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Chem 215-216 HH W12-Notes – Dr. Masato Koreeda - Page 1 of 13
Date: February 13, 2012
Chapter 13. Alcohols, Diols, and Ethers
Overview: Chemistry and reactions of sp3 oxygen groups, particularly oxidation of an
alcohol, ether formation, and reactions of oxirane (epoxide) groups.
I. What are alcohols, phenols, and ethers?
Alcohols (R-OH) Primary alcohols
(1°-alcohols)
pKa ~16-17
CH3OH
CH3CH2OH
CH3CH2CH2OH
Secondary alcohols
(2°-alcohols)
pKa ~17-18
H3C
H3C
H3C
Tertiary alcohols
(3°-alcohols)
pKa ~19
Phenols (Ph-OH)
H3C
H3C
methanol
methyl alcohol
ethanol
ethyl alcohol
n-propyl alcohol
2-methyl-1-propanol
isobutyl alcohol
2,2-dimethyl-1-propanol
neopentyl alcohol
C OH
H
H3C-CH2
Common names
1-propanol
H3C
C CH2OH
H3C H
H3C
C CH2OH
H3C
CH3
IUPAC names
C OH
H
C OH
CH3
2-propanol
isopropyl alcohol
2-butanol
sec-butyl alcohol
2-methyl-2-propanol
tert-butyl alcohol
pKa ~10-12
Ethers (R-O-R')
RO-: alkoxy
CH3CH2-O-CH2CH3
diethyl ether
Ph-O-CH=CH2
phenyl vinyl ether
CH3O
CH3CH2O
ArO-: aryloxy
PhO
methoxy
ethoxy
phenoxy
II. Oxidation
Oxidation –
historical use of the term:
(1) oxide (oxyd/oxyde) – the ‘acid’ form of an element; e.g., S + air → oxide of S (acid of sulfur)
(2) oxidation or oxidize – to make such an acid, to make the oxide
(3) oxygen – Lavoisier: substance in the air that makes acids; “the bringer of acids” = “oxygen”
(4) oxidation or oxidize – to increase the % oxygen in a substance (reduction: to reduce the % oxygen)
More modern definition:
oxidation or oxidize – loss of electrons (coupled with reduction as gain of electrons)
Note: The loss of electrons (oxidation) by one atom or compound must be matched by the gain of electrons
(reduction) by another.
Chem 215-216 HH W12-Notes – Dr. Masato Koreeda - Page 2 of 13
Date: February 13, 2012
III. Oxidation state (or number) counting (see: pp 513-4 of the textbook)
eN
C H
-1 +1
eP
O C
-2 +2
C
0
Therefore,
C
0
The oxidation number of this C is -4.
H
H C H
"the contribution of an H to the oxidation number of the C is -1"
"the contribution of a C to the oxidation number of the H is +1"
H
-2
0
H
H C OH
H
C O
H
H
Other examples of oxidation numbers:
1.
"reducing agent"
H
0 0
-1
H H
+1 H H +1
+1 H
H +1
-2 -2
2.
0
+
Zn
0
0
Br
Br
-1
"oxidizing agent"
0 0
H
-1
Br
H
Br
-1
Br Br
H
00
+2
-1
Br
Zn
Br
-1
An atom with a formal charge: incorporate its charge # to its oxidation number. Namely,
if an atom has a +1 charge, add +1 to its oxidation number.
Example:
For N
O
N
For O
3 x (- 1) from 3 carbon atoms = -3
+1 from oxygen atom = +1
+1 from the charge = +1
-1 from nitrogen atom = -1
-1 from the charge = -1
overall: -1
overall: -2
==================================================================
Hydrocarbon oxidation-reduction spectrum:
"reduction"
(hydrogenation)
-4
H
H C H
H
H
methane
methanol
"oxidation"
(oxygen insertion)
0
-2
H C OH
H
+4
+2
H
H
C O
C O
H
HO
formaldehyde
(methanal)
formic acid
(methanoic acid)
+4
HO
C O
HO
O C O
+
H2O
carbonic acid
"oxidation"
(also: dehydrogenation)
increasing %O; decreasing %H
decreasing %O; increasing %H
note: used in biochem.: oxidase = dehydrogenase enzyme
"oxidation"
"reduction"
Chem 215-216 HH W12-Notes – Dr. Masato Koreeda - Page 3 of 13
Date: February 13, 2012
IV. Oxidation of alcohols
H
1°-alcohol
H
R C O
[ox]
H
[ox]
O
R C
O
- H+
aldehyde
O
H
carboxylic acid
H
R C O
R'
[ox]
R C
R'
- 2H+
R"
3°-alcohol
H
- 2H+
H
2°-alcohol
R C
H
R C O
O
ketone
not easily oxidized
R'
Oxidation methods:
There are hundreds that differ in experimental conditions, but these follow basically the process shown
below.
