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Chapter 13
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Chem 215 F12-Notes – Dr. Masato Koreeda - Page 1 of 13 Date: September 10, 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)
CH3OH methanol methyl alcohol
CH3CH2OH ethanol ethyl alcohol
CH3CH2CH2OH 1-propanol n-propyl alcoholpKa ~16-17
H3CC CH2OH
H3C H2-methyl-1-propanol isobutyl alcohol
H3CC CH2OHH3CCH3
2,2-dimethyl-1-propanol neopentyl alcohol
H3CC OH
H3C HSecondary alcohols(2°-alcohols)
pKa ~17-18
2-propanol isopropyl alcohol
H3C-CH2 C OHH3C H
2-butanol sec-butyl alcohol
H3CC OH
H3C CH3
Tertiary alcohols(3°-alcohols)
pKa ~19
2-methyl-2-propanol tert-butyl alcohol
Phenols (Ph-OH) pKa ~10-12
Ethers (R-O-R') CH3CH2-O-CH2CH3diethyl ether
Ph-O-CH=CH2 phenyl vinyl ether
RO-: alkoxy methoxyethoxy
ArO-: aryloxy phenoxy
CH3CH2OCH3O
PhO
IUPAC names Common names
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 F12-Notes – Dr. Masato Koreeda - Page 2 of 13 Date: September 10, 2012
III. Oxidation state (or number) counting (see: pp 513-4 of the textbook)
ePeN C H-1 +1
O C-2 +2
C C0 0
"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"
C HH
HH
The oxidation number of this C is -4.
C OHH
HH
-2HC
HO
0
Therefore,
HH
Other examples of oxidation numbers:
HH
HHH H
BrBrH H
BrBr-1-10 0-1-1
-2-200
0 0
+1+1+1
+1 "reducing agent" "oxidizing agent"1.
2.Zn + Br
ZnBrBrBr
000 +2
-1-1
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.
N
O For N 3 x (- 1) from 3 carbon atoms = -3+1 from oxygen atom = +1+1 from the charge = +1
overall: -1
For O -1 from nitrogen atom = -1-1 from the charge = -1
overall: -2
Example:
================================================================== Hydrocarbon oxidation-reduction spectrum:
C HH
HH C OH
H
HH
-2HC
HO
0H
HOC O
HO
HOC O
-4 +2 +4+4
methane methanol formaldehyde(methanal)
formic acid(methanoic acid)
carbonic acid
"oxidation"(oxygen insertion)
"oxidation"(also: dehydrogenation)
"reduction"(hydrogenation)
O C O+H2O
increasing %O; decreasing %H "oxidation"decreasing %O; increasing %H "reduction"
note: used in biochem.: oxidase = dehydrogenase enzyme
Chem 215 F12-Notes – Dr. Masato Koreeda - Page 3 of 13 Date: September 10, 2012
IV. Oxidation of alcohols
R C
H
HOH
R C
R'
HOH
R C
H
O R C
O
O
H
R C
R'
O
R C
R'
R"OH
ketone
aldehydecarboxylic acid
1°-alcohol
2°-alcohol
3°-alcohol
[ox] [ox]
- 2H+
[ox]
- 2H+
- H+
not easily oxidized
Oxidation methods: There are hundreds that differ in experimental conditions, but these follow basically the process shown below.
R C
R'
HOH
difficult to remove as H
LG X
-H+
R C
R'
H
OLG
B"E2 - type" reaction
R C
R'
OH B+
LG-
"converting this H to a leaving group"LG: leaving group
Historically, most common reagents involve high-valency metals.
