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?
IUPAC names Common names methyl alcohol ethyl alcohol n-propyl alcohol isobutyl alcohol neopentyl alcohol

Alcohols (R-OH) Primary alcohols

(1-alcohols) pKa ~16-17

CH3OH CH3CH2OH CH3CH2CH2OH H3C C CH2OH H3C H H3C C CH2OH H3C CH3 H3C H3C C OH H C OH H

methanol ethanol 1-propanol 2-methyl-1-propanol 2,2-dimethyl-1-propanol

Secondary alcohols (2-alcohols) pKa ~17-18

2-propanol

isopropyl alcohol

H3C-CH2 H3C

2-butanol

sec-butyl alcohol

Tertiary alcohols (3-alcohols) pKa ~19

H3C H3C

C OH CH3

2-methyl-2-propanol

tert-butyl alcohol

Phenols (Ph-OH) Ethers (R-O-R')

pKa ~10-12 CH3CH2-O-CH2CH3 Ph-O-CH=CH2 RO-: alkoxy ArO-: aryloxy CH3O CH3CH2O PhO methoxy ethoxy phenoxy diethyl ether phenyl vinyl ether

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)
eN eP C H -1 +1 O C -2 +2 C 0 C 0 Therefore, The oxidation number of this C is -4. H H C H H H H C OH 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"

-2
H H

0
C O

Other examples of oxidation numbers:

1.

+1 H H +1 +1 H -2 -2 0
Zn

H +1

"reducing agent" H 0 0 -1 H H

-1

"oxidizing agent" 0 0
Br Br

-1
H

Br Br

-1
H

00

2.

0
Br

0
Br

+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: O N For O For N 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) H H C H H

+4 0
H C O HO HO

-4

H H

-2
H H

+2

HO C O

+4

H C OH

C O

O C O + H2O

methane

methanol

formaldehyde (methanal)

formic acid (methanoic acid)

carbonic acid

"oxidation" (oxygen insertion)

"oxidation" (also: dehydrogenation) increasing %O; decreasing %H decreasing %O; increasing %H "oxidation" "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

H

1-alcohol

R C O H H H

[ox] - 2H+ [ox] - 2H+

R C H

[ox] - H+

R C O

O H

aldehyde
O

carboxylic acid
R C R'

2-alcohol

R C O R' R" H

ketone

3-alcohol

R C O R'

not easily oxidized

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 R C O R' LG X R C R' O LG O R C

+ H B

-H+ "converting this H to a leaving group"

- LG
LG: leaving

R'

group

Historically, most common reagents involve high-valency metals.

1. Cr (VI)-based reagents - all Cr(VI) reagents have toxicity problems

+6
CrO3 O Cr O O chromium trioxide (chromic anhydride)

"to be oxidized"
RCH2OH +

"to be reduced"
CrO3 O R C H + Cr3+

oxidizing agent

Balancing the oxidation-reduction reaction

3 x 2 x Overall,
3 R - CH2OH + 2 Cr+6 O 3 R C H + 6 H+ + 2 Cr+3 R - CH2OH Cr+6 + 3e O R C H Cr3+ + 2H + 2e

("two-electron" oxidation)

"stoichiometry"

Chem 215 F12-Notes Dr. Masato Koreeda - Page 4 of 13 1a Chromic acid [ CrO3 + H2O ! H2CrO4] (hydrous conditions)
O Cr HO OH O

Date: September 10, 2012

+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: Dichromate: Na2CrO4 (sodium chromate)/H2SO4/H2O Na2Cr2O7 (sodium dichromate)/H2SO4/H2O
Na2Cr2O7 Na

1b. Anhydrous Cr CrO3pyridine

+6

O O O Cr O Cr O Na O O

pyridinium chlorochromate (PCC): one of the most widely used oxidants!

pyridinium dichromate (PDC) [(pyH+)2Cr2O7-2]
O Cr N H Cl O 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' O-H C H more electrophilic than the Cr in CrO3 because of Cl O O Cr Cl O
N H

R R' C H

H O

O Cr O O Cl

N H

-Cl often referred to as "Chromate" ester R R' B: C H O O Cr O O extremely acidic! B: R R' C H H O O Cr O O still Cr+6
N H

R C O R' + O O Cr O

oxidation step

Cl

Cr+4 (chromium is reduced!) Cr+4 becomes Cr+3

still Cr+6 Cl

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:

H R C O H H CrO3, H2SO4 H2O

aldehyde
R C H not isolable O

acetone (solvent)
more than 2 mol equiv. of the reagent needed

faster step

R C O

O H

1-alcohol

carboxylic acid

Often, an ester R-C(=O)-OR is a by-product. Mechanism:

+6
O HO Cr O OH -A R CH2OH H A O HO Cr OH R C H H H O O O HO Cr H A O OH OH R C H H B HO Cr O OH OH R C O H A + Cr+4

oxidation step

Cr+6 "chromate ester" Cr+6 "chromate ester"

HO R H B C O OH Cr O OH OH R H HO C H O OH Cr OH O OH R

Cr+3 aldehyde: doesn't stop here!

-A A HO C H O Cr OH A H O H O HO HO R C H A H O H H R C H O OH2

oxidation step!

HO R C O + Cr+4 2 Cr+4 Cr+3

+ Cr+5 , etc.

carboxylic acid

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
1. O H R C H O H H3C Cl C C Cl O oxalyl chloride Cl Cl O C C Cl O H3C S CH3 O C C O O H3C Cl S CH3 Cl O C O C Cl O O S CH3 dimethyl sulfoxide 2. N(CH2CH3)3 triethylamine O R C H

Mechanism:
H3C O S CH3

Cl

This is the species in the solution after step 1.

