Chem 215-216 HH W11-Notes – Dr. Masato Koreeda - Page 1 of 13 Date: February 9, 2011

Chapter 13. , Diols, and Ethers

Overview: Chemistry and reactions of sp3 oxygen groups, particularly oxidation of an , ether formation, and reactions of oxirane () groups.

I. What are alcohols, phenols, and ethers?

IUPAC names Common names

Alcohols (R-OH) Primary alcohols CH3OH methyl alcohol (1°-alcohols) CH3CH2OH ethyl alcohol pKa ~16-17 CH3CH2CH2OH 1-propanol n-propyl alcohol

H3C C CH2OH 2-methyl-1-propanol isobutyl alcohol H3C H H3C C CH2OH 2,2-dimethyl-1-propanol H3C CH3 H C Secondary alcohols 3 C OH 2-propanol (2°-alcohols) H3C H pKa ~17-18 H C-CH 3 2 C OH 2- sec-butyl alcohol H3C H

Tertiary alcohols H3C C OH 2-methyl-2-propanol tert-butyl alcohol (3°-alcohols) H3C CH pKa ~19 3

Phenols (Ph-OH) pKa ~10-12 Ethers (R-O-R') CH3CH2-O-CH2CH3

Ph-O-CH=CH2 phenyl vinyl ether

RO-: alkoxy CH3O methoxy CH3CH2O ethoxy ArO-: aryloxy PhO 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 W11-Notes – Dr. Masato Koreeda - Page 2 of 13 Date: February 9, 2011

III. Oxidation state (or number) counting (see: pp 513-4 of the textbook)

Therefore, eN eP C H O C C C -1 +1 -2 +2 0 0 The oxidation number of this C is -4. H H C H -2 0 "the contribution of an H to the oxidation number of the C is -1" H "the contribution of a C to the oxidation number of the H is +1" H H H C OH C O H H Other examples of oxidation numbers: 1. -1 -1 +1H H +1 "reducing agent" "oxidizing agent" Br Br 0 0 H H 0 0 +1 H H +1 -1 -1 H H -2-2 H H Br Br 0 0

2. 0 0 0 +2 Zn + Zn Br Br Br Br -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.

Example: For N 3 x (- 1) from 3 carbon atoms = -3 O +1 from oxygen atom = +1 overall: -1 +1 from the charge = +1 N For O -1 from nitrogen atom = -1 overall: -2 -1 from the charge = -1

======Hydrocarbon oxidation-reduction spectrum:

"reduction" (hydrogenation) +4 -4 -2 0 +2 +4 H O C O H H H HO H C H H C OH C O C O C O + H H H HO HO H2O methane methanol formaldehyde formic acid carbonic acid (methanal) (methanoic acid)

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

note: used in biochem.: oxidase = dehydrogenase enzyme

Chem 215-216 HH W11-Notes – Dr. Masato Koreeda - Page 3 of 13 Date: February 9, 2011

IV. Oxidation of alcohols H H [ox] O [ox] O 1°-alcohol R C O R C R C

H + H + O - 2H aldehyde - H H carboxylic acid H H [ox] O 2°-alcohol R C O R C

R' - 2H+ R' ketone R" H 3°-alcohol R C O not easily oxidized R'

Oxidation methods: There are hundreds that differ in experimental conditions, but these follow basically the process shown below. difficult to remove as H B "E2 - type" reaction H H H O LG X LG R C O R C O R C + H B

R' -H+ R' - LG R'

"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

+6 O O CrO3 Cr "to be oxidized" "to be reduced" O O chromium trioxide RCH OH + CrO + 3+ (chromic anhydride) 2 3 R C Cr H oxidizing agent

Balancing the oxidation-reduction reaction O 3 x R - CH2OH R C + 2 H + 2 e ("two-electron" oxidation) H

2 x Cr+6 + 3e Cr3+

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

"stoichiometry" Chem 215-216 HH W11-Notes – Dr. Masato Koreeda - Page 4 of 13 Date: February 9, 2011

1a Chromic acid [ CrO3 + H2O → H2CrO4] (hydrous conditions)

O O Cr +6 problems: 1. acidic conditions HO OH 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 O Na2Cr2O7 Na O Cr O Cr O Na O O 1b. Anhydrous Cr+6

• CrO3•pyridine • pyridinium chlorochromate (PCC): one of the most widely used oxidants! + -2 • pyridinium dichromate (PDC) [(pyH )2•Cr2O7 ]

O O Cr +6 N Cl O H 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 stops at the stage of an aldehyde.

