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CHEM 2331H
T.Andrew Taton

Chapter 11 Book Notes Reactions of Alcohols 11.1) Oxidation States of Alcohols and Related Functional Groups • oxidize alcohols  ketones, aldehydes, carboxylic acids undergo other rxns • Inorganic chem: oxidation = lose electrons, reduction = gain electrons; but in ochem, loss/gain of electrons isn’t as obvious o oxidation = result of adding oxidizing agent (O , Br2, et2) o reduction = result of adding reducing agent (H , Na2H , etc)4 o Ochem rules o Oxidation: addition of O or O ; a2dition of X (hal2gens); loss of H ; 2 o Reduction: addition of H (or2H); loss of O or O ; los2 of X ; 2 o Neither: addition/loss of H , OH, H O, HX, etc. 2 • Oxidation converts C-H bonds  C-O bonds (more oxidized molecules have more C-O bonds) o primary alcohol = more oxidized than alkane b/c carbinol (C-OH) C bonded to O, but alkane C not o oxidize primary alcohol aldehyde, carbonyl C has to bonds to O o oxidize aldehyde acid, now 3 bonds to O o further oxidize break C-C bond 4 bonds to O, oxidation state of CO 2 • comparing oxidization of primary, secondary, tertiary alcohols o [O] = unspecified oxidizing agent o oxidize primary/secondary alcohol carbonyl (C=O) group by removing 2 H’s (one from carbinol C and other from hydroxyl group) o tertiary alcohol doesn’t oxidize easily b/c no H available on carbinol C 11.2) Oxidation ofAlcohols • Primary/secondary alcohols easily oxidized by variety of reagents (ex: chromium oxides, permanganate, nitric acid, even household bleach (NaOCl, sodium hypochlorite)); choose reagent depending on alcohol value o large scale oxidation of simple, inexpensive alcohols cheap oxidants o delicate valuable alcohols most effective and selective reagents regardless of cost o many traditional oxidants based on chromium(VI) compounds: highly toxic, difficult to dispose properly chemists gradually move toward less toxic oxidants • All oxidizing agents have element (Cr, Cl, I, or S) in high oxidation state bonded to O; all have similar mechanisms (ex: hypochlorous acid (HOCl, from household bleach) rxn w/ secondary alcohol) o step 1: forms intermediate, in which alcohol O replaces one of oxidant’s original bonds to O o step 2: base (water or other solvent) removes proton from carbinol C double bond to O, which leaves it oxidized o oxidant leaves w/ fewer bonds to O and one more electron pair has lower/reduced oxidation state • 11.2A) Oxidation of SecondaryAlcohols o secondary alcohols easily reduced ketones in good yields  done w/ chromic acid reagent: prepared by dissolving sodium dichromate (Na 2r 2 )7in sulfuric acid + water mixture  active species in mixture most likely = H 2rO (4hromic acid) or chromate - ion (HCrO )4  can get same result by adding chromium trioxide (CrO ) t3 dilute sulfuric acid o mechanism of chromic acid oxidation probably involves forming chromate ester nd (elimination) ketone, carbinol C retains O, but loses H and gains 2 bond to O o chromium(IV) species further reacts stable reduced form = chromium(III)  sodium dichromate and chromic acid = orange, but chromic ion (Cr ) = 3+ deep blue  color progresses through various green shades greenish blue  color change used to test presence of oxidizable alcohol • 11.2B) Oxidation of PrimaryAlcohols o oxidize primary alcohol  aldehyde (easily oxidized) carboxylic acid (unlike ketone)  hard to obtain aldehyde b/c if most oxidizing agents strong enough to oxidize primary alcohol, also oxidizes aldehyde  chromic acid oxidizes primary alcohol all the way carboxylic acid o pyridinium chlorochromate (PCC) = better reagent for limited oxidation of primary alcohol  aldehyde in good yields  = complex of chromium trioxide w/ pyridine and HCl  soluble in nonpolar solvents (unlike most other oxidants) like dichloromethane (CH Cl2) 2good solvent for most organic compounds)  also = mild reagent for oxidizing secondary alcohols  ketones • 11.2C) Resistance of TertiaryAlcohols to Oxidation o Tertiary alcohols have no H on carbinol C, so must break C-C bonds to oxidize, needs severe conditions and  product mixtures o chromic acid test for primary/secondary alcohols  when primary/secondary alcohol added to chromic acid reagent, orange green/blue  when nonoxidizable substance (tertiary alcohol, ketone, alkane) added, no immediate color change 11.3)Additional Methods for OxidizingAlcohols • Other