R O H3C H S C H N(CH2CH3)3 H C H H B H
H3C S CH3 H O

B
R C H CH3 Cl S CH3 H O C H R H H CO2, CO, Cl

highly acidic Hs!

pKa ~ 12-13 HN(CH2CH3)3

R O H3C S C H H C H H

Oxidation step! "intramolecular process"

R O C H

H3C

S H

C H H

Note:
O H D

1.

H3C Cl O C

O S CH3 O 2. N(CH2CH3)3 O

H3C

CH2D

C Cl

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
S
O H Cl Cl S H O O Cl H S Cl H O B O H S O
N

H Cl
or

BH
N

Cl

S O

Cl

highly electrophilic S Alternatively,

O N S Cl

or

that can be formed from SOCl2

R
H Cl
+ SO2 (gas) + Cl

and pyridine may be the reagent that puts S(=O)Cl onto the OH group.

SN 2 product

*Similar reactions and mechansims for the formation of bromides from alcohols with PBr3.

Chem 215 F12-Notes Dr. Masato Koreeda - Page 8 of 13

Date: September 10, 2012

VI. Ethers (R O R)
1. Synthesis

a.Williamson synthesis
SN2 reaction
O H H Na

R O

R'

R O R'

ether R - X: alkyl halides (usually bromide and iodide, sometimes chloride) or tosylates R: usually primary; methyl, allyl (CH2=CH-CH2- ), benzyl (PhCH2-).
NaH (1 mol equiv) I CH2CH3 (excess; typically, 1.5 mol equiv) Na O H H (gas) H2C I CH3 O CH2CH3 + H2 (gas) + NaI

Mechanism:

NaI H H Na H

pKa ~40 a strong base

sodium alkoxide

Sodium alkoxides can also be prepared by the treatment of alcohols with Na.
R O H + Na R O Na +
1 2

This H in Na-H has no nucleophilicity.

H2

Mechanism:
Na Na + e

MO interpretation: anion radical !* !

anti-bonding orbital bonding orbital

R O H + Na

R O H

Na

R O

Na

H H2

O-H bond of the anion radical

3 electrons in the O-H bond!

H + H

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).
Na O H H C H O CH3 C CH3 CH3 CH3 C CH3 Br

E2!

OH

CH3 H2C C CH3 + NaBr

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

1. NaOH 2.
I

O N O O

80%

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 Brnsted 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 I (heat)

H O

CH3

O I

H3C I

VII. Intramolecular ether formation

Cyclic ethers: by an intramolecular SN2 reaction of an alkoxide
Cl NaOH O H O H Na Na H2O Cl O +

SN2

NaCl

95%

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
OH Br OH Br NaH H2

trans

Na O

trans
Br

A The alkoxide from A can't undergo an SN2 reaction with the C-Br.

SN2 reacton possible! equatorial

O

too far away

axial

O Br

axial

Br

no SN2!

equatorial

more favored/stable conformer

No cyclic ether formation

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)
epoxides (or oxiranes): 61.5 O The ring is strained; more polarized C-O bonds unstable and reactive! ethers:
H3C O 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 Cl NaOH H 2O 25 C, 1 hr O Cl
more favored/stable conformer

O Cl C-O and C-Cl bonds are not oriented for an SN2 process to take place. Cl

SN2
Cl

H H

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 H3C H CH3 HBr 0 C H3C H OH H CH3 + HO H H 3C CH3 H Br

Br

meso

(2S,3S)
racemic mixture H

(2R,3R)
H O

SN2-like inversion of stereochemistry here! Cyclic-fused epoxides

O H CH3OH

O H H 3C Br H CH3 H H 3C

H CH3 Br

SN2-like inversion of stereochemistry here!

O H O H O H O H CH3 inversion of stereochemistry H O CH3

O H

transproduct

O CH3

+ enantiomer

CH3 or simply B

Chem 215 F12-Notes Dr. Masato Koreeda - Page 11 of 13

Date: September 10, 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 bromonium ion intermediate Br

trans-product
Br

Br

inversion of stereochemistry

+ enantiomer

Stereochemical/regiochemical issues:
O H3C D3C H CH3 H3O18 0 C HO18 H3C D3C OH H CH3 retention Specific incorporation of HO18 here!

regiochemically, stereochemically clean formation of this diol.

stereochemical inversion observed 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 O H CH3 H3C D3C H CH3 H3C D3C O H CH3 H

H H O H3C D3C O18 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).

Can accommodate charge better here!

O H3C D3C H2O18

H CH3

H3C D3C HO18

OH H CH3 retention Specific incorporation of HO18 here!

an SN2-like stereochemical inverstion at a more substituted carbon center

stereochemical inversion observed 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.
O H3C H3C H D H3CCH2O Na H3CCH2OH O H H3C D H3C H3CCH2O Na OCH2CH3 + Na Na O H3C H3C H OCH2CH3 H

OCH2CH3 HO H3C H3C H

less-substituted C; SN2 reaction here!

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 H 3O OH OH OH HO more stable conformer

H O

H axial OH axial-like This is the conformer produced first, then it inverts to the more stable diequatorial OH conformer shown above.

axial-like H2O only 1,2-diaxial transition state feasible for an SN2 like process to occur

OH

axial

thermodynamically less favored conformer

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.
Br Br Br2 H Br H Br H Br H Br Br H Br Br H Br H Br

Br

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