1. Cr (VI)-based reagents - all Cr(VI) reagents have toxicity problems
OCr
O
Ochromium trioxide
(chromic anhydride)
CrO3
+6
RCH2OH + CrO3 R CH
O+ Cr3+
"to be oxidized" "to be reduced"
oxidizing agent Balancing the oxidation-reduction reaction
R - CH2OH R CH
O+ 2 H + 2 e3 x ("two-electron" oxidation)
Cr+6 + 3e Cr3+2 x
Overall,
3 R - CH2OH + 2 Cr+6 R CH
O+ 6 H+ + 2 Cr+33
"stoichiometry"
Chem 215 F12-Notes – Dr. Masato Koreeda - Page 4 of 13 Date: September 10, 2012 1a Chromic acid [ CrO3 + H2O → H2CrO4] (hydrous conditions)
CrO O
HO OH+6 problems: 1. acidic conditions
2. can't stop at the stage of an aldehyde because of the presence of water
• Jones’ reagent: CrO3/H2SO4/H2O historically, one of the most commonly used chromium +6-based reagents for the oxidation of alcohols
• Chromate: Na2CrO4 (sodium chromate)/H2SO4/H2O • Dichromate: Na2Cr2O7 (sodium dichromate)/H2SO4/H2O
O Cr O Cr O
O
O
O
ONaNaNa2Cr2O7
1b. Anhydrous Cr+6 • CrO3•pyridine • pyridinium chlorochromate (PCC): one of the most widely used oxidants! • pyridinium dichromate (PDC) [(pyH+)2•Cr2O7
-2]
NH
CrO O
Cl O+6
prepared from pyridine, HCl, and CrO3pyridinium chlorochromate
(PCC)
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:
CR
R' H
O-H
CrO
O
OCl
more electrophilic than the Cr in CrO3 because of Cl
CR
R'OH
CrO
OO
HCl
NH
NH
CR
R'OH
CrO
HNHO
O
-Cl
Clstill Cr+6
B:extremely acidic!
CR
R'O Cr
O
H
NH
OO
Cl
still Cr+6
often referred to as"Chromate" ester
oxidation step
B:
C OR
R'Cr
O
OO
+
Cr+4
(chromium is reduced!)
Cr+4 becomes Cr+3 through redox-disproportionation.
Chem 215 F12-Notes – Dr. Masato Koreeda - Page 5 of 13 Date: September 10, 2012 The oxidation of primary alcohols with Jones’ reagent:
R C
H
HO
HR C
H
O R C
O
O
H
aldehyde
carboxylic acid1°-alcohol
CrO3, H2SO4H2O
acetone(solvent)
not isolablemore than 2 mol equiv. of the reagent needed
faster step
Often, an ester R-C(=O)-OR is a by-product. Mechanism:
OCr
O+6
HO OH
H A
OCr
O
HO OH
H
-AR CH2OH
OCr
OHHO
OHO
CRH H
H
A
OCr OHHO
OHO
CRH H
B
Cr+4O
CR
H
Cr+6
Cr+3
"chromate ester"
+oxidation
stepaldehyde:
doesn't stop here!
OCR
H
HO
H
H A
OCR
H
H
OH2
HOCR
H
HO H
AO Cr
O
HO OH
H
OCR
H
HO H
OCr
OH
OHOH
B
OCR
H
HO
O
Cr
OH
OHOH
A
A
oxidation step!
OCR
HO
carboxylic acid
Cr+4+
Cr+6
"chromate ester"-A
2 Cr+4 Cr+3 + Cr+5 , etc.
Chem 215 F12-Notes – Dr. Masato Koreeda - Page 6 of 13 Date: September 10, 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
R CO
HH
HH3C S
CH3
O dimethylsulfoxide
oxalyl chloride
1.N(CH2CH3)32.triethylamine
R CO
H
Mechanism:
H3C SCH3
O
ClC
CCl
OO
ClC
CCl
OO H3C S
CH3
O
Cl
C C
ClO
OH3C S
CH3
O C CClO
O
Cl
Cl SCH3
CH3
Cl
CO2, CO, Cl
O CR
HH
H
O CR
HH
SCH3
H3C
HO C
R
HH
SC
H3C
B
H BHH
H
N(CH2CH3)3
This is the species in the solution after step 1.
O CR
H
H
SC
H3C
H H
HN(CH2CH3)3
highly acidic Hs!
pKa ~ 12-13
O CH
R H3C SC
H H
H+Oxidation step!
