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Chem 215-216 HH W12-Notes – Dr. Masato Koreeda - Page 1 of 13 Date: February 13, 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) pKa ~16-17 CH3OH CH3CH2OH CH3CH2CH2OH Secondary alcohols (2°-alcohols) pKa ~17-18 H3C H3C H3C Tertiary alcohols (3°-alcohols) pKa ~19 Phenols (Ph-OH) H3C H3C methanol methyl alcohol ethanol ethyl alcohol n-propyl alcohol 2-methyl-1-propanol isobutyl alcohol 2,2-dimethyl-1-propanol neopentyl alcohol C OH H H3C-CH2 Common names 1-propanol H3C C CH2OH H3C H H3C C CH2OH H3C CH3 IUPAC names C OH H C OH CH3 2-propanol isopropyl alcohol 2-butanol sec-butyl alcohol 2-methyl-2-propanol tert-butyl alcohol pKa ~10-12 Ethers (R-O-R') RO-: alkoxy CH3CH2-O-CH2CH3 diethyl ether Ph-O-CH=CH2 phenyl vinyl ether CH3O CH3CH2O ArO-: aryloxy PhO methoxy ethoxy 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 W12-Notes – Dr. Masato Koreeda - Page 2 of 13 Date: February 13, 2012 III. Oxidation state (or number) counting (see: pp 513-4 of the textbook) eN C H -1 +1 eP O C -2 +2 C 0 Therefore, C 0 The oxidation number of this C is -4. H H C 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" H -2 0 H H C OH H C O H H Other examples of oxidation numbers: 1. "reducing agent" H 0 0 -1 H H +1 H H +1 +1 H H +1 -2 -2 2. 0 + Zn 0 0 Br Br -1 "oxidizing agent" 0 0 H -1 Br H Br -1 Br Br H 00 +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: For N O N For O 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) -4 H H C H H H methane methanol "oxidation" (oxygen insertion) 0 -2 H C OH H +4 +2 H H C O C O H HO formaldehyde (methanal) formic acid (methanoic acid) +4 HO C O HO O C O + H2O carbonic acid "oxidation" (also: dehydrogenation) increasing %O; decreasing %H decreasing %O; increasing %H note: used in biochem.: oxidase = dehydrogenase enzyme "oxidation" "reduction" Chem 215-216 HH W12-Notes – Dr. Masato Koreeda - Page 3 of 13 Date: February 13, 2012 IV. Oxidation of alcohols H 1°-alcohol H R C O [ox] H [ox] O R C O - H+ aldehyde O H carboxylic acid H R C O R' [ox] R C R' - 2H+ R" 3°-alcohol H - 2H+ H 2°-alcohol R C H R C O O ketone not easily oxidized R' 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 LG X R C O R' R C O O LG R' -H+ R' - LG "converting this H to a leaving group" + H B R C 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 CrO3 Cr O O chromium trioxide (chromic anhydride) "to be oxidized" "to be reduced" RCH2OH + O R C H CrO3 + Cr3+ oxidizing agent Balancing the oxidation-reduction reaction 3 x 2 x R - CH2OH Cr+6 + 3e O R C H + 2H + 2e ("two-electron" oxidation) Cr3+ Overall, 3 R - CH2OH + 2 Cr+6 "stoichiometry" O 3 R C H + 6 H+ + 2 Cr+3 Chem 215-216 HH W12-Notes – Dr. Masato Koreeda - Page 4 of 13 Date: February 13, 2012 1a Chromic acid [ CrO3 + H2O → H2CrO4] (hydrous conditions) O O Cr HO problems: 1. acidic conditions 2. can't stop at the stage of an aldehyde because of the presence of water +6 OH • 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 +6 O O O Cr O Cr O Na O O 1b. Anhydrous Cr • CrO3•pyridine • pyridinium chlorochromate (PCC): one of the most widely used oxidants! • pyridinium dichromate (PDC) [(pyH+)2•Cr2O7-2] O O Cr Cl N H 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' more electrophilic than the Cr in CrO3 because of Cl O-H C H H O R O O Cr Cl O R' C H O Cr O O