B
difficult to remove as H
"E2 - type" reaction
H
H
H
LG X
R C O
R'
R C
O
O
LG
R'
-H+
R'
- LG
"converting this H to a leaving group"
+ H B
R C
LG: leaving
group
Historically, most common reagents involve high-valency metals.
1. Cr (VI)-based reagents - all Cr(VI) reagents have toxicity problems
+6
O
CrO3
Cr
O
O
chromium trioxide
(chromic anhydride)
"to be oxidized"
"to be reduced"
RCH2OH
+
O
R C
H
CrO3
+
Cr3+
oxidizing agent
Balancing the oxidation-reduction reaction
3 x
2 x
R - CH2OH
Cr+6
+ 3e
O
R C
H
+
2H + 2e
("two-electron" oxidation)
Cr3+
Overall,
3 R - CH2OH
+
2 Cr+6
"stoichiometry"
O
3 R C
H
+
6 H+
+
2 Cr+3
Chem 215-216 HH W12-Notes – Dr. Masato Koreeda - Page 4 of 13
Date: February 13, 2012
1a Chromic acid [ CrO3 + H2O → H2CrO4] (hydrous conditions)
O
O
Cr
HO
problems: 1. acidic conditions
2. can't stop at the stage of an aldehyde
because of the presence of water
+6
OH
• Jones’ reagent: CrO3/H2SO4/H2O
historically, one of the most commonly used chromium +6-based
reagents for the oxidation of alcohols
• Chromate:
• Dichromate:
Na2CrO4 (sodium chromate)/H2SO4/H2O
Na2Cr2O7 (sodium dichromate)/H2SO4/H2O
Na2Cr2O7
Na
+6
O
O
O Cr O Cr O Na
O
O
1b. Anhydrous Cr
• CrO3•pyridine
• pyridinium chlorochromate (PCC): one of the most widely used oxidants!
• pyridinium dichromate (PDC) [(pyH+)2•Cr2O7-2]
O
O
Cr
Cl
N
H
O
+6
pyridinium chlorochromate
(PCC)
prepared from pyridine, HCl, and CrO3
Oxidation reactions of alcohols using these reagents are carried out in anhydrous organic solvents such as
dichloromethane and, thus, the oxidation of a primary alcohol stops at the stage of an aldehyde.
Mechanism for the oxidation with PCC:
R
R'
more electrophilic than the
Cr in CrO3 because of Cl
O-H
C
H
H
O
R
O
O
Cr
Cl
O
R'
C
H
O
Cr O
O
Cl
N
H
N
-Cl
H
R
C O
R'
+
O
oxidation
step
becomes
Cr+3
O
C
H
O
Cr+4
R
R'
O Cr
Cr+4
(chromium is reduced!)
extremely acidic!
often referred to as
"Chromate" ester
B:
B:
O
Cr O
R
R'
O
C
H
O
Cr O
O
still Cr+6
still Cr+6
through redox-disproportionation.
H
O
N
H
Cl
N
Cl
H
Chem 215-216 HH W12-Notes – Dr. Masato Koreeda - Page 5 of 13
Date: February 13, 2012
The oxidation of primary alcohols with Jones’ reagent:
H
aldehyde
CrO3, H2SO4
H2O
H
R C O
R C
acetone
(solvent)
H
O
faster step
H
O
1°-alcohol
more than 2 mol equiv.
of the reagent needed
O
R C
H
carboxylic acid
not isolable
Often, an ester R-C(=O)-OR is a by-product.