"intramolecularprocess"
Note:O H
DO H3C
SCH2D
H3C SCH3
O1.
N(CH2CH3)32.
ClC
CCl
OO
+
Chem 215 F12-Notes – Dr. Masato Koreeda - Page 7 of 13 Date: September 10, 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
+ +
OHH
S
H Cl
R
ClSO2(gas)
SN 2 product
SO
Cl
Cl
N SO
Cl
OHH
SO
Cl
Cl
OH
H
SO
Cl
N
Bor
OH
SO
ClCl
highly electrophilic S
Alternatively, that can be formed from SOCl2
and pyridine may be the reagent that puts S(=O)Cl onto the OH group.
*Similar reactions and mechansims for the formation of bromides from alcohols with PBr3.
BH
N H
or
Chem 215 F12-Notes – Dr. Masato Koreeda - Page 8 of 13 Date: September 10, 2012
VI. Ethers (R – O – R’) 1. Synthesis
+R O R' Xa.Williamson synthesis R O R'
etherX
SN2 reaction R’ - X: alkyl halides (usually bromide and iodide, sometimes chloride) or tosylates R’: usually primary; methyl, allyl (CH2=CH-CH2- ), benzyl (PhCH2-).
+ +
+
+
HO
CH2CH3O
NaH (1 mol equiv)I CH2CH3
(excess; typically, 1.5 mol equiv)
+ H2 + NaIH
Na
ONa
H2CCH3
I
Mechanism:
H H(gas)
(gas)
NaIH H pKa ~40Na H
a strong baseThis H in Na-H hasno nucleophilicity.
Sodium alkoxides can also be prepared by the treatmentof alcohols with Na.
R O
sodium alkoxide
R O H Na Na 12 H2
+
+R O
R O H
Na Na
H
e
R O H•
•
anion radical
• H2H • H
O-H bondof the anion radical
σ
σ*
MO interpretation:
3 electrons in the O-H bond!
anti-bondingorbital
bondingorbital
Mechanism:
Na
Na
Na
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).
+ +ONa
C CH3
Br
CH3CH
HH
CCH3
CH3H2COH NaBr
OCCH3
CH3CH3 Not formed!
Then, how do you make this t-butyl n-propyl ether?
E2!
Phenyl ethers: More acidic than alcohol OHs. A milder base such as NaOH can be used to generate phenoxides (PhO ).
N
O
O
O
H 1. NaOH2. I N
O
O
O80%
Chem 215 F12-Notes – Dr. Masato Koreeda - Page 9 of 13 Date: September 10, 2012
VI 2. Cleavage of ethers, pp In general, difficult to cleave ether C-O bonds (for exceptions, see VIII, pp 10-13). 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.
CH3O IH
CH3O
I
H
HO
H3C I+Δ
(heat)
VII. Intramolecular ether formation
+OH
ClNaOHH2O O
ClO
NaHONa
NaCl
Cyclic ethers: by an intramolecular SN2 reaction of an alkoxide
SN2
• 5- and 6-membered cyclic ether formation: fast• In general, intramolecular reactions are faster than the corresponding intermolecular (bi-molecular) reactions.• An intermolecular SN2 reaction of an alkoxide or hydroxide ion with an alkyl chloride is slow.
95%
OH
Cl
HO
slow!
Geometrical and stereochemical effects on cyclic ether formation:
Which of the two diastereomeric hydroxy-bromide could form its cyclic ether derivative?
Na
BrOH
BrOH
A B
cis trans
The alkoxide from A can't undergoan SN2 reaction with the C-Br.
BrO
trans
NaH
H2
Br
O O
Br
equatorial
axial
axial
equatorialmore favored/stable conformer
SN2 reacton possible!
too far away
no SN2!