Cl N H N -Cl H R C O R' + O oxidation step becomes Cr+3 O C H O Cr+4 R R' O Cr Cr+4 (chromium is reduced!) extremely acidic! often referred to as "Chromate" ester B: B: O Cr O R R' O C H O Cr O O still Cr+6 still Cr+6 through redox-disproportionation. H O N H Cl N Cl H Chem 215-216 HH W12-Notes – Dr. Masato Koreeda - Page 5 of 13 Date: February 13, 2012 The oxidation of primary alcohols with Jones’ reagent: H aldehyde CrO3, H2SO4 H2O H R C O R C acetone (solvent) H O faster step H O 1°-alcohol more than 2 mol equiv. of the reagent needed O R C H carboxylic acid not isolable Often, an ester R-C(=O)-OR is a by-product. Mechanism: H A +6 O Cr HO O O OH OH HO Cr O Cr HO O O H OH R C -A H H R CH2OH O HO Cr H A OH OH OH O H oxidation step R C H H B A R C O Cr A HO OH OH R O H C H B H O OH Cr OH O H O HO OH R C HO R H H C O Cr OH HO A HO C O carboxylic acid + Cr+4 2 Cr+4 Cr+3 H H O H H O oxidation step! R H -A OH HO + Cr+4 Cr+3 aldehyde: doesn't stop here! Cr+6 "chromate ester" Cr+6 "chromate ester" O R C + Cr+5 , etc. A R C H O OH2 Chem 215-216 HH W12-Notes – Dr. Masato Koreeda - Page 6 of 13 Date: February 13, 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 O H3C S dimethyl sulfoxide H O C C H O Mechanism: Cl S C O CH3 C H3C O C C O S CH3 Cl S C H O H H3C R C S Cl O CH3 CO2, CO, Cl H H CH3 CH3 H B H S B H H C C O H3C Cl R C O Cl O This is the species in the solution after step 1. O O Cl Cl O C oxalyl chloride Cl H3C O R Cl H H3C N(CH2CH3)3 triethylamine 2. CH3 Cl H R S O CH3 H C H H N(CH2CH3)3 highly acidic Hs! pKa ~ 12-13 HN(CH2CH3)3 R O H3C C H H S + O C "intramolecular process" C H R Oxidation step! H H3C S C H H H H 1. Note: O H3C S O H CH3 Cl D O C C Cl O 2. N(CH2CH3)3 O + H3C S CH2D Chem 215-216 HH W12-Notes – Dr. Masato Koreeda - Page 7 of 13 Date: February 13, 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 H O H Cl Cl S H H S Cl O Cl H O O N S Cl O B or highly electrophilic S Alternatively, O H S O N that can be formed from SOCl2 and pyridine may be the reagent that puts S(=O)Cl onto the OH group. H Cl or BH Cl O S Cl O N H R H Cl SN 2 product *Similar reactions and mechansims for the formation of bromides from alcohols with PBr3. + SO2 (gas) + Cl Chem 215-216 HH W12-Notes – Dr. Masato Koreeda - Page 8 of 13 Date: February 13, 2012 VI. Ethers (R – O – R’) 1. Synthesis a.Williamson synthesis R O R' X + R O R' X ether R’ - X: alkyl halides (usually bromide and iodide, sometimes chloride) or tosylates R’: usually primary; methyl, allyl (CH2=CH-CH2- ), benzyl (PhCH2-). SN2 reaction O O NaH (1 mol equiv) I CH2CH3 (excess; typically, 1.5 mol equiv) H H Na Mechanism: CH2CH3 NaI Na H2C H H (gas) CH3 Na H a strong base I sodium alkoxide This H in Na-H has no nucleophilicity. Sodium alkoxides can also be prepared by the treatment of alcohols with Na. + Na 1 2 + R O Na H2 MO interpretation: Mechanism: anion radical Na + e Na R O• H R O H + Na R O + Na + NaI pKa ~40 H H O R O H + H2 (gas) H• + H • anti-bonding orbital σ* Na bonding orbital σ O-H bond of the anion radical 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). H Na O H C H O CH3 C CH3 CH3 CH3 C CH3 E2! OH + CH3 + H2C C NaBr CH3 Br 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 O 1. NaOH 2. I N O O 80% Chem 215-216 HH W12-Notes – Dr. Masato Koreeda - Page 9 of 13 Date: February 13, 2012 