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Home , Chromate ester, Chromic acid, Neopentyl alcohol, Swern oxidation

Chem 215 F12-Notes – Dr. Masato Koreeda - Page 1 of 13 Date: September 10, 2012

Chapter 13. , Diols, and Ethers

Overview: Chemistry and reactions of sp3 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 ‘’ 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 ; “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. (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" "" 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 F12-Notes – Dr. Masato Koreeda - Page 3 of 13 Date: September 10, 2012

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

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

R' - 2H+ R' 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 problems

+6 O O CrO3 Cr "to be oxidized" "to be reduced" O O 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 F12-Notes – Dr. Masato Koreeda - Page 4 of 13 Date: September 10, 2012

1a [ 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• • 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 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" 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 -disproportionation. H Chem 215 F12-Notes – Dr. Masato Koreeda - Page 5 of 13 Date: September 10, 2012

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 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! ""

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 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 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

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 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 F12-Notes – Dr. Masato Koreeda - Page 7 of 13 Date: September 10, 2012

IV 2. Non chromium-based Oxidation Reactions: “greener” methods ii) (NaOCl): Bleach

Usually under acidic conditions (e.g., in acetic acid); HOCl () 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 F12-Notes – Dr. Masato Koreeda - Page 8 of 13 Date: September 10, 2012

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 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.

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! 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 F12-Notes – Dr. Masato Koreeda - Page 10 of 13 Date: September 10, 2012

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 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. 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 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.

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

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

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