215%20F08-notes-9-15-08

215%20F08-notes-9-15-08 - Chapter 13: Alcohols and Ethers...

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Unformatted text preview: Chapter 13: Alcohols and Ethers Masato Koreeda (subbing for Dr. Brian Coppola) 9—15—08 pl 1-]. Oxidation of alcohols 1°-alcohol R—CIJ—O® JET> R-Cfiéo —[%XJ—> R—Céo l H —2H+ H aldehyde ‘H+ O‘H GD carboxylic acid ox O 2°-alcohol R—Cf-OQD —[—]fi‘—> R—Cé | R, -2H+ RI ketone 5‘ ,H . . . 3°-alcohol R—?—o not eas11y OdelZCd RI Oxidation methods: There are hundreds that differ in experimental conditions, but these follow basically the process shown below. . . e dlfficult to remove as H 2 B @r J Hf "E2 - type” reaction — | LG /0 R-(ID-O —£—XT——> R—clslo/v —T> R—CID/ + H-B® R' _H+ R' — LG RI "converting this H to a leaving group" LG: leaving group Historically, most common reagents involve high-valency transition metals. (1). Cr (VD-based reagents — all Cr(VI) reagents have toxicity problems O\\ //O CF03 E CF 5 "to be oxidized" "to be reduced" chromium trioxide K. ( 00 3+ (chromic anhydride) RCHZoH + C3333 R_C\H + Gr oxidizing agent Balancin the oxidation—reduction reaction ___—._ ’10 ED 9 n u - - 3 x [ R-CHZOH ___ R—C\ + 2H + 2e (two-electron oxrdation) H 2 x [CP‘G + see :— Cr3+ Overall, 00 + 3R-CH20H + ZCr+6 : 3 R—C\ + 6H + 2Cr+3 k / H "stoichiometry" MAK — p 2. a Chromic acid [CrO3 + H20 —> HZCrO4'I (hydrous conditions) problems: 1. acidic conditions 2. can't stop at the stage of an aldehyde because of the presence of water 0 Jones’ reagent: CrO3/HZSO4/HZO historically, one of the most commonly used chromium +6—based reagents for the oxidation of alcohols ° Chromate: NaZCrO4 (sodium chromate)/H2$O4/HZO - Dichromate: NaZCrZO7 (sodium dichromate)/HZSO4/H20 @ (I? 9 e 69 Na2Cr207 E Nae O-(fir-O-(IDIr-O Na 0 O b. Anhydrous Cr+6 - CrO3-pyridine - pyridinium chlorochromate (PCC): one of the most widely used oxidants! 0 pyridinium dichromate (PDC) [(pyH+)2°Cr207'2] pyr‘dm'“ma§glgocmomate prepared from pyridine, HC1, 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: more electrophilic than the . H .. e .. Cr in CrO because ofCl :O: a 93 new . : RI,C\ U\\ l/O ————— RV? '6?) r\:C:|' @q‘ H (gum O H 9.. H @N/ H often referred to as CXtremely aCidiC! "Chromate" ester 3; d H/ .. ".9 R '“r 10' H \ ,C:0 9.. R‘§Q\ér20: I / R' + e p: <— m .5 9* o—Cr\\0_ H -- ole H Cr+4 still Cr+6 (chromium is reduced!) W of3 Cr+4 becomes Cr“3 through redox—disproportionation. MAK—p3 Oxidation of primary alcohols with Jones’ reagent: H H Croal H2804 aldehyde | R—C—o’ H20 R-Céo R—C‘o | acetone | faster step I H (solvent) H OH 1°—alcohol carboxylic acid not isolable of the reagent needed Often, an ester R-C(=O)—OR is a by—product. Strictly speaking 2 x 2/3 mol equiv of CrO3 needed (see page 1) Mechanism: r‘ O L0 f f'H—A H H OH " ,OH /H_A .. f. I 69 HO_Cr/ HO—Cr\ .. O\\ 40: O\\ ¢Oi / \OH 9 OH 40: /Cr\ "‘— /Cr\ (90‘) O: _ _ R—C + Cr+4 HO OH HO >014 R_C/~\H R706" OXIdatlon \H -A9 H/ \H ( e H H Step 9‘04ng A Bi) aldehyde: Cr+6 doesn't stop here! "chromate ester" Cr+6 _Ae "chromate ester" A6 carboxylic acid LI (2). Non chromium-based Oxidation Reactions: “greener” methods i) Swern oxidation: 0 usually using dichloromethane (CHZCIZ) as the solvent 0 anhydrous (i.e., no water present!), non—acidic conditions 0 1°—a1coh01: stops at an aldehyde; 2°—alcohol: gives a ketone e 1- H 0338/0 dimethyl 0—H 3 sulfoxide :N(CHZCH3)3 O / CH3 triethylamine // R—C\ ———-——> ——> R—C H H 9| \H C\ /O 04 C’ (I), oxalyl chloride Mechanism: (CI 95' , O ' .. ‘ .. // ..Q .. I /O _ Q IO: d ('3' Q [0—C—C’ g Q HsC—S " —> H C—S " l \ HaC—S: . . CI ..\ 3 o.\ :0: \ .0- CH3 2.) I CH3 "6 e-- / CH3 Cl :Cl: This is the species in the solution after step 1. r“ :B R H 9.. \7 .. / I7 /R 002, CO,:CI: .. HC®S' \HH HC®S(@\HH 3 _ \' 7 3 _ \' /CQH H—Bfi CH3 \ /CH3 . /R H IL CIJ—S§V:/O_C\\H N CH CH highly acidic Hs.’ ( 2 3>3 [7(Ka ~ 12-13 HN(CHZCH3)3 G) Oxidation step! "intramolecular process" 1 06 Note: Hag—3’ O—H CH 2. :N(CH CH ) S ———>3 ———>2 33 o + Hac’ \CH2D CI D l O C\ / O C’ MAK—pS. I-l 1) Oxidation with bleach (sodium hypochlorite, NaOCl): O acetic acid I, (pKa 4.7) /C\ ,H 0—H NaOCl H30 0 medium slightly acidic. Mechanism: NaOCI + H3063 === Na® + H-O-Cl + H20 H | H-O—CI + H309 =~ Cl/Q?)H + H20 *3 H’9:'\ H H H@ / 1® (\ _ u H ; O\ O O l = m = CX-l H "electrophilic Cl" H {I . . B OXIdatIon steml Ozo + H—B® + one note: Under acidic conditions (NaOCl, acetic acid), 2°—alcohols get readily oxidized to their ketone derivatives. But, the oxidation of 1°—alcohols is quite slow under these conditions. In contrast, if the oxidation is carried out under basic conditions (NaOCl, KOH), 1°—alcohols can be oxidized to their corresponding aldehydes. I-2. Reactions of alcohols (1). Alcohols to alkyl halides a. With anhydrous (gaseous) HX 9 6Br From 1°—alcohols: Br L Br /\/\,0’ H ——‘L> Mr H ——> A) + H20 :06) s 21 \rH—rlgr |1| N ' MAK—p6 From 2°—alcohols: @Br ! /\/\/\ W /®\5\/\ S 2' H/n H/..\H N . only in a small amount a major pathway :>J SNl! H (WH Path a Path b e <————— —> 1,2—hydride 1,2—hydride H shift shift All of these three carbo- cationic intermediates have similar stabilities. H Br ‘ 3H H Almost equal amounts of these three racemates formed. - It is more common to convert 1°— and 2°—alcohols to their corresponding sulfonate derivatives such as p— toluenesulfonates (or tosylates) and methanesulates (or mesylates), then to treat them with NaBr (5N2). H/Q _ N: (pyridine) * p—toluenesulfonyl chloride g§ (tosyl chloride or TsCl) p—toluenesulfonate very good leaving grp ot tosylate (GOTS) From 3 -alcohols: >L HCI (anhydrous) )\ >L OH 69 Cl an However, at high temperatures, * (E1 product) formed preferentially. I-2 (1)b. With SOC]2 (thionyl chloride) or PBr3 (phosphorus tribromide) S R SOCI / \ G) ' . 2 + <:N-He + 302? /O: H pyrldme H 'CI ' Cl (gas) SN 2 product MAK—pT Mechanism for an alcohol to the chloride with SOClz/pyridine 5) / \ G /O R Alternatively, N—S: that can be formed from SOC12 ) ' ' — W'l' + and pyridine may be the reagent that puts S(=O)Cl onto H CI (gas) the OH group. SN 2 product *Similar reactions and mechansims for the formation of bromides from alcohols with PBr3. I-3. Ethers (R — O — R’) (1). Synthesis . . . ..e -- .. e a.W1111amson synthe31s R—OL/ R'—X= —> R-O-R' + :X: H k" ether " 8N2 reaction R’ - X: alkyl halides (usually bromide and iodide, sometimes chloride) or tosylates R’: usually primary; methyl, allyl (CH2=CH—CH2— ), benzyl (PhCH2—). a: . 0x 0/ H) NaH (1 mol equ1v) 0/ CH2CH3 + H2 T + Nal e _H I—CHgCH3 (gas) N e ' (excess; typically, 1.5 mol equiv) a . _ e Mechanism\ Na H e Nal 9‘\ CH U “2? 3 (gas) :1} k a strong base sodium alkoxide ' ThisetH in Na-H has no nucleophilicity. Sodium alkoxides can also be prepared by the treatment of alcohols with Na. .. ..e (D 1 R—Q-H + Na —>R—QI Na + —H2 MO interpretation: anti-bonding l 0* orbital 1 O bonding orbital Mechanism: 9 e anion radical i! R—o—H + Na ——> [R-QLHJG Neia Na—>Na + e l ..e R—Qt Nae) O—H bond of the anion radical 3 electrons in the 0-H bond! MAK—pa 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 CH N869 "1’ SH E2! OH ’CH3 H-IC (‘3’ 3 /\/ + HQC=C\ + NaBr H :B’r:\' CH3 /\/0\ /CH3 9\CH3 Notformed.’ 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 (PhOe). 