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. O CH3 H O H I O CH3 Δ H + I H3C I (heat) VII. Intramolecular ether formation Cyclic ethers: by an intramolecular SN2 reaction of an alkoxide NaOH Cl O H2O + Cl SN2 O H O H NaCl O 95% Na Na • 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 Na trans OH OH trans O Br Br A B Br NaH H2 The alkoxide from A can't undergo an SN2 reaction with the C-Br. SN2 reacton possible! equatorial O axial too far away Br axial O Br no SN2! equatorial more favored/stable conformer No cyclic ether formation O O Chem 215-216 HH W12-Notes – Dr. Masato Koreeda - Page 10 of 13 Date: February 13, 2012 VIII. Epoxides (or Oxiranes): Special kind of cyclic ethers (3-membered ethers) ethers: epoxides (or oxiranes): 61.5° O O H3C The ring is strained; more polarized C-O bonds unstable and reactive! 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 NaOH O O H 2O 25 °C, 1 hr Cl more favored/stable conformer O Cl O H SN2 Cl H Cl C-O and C-Cl bonds are not oriented for an SN2 process to take place. Cl 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 CH3 H H3C HBr H H3C 0 °C H CH3 Br meso HO OH + CH3 H H H 3C (2S,3S) Br (2R,3R) racemic mixture H H SN2-like inversion of stereochemistry here! O O H H CH3 H 3C H H H 3C CH3 SN2-like inversion of stereochemistry here! Br Br Cyclic-fused epoxides O H O H O O CH3 O H CH3OH H O H CH3 inversion of stereochemistry H O transproduct O H CH3 CH3 or simply B + enantiomer Chem 215-216 HH W12-Notes – Dr. Masato Koreeda - Page 11 of 13 Date: February 13, 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 Br bromonium ion intermediate trans-product Br inversion of stereochemistry Br + enantiomer Stereochemical/regiochemical issues: O H3C D3C H3O18 H CH3 H3C D3C H CH3 0 °C HO18 stereochemical inversion observed here! regiochemically, stereochemically clean formation of this diol. OH retention Specific incorporation of HO18 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 H O18 H O O O H3C D3C H H H3C H CH3 D3C H CH3 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). H H3C D3C CH3 Can accommodate charge better here! O H3C D3C H2O18 H3C D3C HO18 stereochemical inversion observed here! OH H CH3 retention Specific incorporation of HO18 here! H H CH3 an SN2-like stereochemical inverstion at a more substituted carbon center Chem 215-216 HH W12-Notes – Dr. Masato Koreeda - Page 12 of 13 Date: February 13, 2012 Epoxide-ring opening under basic conditions A straight SN2 process at the less-substituted carbon with a stereochemical inversion. O H H3C H3C D H3CCH2O Na H H3C D H3C H3CCH2O H3CCH2OH less-substituted C; SN2 reaction here! H OCH2CH3 Na O O H H3C H3C D OCH2CH3 Na HO OCH2CH3 + Na H3C H3C H D 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 OH H 3O OH OH O H O HO more stable conformer H axial OH axial-like axial-like H2O only 1,2-diaxial transition state feasible for an SN2 like process to occur OH This is the conformer produced first, then it inverts to the more stable diequatorial OH conformer shown above. axial thermodynamically less favored conformer Chem 215-216 HH W12-Notes – Dr. Masato Koreeda - Page 13 of 13 Date: February 13, 2012 The above examples are quite similar to the bromination reaction of cyclohexene systems. Br Br Br Br Br2 H Br Br Br H H Br H Br Br H Br H Br H 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