No cyclic ether formation OO
Chem 215 F12-Notes – Dr. Masato Koreeda - Page 10 of 13 Date: September 10, 2012
VIII. Epoxides (or Oxiranes): Special kind of cyclic ethers (3-membered ethers)
O61.5° H3CO
CH3112°
The ring is strained; more polarized C-O bonds
ethers:
stable
epoxides (or oxiranes):
unstable and reactive!
a. Formation: (1) Epoxidation of alkenes with peroxyacids (e.g., m-chloroperoxybenzoic acid; see Ch. 8 ) (2) From halohydrin with a base
Cl
O HNaOHH2O
25 °C, 1 hrCl
O
ClCl
O
Omore favored/stable
conformer
C-O and C-Clbonds are not
oriented for an SN2process to take place.
O 70%
O
H
H
Cl
SN2
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.
H3C CH3
OH H
mesoBr
H3C
CH3
OHH
H
(2S,3S) (2R,3R)H3C
CH3
HHBr
HOHBr0 °C
racemic mixture
H Br
H3C CH3
OH H
H
Br
H3C CH3
OH H
H
Br
SN2-likeinversion of
stereochemistryhere!
SN2-likeinversion of
stereochemistryhere!
OH
CH3OHO H
H O CH3
O H
HO CH3
HO CH3
or simply B
O H
O CH3
Acyclic epoxides
Cyclic-fused epoxides
inversion ofstereochemistry
+ enantiomer
trans-product
Chem 215 F12-Notes – Dr. Masato Koreeda - Page 11 of 13 Date: September 10, 2012
Br
Note: The mechanism for the ring-opening of epxodies under acidic conditions is quite similar to that of bromination of alkenes.
BrBr Br
inversion ofstereochemistry
Br
Br
trans-product
+ enantiomer
bromonium ion
intermediate
Stereochemical/regiochemical issues:
D3C CH3
OH3C H 0 °C
H3O18
HO18
D3C
CH3
OHH
H3C regiochemically, stereochemicallyclean formation of this diol.
retentionstereochemicalinversion
observed here! Specific incorporation of HO18 here!
Mechanistic interpretation on the stereochemical/regiochemical outcome under acidic conditions:
D3C CH3
OH3C H
H
D3C CH3
OH3C H
H2O18
HO18
D3C
CH3
OHH
H3C
retentionstereochemicalinversion
observed here! Specific incorporation of HO18 here!
HO18
HH
D3C CH3
OH3C H
H
D3C CH3
O
H3C H
H
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).
more elongated C--OH bond; -charge delocalized because
this more substituted C canbetter stalilize the postive charge
an SN2-like stereochemicalinverstion at a more substituted
carbon center
Can accommodate charge better here!
Chem 215 F12-Notes – Dr. Masato Koreeda - Page 12 of 13 Date: September 10, 2012
Epoxide-ring opening under basic conditions A straight SN2 process at the less-substituted carbon with a stereochemical inversion.
+
H3C D
OH3C H
H3CCH2O NaH3CCH2OH
H3CD
O
H3CH
H3C
DO
H3CH
OCH2CH3
H OCH2CH3
H3CCH2O
H3C
DHO
H3CH
OCH2CH3
OCH2CH3
Na
Na
Na
less-substituted C;SN2 reaction here!
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)
OH3O
OH
OH
OH O
H2O
H
axial-like
axial-like
OHaxial
only 1,2-diaxial transition state feasiblefor an SN2 like process to occur
OH axial
thermodynamicallyless favored conformer
HO
OH
more stable conformer
This is the conformer produced first, then it inverts to the more stable diequatorial OH conformershown above.
Chem 215 F12-Notes – Dr. Masato Koreeda - Page 13 of 13 Date: September 10, 2012 The above examples are quite similar to the bromination reaction of cyclohexene systems.
H
Br
H
Br
H
Br2H
Br
HBr
Br
BrH
Br
Br
H
Br
Br
Br
Br
Problems: Show the structure of the expected major product for each of the following reactions.
O
CH3OH, H+
CH3OHH3CO Na
Br2
1. MCPBA
2. aq HClO4
(1)
(2)