Mechanism:
H A
+6
O
Cr
HO
O
O
OH
OH
HO Cr
O
Cr
HO
O
O
H
OH
R C
-A
H H
R CH2OH
O
HO Cr
H A
OH
OH
OH
O
H
oxidation
step
R C
H H
B
A
R
C
O
Cr
A
HO
OH
OH
R
O
H
C
H
B
H
O
OH
Cr OH
O
H
O
HO
OH
R
C
HO
R
H
H
C
O
Cr
OH
HO
A
HO
C
O
carboxylic acid
+ Cr+4
2 Cr+4
Cr+3
H
H
O
H
H
O
oxidation step!
R
H
-A
OH
HO
+ Cr+4
Cr+3
aldehyde:
doesn't stop here!
Cr+6
"chromate ester"
Cr+6
"chromate ester"
O
R C
+ Cr+5 , etc.
A
R C
H
O
OH2
Chem 215-216 HH W12-Notes – Dr. Masato Koreeda - Page 6 of 13
Date: February 13, 2012
2. Non chromium-based Oxidation Reactions: “greener” methods
i) Swern oxidation: • usually using dichloromethane (CH2Cl2) as the solvent
• anhydrous (i.e., no water present!), non-acidic conditions
• 1°-alcohol: stops at an aldehyde; 2°-alcohol: gives a ketone
1.
O H
R
C
O
H3C
S
dimethyl
sulfoxide
H
O
C
C
H
O
Mechanism:
Cl
S
C
O
CH3
C
H3C
O
C C
O
S
CH3
Cl
S
C
H
O
H
H3C
R
C
S
Cl
O
CH3
CO2, CO, Cl
H
H
CH3
CH3
H B
H
S
B
H
H
C
C
O
H3C
Cl
R
C
O
Cl
O
This is the species in the solution after step 1.
O
O
Cl
Cl
O
C
oxalyl chloride
Cl
H3C
O
R
Cl
H
H3C
N(CH2CH3)3
triethylamine
2.
CH3
Cl
H
R
S
O
CH3
H
C
H
H
N(CH2CH3)3
highly acidic Hs!
pKa ~ 12-13
HN(CH2CH3)3
R
O
H3C
C
H
H
S
+
O C
"intramolecular
process"
C
H
R
Oxidation step!
H
H3C
S
C H
H
H
H
1.
Note:
O
H3C
S
O H
CH3
Cl
D
O
C
C
Cl
O
2.
N(CH2CH3)3
O
+
H3C
S
CH2D
Chem 215-216 HH W12-Notes – Dr. Masato Koreeda - Page 7 of 13
Date: February 13, 2012
IV 2. Non chromium-based Oxidation Reactions: “greener” methods
ii) Sodium hypochlorite (NaOCl): Bleach
Usually under acidic conditions (e.g., in acetic acid); HOCl (hypochlorous acid) is the actual oxidant.
As HOCl is not stable, it has to be generated in situ in the reaction medium.
V. Reactions of alcohols: Direct conversion of alcohols to alkyl halides
With SOCl2 (thionyl chloride) or PBr3 (phosphorus tribromide)
Mechanism for an alcohol to the chloride with SOCl2/pyridine
S
H
O
H
Cl
Cl
S
H
H
S
Cl
O
Cl
H
O
O
N S
Cl
O
B
or
highly electrophilic S
Alternatively,
O
H
S
O
N
that can be formed from SOCl2
and pyridine may be the reagent that puts S(=O)Cl onto
the OH group.
H
Cl
or
BH
Cl
O
S
Cl
O
N
H
R
H
Cl
SN 2 product
*Similar reactions and mechansims for the formation of bromides from alcohols with PBr3.
+ SO2
(gas)
+ Cl
Chem 215-216 HH W12-Notes – Dr. Masato Koreeda - Page 8 of 13
Date: February 13, 2012
VI. Ethers (R – O – R’)
1. Synthesis
a.Williamson synthesis
R O
R'
X
+
R O R'
X
ether
R’ - X: alkyl halides (usually bromide and iodide, sometimes chloride) or tosylates
R’: usually primary; methyl, allyl (CH2=CH-CH2- ), benzyl (PhCH2-).