Mechanism for the oxidation with PCC:

more electrophilic than the H Cr in CrO3 because of Cl O R O-H R O Cr O C O O C N R' R' H Cr O Cl H Cl H O N -Cl H often referred to as extremely acidic! "Chromate" ester B: H O R oxidation O R O C O R O Cr O step Cr O C N R' + O C R' R' O H O Cr O H Cl O H +4 still Cr+6 Cr B: still Cr+6 (chromium is reduced!) N Cl Cr+4 becomes Cr+3 through redox-disproportionation. H Chem 215-216 HH W11-Notes – Dr. Masato Koreeda - Page 5 of 13 Date: February 9, 2011

The oxidation of primary alcohols with Jones’ reagent:

aldehyde H CrO , H SO H 3 2 4 H O O O R C O 2 R C R C acetone faster step H H O (solvent) H 1°-alcohol carboxylic acid not isolable more than 2 mol equiv. of the reagent needed

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

Mechanism:

O O H A +6 H A H OH OH HO Cr HO Cr O O O O OH O Cr Cr OH R C + +4 O O Cr HO OH HO OH H oxidation R C R C H step -A H H H H A +3 R CH2OH B aldehyde: Cr Cr+6 doesn't stop here! "chromate ester"

Cr+6 -A "chromate ester" A OH H H HO HO HO H HO H OH O Cr O OH O O O R C R C R C R OH C H R C Cr OH O H H H H H H OH O OH O A 2 B O Cr OH oxidation step! HO A

HO C +4 R + Cr O +5 2 Cr+4 Cr+3 + Cr , etc. carboxylic acid

Chem 215-216 HH W11-Notes – Dr. Masato Koreeda - Page 6 of 13 Date: February 9, 2011

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

Mechanism: Cl Cl O O O C C O Cl O C C H3C S C O H3C S H3C S Cl O Cl O CH O C 3 CH3 CH3 Cl Cl This is the species in the solution after step 1. B R H R CO2, CO, Cl O C O C H H H3C S H H3C S H C CH CH3 R H B 3 H H Cl S O C H H CH3 H H N(CH CH ) highly acidic Hs! 2 3 3

pKa ~ 12-13

HN(CH2CH3)3

R O C H R Oxidation step! H C S + 3 H O C C H H3C S "intramolecular H C process" H H H H

1. O Note: H3C S O H CH3 2. N(CH2CH3)3 S O + H3C CH2D Cl D C O O C Cl

Chem 215-216 HH W11-Notes – Dr. Masato Koreeda - Page 7 of 13 Date: February 9, 2011

IV 2. Non chromium-based Oxidation Reactions: “greener” methods (continued) 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 H H H O Cl O Cl O H H H Cl O Cl S S Cl S O BH S Cl O Cl B O or or O highly electrophilic S N N H

O R Alternatively, N S that can be formed from SOCl2 Cl + SO2 + Cl and pyridine may be the reagent that puts S(=O)Cl onto H Cl (gas) the OH group. SN 2 product

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

Chem 215-216 HH W11-Notes – Dr. Masato Koreeda - Page 8 of 13 Date: February 9, 2011

VI. Ethers (R – O – R’) 1. Synthesis a.Williamson synthesis R O R' X R O R' + X ether SN2 reaction R’ - X: alkyl halides (usually bromide and iodide, sometimes chloride) or tosylates R’: usually primary; methyl, allyl (CH2=CH-CH2- ), benzyl (PhCH2-). O O H NaH (1 mol equiv) CH2CH3 + H2 + NaI I CH2CH3 (gas) H (excess; typically, 1.5 mol equiv) Na Mechanism: NaI Na H H pK ~40 O a CH3 H H H2C Na H (gas) I a strong base sodium alkoxide This H in Na-H has no nucleophilicity. Sodium alkoxides can also be prepared by the treatment of alcohols with Na. 1 R O H + Na R O Na + H 2 2 MO interpretation: Mechanism: anion radical anti-bonding + e Na Na σ* orbital R O H + Na R O • H Na σ bonding orbital O-H bond R O Na + H • of the anion radical + H • 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).

Na H CH3 E2! CH3 O CH OH H C C 3 + H2C C + NaBr CH H Br 3

O CH3 C Not formed! CH3 CH3 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 O 1. NaOH O O N 2. I N 80% O O Chem 215-216 HH W11-Notes – Dr. Masato Koreeda - Page 9 of 13 Date: February 9, 2011

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.

