Chapter 13. Alcohols, Diols, and Ethers - umich.educhem215/215-216 HH W13-notes-Ch 13.pdf · Chapter 13. Alcohols, Diols, and Ethers Overview: Chemistry and reactions of sp3 oxygen

Chem 215-216 HH W13-Notes – Dr. Masato Koreeda - Page 1 of 13 Date: February 20, 2013

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

H3C C CH2OHH3C H

2-methyl-1-propanol isobutyl alcohol

H3C C CH2OHH3CCH3

2,2-dimethyl-1-propanol neopentyl alcohol

H3C C OHH3C H

Secondary alcohols(2°-alcohols)

pKa ~17-18

2-propanol isopropyl alcohol

H3C-CH2 C OHH3C H

2-butanol sec-butyl alcohol

H3C C OHH3C 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-CH2CH3 diethyl 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 215-216 HH W13-Notes – Dr. Masato Koreeda - Page 2 of 13 Date: February 20, 2013

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 Zn

BrBrBr000 +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 215-216 HH W13 - Notes – Dr. Masato Koreeda - Page 3 of 13 Date: February 20, 2013

IV. Oxidation of alcohols

R CH

HOH

R C

R'

HOH

R CH

O R CO

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 215-216 HH W13 - Notes – Dr. Masato Koreeda - Page 4 of 13 Date: February 20, 2013 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 215-216 HH W13 - Notes – Dr. Masato Koreeda - Page 5 of 13 Date: February 20, 2013 The oxidation of primary alcohols with Jones’ reagent:

R CH

HO

HR C

H

O R CO

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 AO

CrO

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.


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 C

ClO

O

ClC C

ClO

O H3C SCH3

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

HH

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 S CH2D

H3C SCH3

O1.

N(CH2CH3)32.

ClC C

ClO

O

+


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

S O

Cl

Cl

N SO

Cl

OHH

S O

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


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 CH2CH3

ONaH (1 mol equiv)I CH2CH3

(excess; typically, 1.5 mol equiv)

+ H2 + NaIH

Na

ONa

H2C CH3

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

O C CH3

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%


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

HOH3C 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


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

CH3HH

Br

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


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!


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.

H

O

H

O

H318OH218O

H318OH218O

H

O

HO

H

OH

HO

H

OH

HO

H218O

H218O

H

H

Because these are trans-fused decalins, these diaxial diols can't invert conformations to become diequatorial diols.

2)

18

18

Chem 215-216 HH W13 - Notes – Dr. Masato Koreeda - Page 13 of 13 Date: February 20, 2013 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)

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Chapter 13. Alcohols, Diols, and Ethers - umich.educhem215/215-216 HH W13-notes-Ch 13.pdf · Chapter 13. Alcohols, Diols, and Ethers Overview: Chemistry and reactions of sp3 oxygen