SN2 reaction
O
O
NaH (1 mol equiv)
I CH2CH3
(excess; typically, 1.5 mol equiv)
H
H
Na
Mechanism:
CH2CH3
NaI
Na
H2C
H H
(gas)
CH3
Na H
a strong base
I
sodium alkoxide
This H in Na-H has
no nucleophilicity.
Sodium alkoxides can also be prepared by the treatment
of alcohols with Na.
+
Na
1
2
+
R O Na
H2
MO interpretation:
Mechanism:
anion radical
Na + e
Na
R O• H
R O H + Na
R O
+
Na
+ NaI
pKa ~40
H H
O
R O H
+ H2
(gas)
H• + H •
anti-bonding
orbital
σ*
Na
bonding
orbital
σ
O-H bond
of the anion radical
H•
H2
3 electrons in the O-H bond!
2°-alkyl halides and tosylates are occasionally used in the Williamson synthesis, but
elimination (E2) competes or dominates, and yields of the ether products are often quite low.
3°-alkyl halides: exclusive elimination (E2).
H
Na
O
H C
H
O
CH3
C
CH3
CH3
CH3
C CH3
E2!
OH
+
CH3
+
H2C C
NaBr
CH3
Br
Not formed!
Then, how do you make this t-butyl n-propyl ether?
Phenyl ethers: More acidic than alcohol OHs. A milder base such as NaOH can be used to
generate phenoxides (PhO ).
O H
N
O
O
O
1. NaOH
2.
I
N
O
O
80%
Chem 215-216 HH W12-Notes – Dr. Masato Koreeda - Page 9 of 13
Date: February 13, 2012
VI 2. Cleavage of ethers
In general, difficult to cleave ether C-O bonds (for exceptions, see VII).
Can be cleaved by heating with HI (more common) or HBr.
Need a strong Brönsted or Lewis acid and a strong nucleophile.
Usually, methyl ether C-O and benzyl ether C-O are those that can be cleaved.
Modern methods for cleaving ethers include the use of BBr3 and AlCl3 + HSCH2CH3.
O
CH3
H
O
H I
O
CH3
Δ
H
+
I
H3C I
(heat)
VII. Intramolecular ether formation
Cyclic ethers: by an intramolecular SN2 reaction of an alkoxide
NaOH
Cl
O
H2O
+
Cl
SN2
O
H
O H
NaCl
O
95%
Na
Na
• 5- and 6-membered cyclic ether formation: fast
• In general, intramolecular reactions are faster than the corresponding
intermolecular (bi-molecular) reactions.
Cl
• An intermolecular SN2 reaction of an alkoxide or
slow!
hydroxide ion with an alkyl chloride is slow.
O
O H
H
Geometrical and stereochemical effects on cyclic ether formation:
Which of the two diastereomeric hydroxy-bromide could form its cyclic ether derivative?
cis
Na
trans
OH
OH
trans
O
Br
Br
A
B
Br
NaH
H2
The alkoxide from A can't undergo
an SN2 reaction with the C-Br.
SN2 reacton possible!
equatorial
O
axial
too far
away
Br
axial
O
Br
no
SN2!
equatorial
more favored/stable conformer
No cyclic
ether formation
O
O
Chem 215-216 HH W12-Notes – Dr. Masato Koreeda - Page 10 of 13
Date: February 13, 2012
VIII. Epoxides (or Oxiranes): Special kind of cyclic ethers (3-membered ethers)
ethers:
epoxides (or oxiranes):
61.5° O
O
H3C
The ring is strained;
more polarized C-O bonds
unstable
and reactive!
CH3
112°
stable
a. Formation:
(1) Epoxidation of alkenes with peroxyacids (e.g., m-chloroperoxybenzoic acid; see Ch. 8 )
(2) From halohydrin with a base
O H
NaOH
O
O
H 2O
25 °C, 1 hr
Cl
more favored/stable
conformer
O
Cl
O
H
SN2
Cl
H
Cl
C-O and C-Cl
bonds are not
oriented for an SN2
process to take place.
Cl
O
70%
b. Ring-opening reactions of epoxides: Epoxides are highly strained and easily undergo
ring-opening reactions under both acidic and basic conditions.
