the presence of nucleophiles (i.e. NOT acid
  conditions)

O
O
OH
OH
70
51
Epoxides Reactions
B51

• i) Acid catalysed Ring Openings

H-Br
O
48 HBr
o
H
0
H
trans
(attack at either carbon)
Stereocontrolled Reaction
52
Epoxides Reactions
B52
O
48 HBr
R
R
H
o
0
H
trans

• The opposite trans configurated oxirane i.e.
  (S,S) yields the other diastereomer
  (2S,3R)-3-bromo-2-butanol
• Sn2 conditions prevail as a good nuclephile is
  present (Br-)
• Attack of the nucleophile results in inversion of
  configuration. The hydroxy carbon has retention
  of configuration.

53
Epoxides Reactions
B53

• With the cis molecule

54
Epoxides Reactions
B54

• For unsymmetrical oxiranes (acid catalysed
  ring-openings)

H
O
O
OH
C
C
H
H
H
H
OH
OH
deprotonation
C
C
C
C
H
H
55
Epoxides Reactions
B55

• ii) Ring Opening with Nucleophiles

O
H
O
H
HO
C
C
C
C
H
protonation
56
Epoxides Reactions
B56

• Ring openings with Nucleophiles
• Nucleophile attacks the less highly substitued
  carbon(steric reasons)
• Incoming nucleophile the formed hydroxyl
  group are anti to each other
• An array of nucleophiles can be usedcarbon
  nucleophiles e.g. grignard reagents HC?Cazid
  e ionsamine, sulfur and oxygen nucleophiles

57
Epoxides Reactions (Summary)
B57
O
H
Nucleophilic
H
HO
OH
H
HO
C
C
C
C
C
C
H
Br
48 HBr, Oo
CH3OH, H2SO4
CH3ONa, CH3OH