0+1 o/\/A\ (I e (I e Moo 2-/\/\1 Nan g g 80% 1-3 (2). Cleavage of ethers In general, difficult to cleave ether C—O bonds (for exceptions, see I-5). Can be cleaved by heating with HI (more common) or HBr. Need a strong Bronsted or Lewis acid and a strong nucleophile. Usually, methyl ether C—0 and benzyl ether CD are those that can be cleaved. Modern methods for cleaving ethers include the use of BBr3 and AlCl3 + HSCHzCH3. H 6“ H '1': _ 0\ “\CH3 ' CH3 O H ..e ——> + H C—l (heat) I-4 Intramolecular ether formation Cyclic ethers: by an intramolecular 5N2 reaction of an alkoxide NaOH CID 61C) ——» z > + NaCl kg O H 9 ® fl H2O SN2 e:Ej-H Na Na® .. ' 5— and 6-membered cyclic ether formation: fast 0 In general, intramolecular reactions are faster than the corresponding intermolecular (bi—molecular) reactions. \ - An intermolecular 8N2 reaction of an alkoxide or I I Cl\/—> MmMMMMWanquMMMMMbW sm“ 9 ) O Zé—H \H 95% MAK—p9 Cyclic ether formation Geometrical and stereochemical effects on cyclic ether formation: Which of the two diastereomeric hydroxy—bromide could form its cyclic ether derivative? 6 Nae cis trans trans KO/Br ‘u N A The alkoxide from A can't undergo an 8N2 reaction with the C—Br. 6:9 too far equatorial -- \ \, away % no S 2! r‘ Br N axial more favored/stable conformer No cyclic ether formation I-S. Epoxides (or Oxiranes): Special kind of cyclic ethers (3—membered ethers) 'd ' a e : ethers: epox1 es (or ox1r n s) 61 50%fl /O\ The ring is strained; more polarized C—O bonds 2) Stable (1). Formation: (a) Epoxidation of alkenes with peroxyacids (e. g., m—chloroperoxybenzoic acid) (b) From halohydrin with a base more favored/stable . . e O_H O conformer NaOH u i ..e ’Cl 2 ’Cl c. 25 °C, 1 hr C—0 and C—Cl bonds are not oriented for an 8N2 process to take place. MAK—p. 10 1-5 (2). Ring-opening reactions of epoxides: Epoxides are highly strained and easily undergo ring—opening reactions under both acidic and basic conditions. a 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 F‘H—B}! . H OH HO CH3 HBr H30 “"H ‘W + “"H H3O CH3 Br CH3 H30 Br mesa (28,38) (2R,3F{) \ T racemic mixture T /H i ®/H i SNZ-like ('09 ’0‘) SNZ—like inversion of inversion of stereochemistry H SC > CH3 H30 < stereochemistry here! 9 __ here! ' .8.“ :Br' Cyclic-fused epoxides ® O-H O-H trans— O H O®—H —> O, __> 0’ product U ’u, ' ' ' o. ""b—CH :03) H/@ CH3 .. 3 H' ‘CH3 + enantiomer inversion of H’ CH3 stereochemistry or simply :8 Note: The mechanism for the ring—opening of epxodies under acidic conditions is quite similar to that of bromination of alkenes. @ bromonium Br _ ion __> trans— O‘Brer ——> QED intermediate product ..9 l' in version of :|_3_r: stereochemistry + enantiomer 0°C - -. H C ' h ' ll tereochemicall .0 (+3 3 1 OH regloc emica y, s y H C H H3018 D3073 / clean formation of this diol. 3 ||||| In: D30 C H 3 H 01 8 C H 3 stereochemical R retent’on ’nVers’On Specific incorporation of H078 here! observed here! MAK — p 11. Mechanistic interpretation on the stereochemical/regiochemical outcome under acidic conditions: more elongated C——OH bond; ®—charge delocalized because this more substituted C can (@‘I‘ better stalilize the postive charge 018 ..\ H :0.- . O %’ HSCn-flvH ——> H3C'HAHH E HaC-HH'H D30 CH3 D3C CH3 D30 CH8 . . 18 . . Can accommodate In the transnron state for the attack of H20 (H20 in this case), G Charge better here! /H i the nucleophile attacks preferential] y the carbon center that can ,- better stabilize a positive character (i.e., the more substituted carbon). H39 OH . . D30 3 H an S N2-like stereochemical CH inverstion at a more substituted H018 3 ’ carbon center stereochemical R retentlon in vers’on S ec/fio incor oration of H078 here! observed here! p p I-5 (2) b. Epoxide-ring opening under basic conditions A straight 3N2 process at the less—substituted carbon with a stereochemical inversion. i Na® (H—KVOCHZCHa '0' H HacCHgoeNa® 9,5, H H3C'HA H3CCH20H \ D H3C D H3C""' .. H30 :QCH20H3 . (*3 less-substituted O; Na 8N2 reaction here! 9 \ HO .H D (D :QCHgCH3 + Hag-H Na H3O 2 Summary of epoxide-ring opening reactions: Acidic conditions: SNZ like in terms 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. ...
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215%20F08-notes-9-15-08 - Chapter 13: Alcohols and Ethers...

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