Acidic conditions: ring-opening reactions proceed rapidly at low temperatures (usually at room temp or
below); elongated C-O bonds of the protonated, highly strained epoxides believed to be the origin of high
reactivity.
Acyclic epoxides
H Br
O
H
CH3
H
H3C
HBr
H
H3C
0 °C
H
CH3
Br
meso
HO
OH
+
CH3
H
H
H 3C
(2S,3S)
Br
(2R,3R)
racemic mixture
H
H
SN2-like
inversion of
stereochemistry
here!
O
O
H
H
CH3
H 3C
H
H
H 3C
CH3
SN2-like
inversion of
stereochemistry
here!
Br
Br
Cyclic-fused epoxides
O
H
O H
O
O CH3
O H
CH3OH
H
O
H
CH3
inversion of
stereochemistry
H
O
transproduct
O H
CH3
CH3
or simply B
+ enantiomer
Chem 215-216 HH W12-Notes – Dr. Masato Koreeda - Page 11 of 13
Date: February 13, 2012
Note: The mechanism for the ring-opening of epxodies under acidic conditions is quite similar to that of
bromination of alkenes.
Br
Br Br
Br
bromonium
ion
intermediate
trans-product
Br
inversion of
stereochemistry
Br
+ enantiomer
Stereochemical/regiochemical issues:
O
H3C
D3C
H3O18
H
CH3
H3C
D3C
H
CH3
0 °C
HO18
stereochemical
inversion
observed here!
regiochemically, stereochemically
clean formation of this diol.
OH
retention
Specific incorporation of HO18 here!
Mechanistic interpretation on the stereochemical/regiochemical outcome under acidic
conditions:
more elongated C--OH bond;
-charge delocalized because
this more substituted C can
better stalilize the postive charge
H
H
O18
H
O
O
O
H3C
D3C
H
H
H3C
H
CH3
D3C
H
CH3
In the transition state for the attack of H2O (H2O18 in this case),
the nucleophile attacks preferentially the carbon center that can
better stabilize a positive character (i.e., the more substituted
carbon).
H
H3C
D3C
CH3
Can accommodate
charge better here!
O
H3C
D3C
H2O18
H3C
D3C
HO18
stereochemical
inversion
observed here!
OH
H
CH3
retention
Specific incorporation of HO18 here!
H
H
CH3
an SN2-like stereochemical
inverstion at a more substituted
carbon center
Chem 215-216 HH W12-Notes – Dr. Masato Koreeda - Page 12 of 13
Date: February 13, 2012
Epoxide-ring opening under basic conditions
A straight SN2 process at the less-substituted carbon with a stereochemical inversion.
O
H
H3C
H3C
D
H3CCH2O Na
H
H3C
D
H3C
H3CCH2O
H3CCH2OH
less-substituted C;
SN2 reaction here!
H OCH2CH3
Na
O
O
H
H3C
H3C
D
OCH2CH3
Na
HO
OCH2CH3 +
Na
H3C
H3C
H
D
OCH2CH3
Summary of epoxide-ring opening reactions:
Acidic conditions: SN2 like in term of the stereochemical inversion, but at the
more substituted C.
Ring opening at the more substituted C with the inversion of stereochemistry.
Basic conditions: pure SN2
Ring opening at the less substituted C with the inversion of stereochemistry.
1,2-Diaxial opening of cyclohexene oxides
1)
O
OH
H 3O
OH
OH
O
H
O
HO
more stable conformer
H
axial OH
axial-like
axial-like
H2O
only 1,2-diaxial transition state feasible
for an SN2 like process to occur
OH
This is the conformer produced
first, then it inverts to the more
stable diequatorial OH conformer
shown above.
axial
thermodynamically
less favored conformer
Chem 215-216 HH W12-Notes – Dr. Masato Koreeda - Page 13 of 13
Date: February 13, 2012
The above examples are quite similar to the bromination reaction of cyclohexene systems.
Br
Br
Br
Br
Br2
H
Br
Br
Br
H
H
Br
H
Br
Br
H
Br
H
Br
H
Problems: Show the structure of the expected major product for each of the following
reactions.
(1)
Br2
1. MCPBA
2. aq HClO4
(2)
CH3OH, H+
O
H3CO
Na
CH3OH