H O H I O O CH3 CH3 H + H3C I Δ I (heat)

VII. Intramolecular ether formation

Cyclic ethers: by an intramolecular SN2 reaction of an alkoxide NaOH Cl Cl + NaCl O H O 2 O SN2 O H O H Na 95% Na • 5- and 6-membered cyclic ether formation: fast • In general, intramolecular reactions are faster than the corresponding intermolecular (bi-molecular) reactions. • An intermolecular S 2 reaction of an alkoxide or Cl N 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 trans Na trans OH OH O Br Br Br NaH

A B H2 The alkoxide from A can't undergo SN2 reacton possible! an SN2 reaction with the C-Br. O equatorial O too far axial away no Br SN2! axial Br equatorial more favored/stable conformer

No cyclic ether formation O O

Chem 215-216 HH W11-Notes – Dr. Masato Koreeda - Page 10 of 13 Date: February 9, 2011

VIII. (or Oxiranes): Special kind of cyclic ethers (3-membered ethers)

epoxides (or oxiranes): ethers: O O 61.5° H3C CH3 112° The ring is strained; unstable more polarized C-O bonds stable and reactive! a. Formation: (1) Epoxidation of with peroxyacids (e.g., m-chloroperoxybenzoic acid; see Ch. 8 ) (2) From halohydrin with a base more favored/stable conformer O H O O O NaOH O H H2O S 2 Cl Cl Cl N 25 °C, 1 hr Cl H C-O and C-Cl Cl bonds are not oriented for an SN2 process to take place.

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 OH HO CH3 HBr H3C H H H + H H 0 °C CH H3C CH3 Br 3 H3C Br meso (2S,3S) (2R,3R) racemic mixture

H H SN2-like O O SN2-like H inversion of H H H inversion of

stereochemistry H3C CH3 H3C CH3 stereochemistry here! here! Br Br Cyclic-fused epoxides O H O H trans- H O O H product CH3OH O O CH3 CH3 O H H CH3 + enantiomer O inversion of H CH3 stereochemistry or simply B

Chem 215-216 HH W11-Notes – Dr. Masato Koreeda - Page 11 of 13 Date: February 9, 2011

Note: The mechanism for the ring-opening of epxodies under acidic conditions is quite similar to that of bromination of alkenes. bromonium Br Br Br Br ion trans-product intermediate Br inversion of Br stereochemistry + enantiomer

Stereochemical/regiochemical issues:

H3C O 18 OH regiochemically, stereochemically H3O D3C clean formation of this diol. H C H H 3 0 °C D C CH CH3 3 3 HO18 retention stereochemical inversion Specific incorporation of HO18 here! 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 H better stalilize the postive charge 18 O H H H H O O O H C H H C H H3C H 3 3 D3C CH3 D3C CH3 D3C CH3

18 Can accommodate In the transition state for the attack of H2O (H2O in this case), charge better here! H the nucleophile attacks preferentially the carbon center that can O better stabilize a positive character (i.e., the more substituted H3C carbon). H D3C CH3 18 H2O H3C OH D3C an SN2-like stereochemical H inverstion at a more substituted CH3 HO18 carbon center retention stereochemical inversion Specific incorporation of HO18 here! observed here!

Chem 215-216 HH W11-Notes – Dr. Masato Koreeda - Page 12 of 13 Date: February 9, 2011

Epoxide-ring opening under basic conditions

A straight SN2 process at the less-substituted carbon with a stereochemical inversion.

Na H OCH2CH3 O O H3CCH2O Na H H O H H3C H3C H3CCH2OH D D H3C D H3C H3C H3CCH2O H C 3 OCH2CH3 less-substituted C; Na HO SN2 reaction here! H D + OCH2CH3 H3C Na H3C 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) OH H3O O OH OH HO more stable conformer

H H O OH This is the conformer produced O axial axial-like first, then it inverts to the more stable diequatorial OH conformer shown above. axial axial-like OH H2O thermodynamically only 1,2-diaxial transition state feasible less favored conformer for an SN2 like process to occur 2) H O OH H 18O O 3 H 18O 2 Because these are cis- H 18 H H H2 O HO fused decalins, these diaxial diols can't invert 18 H2 O conformations to become OH diequatorial diols. 18 H3 O O 18 H2 O H H H O HO H

Chem 215-216 HH W11-Notes – Dr. Masato Koreeda - Page 13 of 13 Date: February 9, 2011

The above examples are quite similar to the bromination reaction of cyclohexene systems.

Br Br

Br

H H H Br Br Br Br2

Br H Br Br Br

H H 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