reagents and procedures for oxidizing alcohols developed, some = modified from previous ones o Collins reagent: complex of chromium trioxide and pyridine, original version of PCC o Jones reagent: milder form of chromic acid (diluted in acetone) • All chromium reagents produce by-products and washings w/ hazardous chromium salts o most cases, simple oxidants like household bleach can do same oxidations w/o heavy metals/hazardous waste o household bleach involves mildly acidic/basic conditions, better than chromic acid for acid-sensitive compounds • Potassium permanganate and nitric acid also = strong oxidants o less expensive than chromium reagents, less environmentally-hazardous byproducts o oxidize secondary alcohols ketones and primary alcohols carboxylic acids o used primarily in industry, form explosive mixtures, cleave C-C bonds if T and [] not precisely controlled • Swern oxidation: dimethyl sulfoxide (DMSO) = oxidizing agent, alcohols ketones and aldehydes o DMSO and oxalyl chloride added to alcohol @ low T, then add hindered base like triethylamine o reactive species (CH )3 2l (+charge on S) formed in sol’n, thought to be oxidant o secondary alcohols ketones and primary alcohols only aldehydes o volatile byproducts, easily separated from organic products • Dess-Martin periodinane (DMP) reagent oxidizes oxidizes primary alcohols aldehydes and secondary alcohols ketones w/o chromium/heavy metal compounds o rxn @ mild conditions: room T, neutral pH o good yields o high-valence I good oxidizer o commercially available solid, easily stored 11.4) Biological Oxidation ofAlcohols • Ethanol still = poisonous even if = least toxic alcohol o mild ethanol poisoning = intoxication o animals often eat fermented food w/ alcohol liver produces enzyme called alcohol dehydrogenase (ADH) to detoxify, catalyzes oxidation (removing 2H’s from alcohol molecule) • Nicotinamide adenine dinucleotide (NAD) = oxidizing agent o 2 forms: NAD = oxidized form, NADH = reduced form o alcohol oxidized acetylaldehyde and NAD reduced  NADH • Another oxidation catalyzed by aldehyde dehydrogenase (ALDH) converts acetylaldehyde  acetic acid (normal metabolite) • These oxidations happen w/ most small primary alcohols o but oxidation products of some other alcohols = more toxic than acetic acid o ex: methanol oxidized formaldehyde then formic acid, both more toxic than methanol o ex: ethylene glycol = toxic diol, oxidized oxalic acid (toxic, found in leaves of rhubarb and many other plants) • Lot of methanol/ethylene glycol poisoning cases o alcoholics may drink ethanol denatured by adding methanol methanol oxidized formic acid blindness and death o ethylene glycol in open antifreeze tastes sweet, dogs eat, metabolize it oxalic acid dog’s kidneys fail death • Treatment: intravenous infusions of diluted ethanol o Competitive inhibition of enzyme:ADH enzyme swamped by ethanol kidney has time to excrete most methanol/ethylene glycol before oxidized formic/oxalic acid o enzyme catalyzes oxidation of both methanol/ethanol but lot of ethanol ties up enzyme, more time to excrete most methanol before oxidized 11.5)Alcohols as Nucleophiles and Electrophiles; Formation of Tosylates • Alcohols = versatile chemical intermediates b/c = both nucleophiles and electrophiles o can = weak nucleophile, bonding to strong electrophile (carbocation) o strong nucleophile by forming alkoxide ion attacks weaker electrophile (alkyl halide) • O-H bond broken when alcohol acts as strong/weak nucleophile; C-O bond broken when alcohol = electrophile o alcohol = weak electrophile b/c hydroxyl = poor leaving group o hydroxyl = good leaving group (water) when protonated o ex: HBr reacts w/ primary alcohol by S 2 Nttack of bromide on protonated alcohol C-O bond broken • But need strongly acidic sol’n to protonate alcohol o halide ions stable in acid, but few other good nucleophiles stable in strongly acidic sol’ns o most strong nucleophiles = basic abstract acid proton reagent’s not nucleophilic anymore o ex: acetylide ion instantly protonated if added to protonated alcohol • how to fix? convert alcohol alkyl halide or make its tosylate ester (symbolized ROTs): product of condensation of alcohol w/ p-toluenesulfonic acid (TsOH) o tosylate group = good leaving group, alkyl tosylates undergo substitution/elimination like alkyl halides o many cases, tosylate = more reactive than equivalent alkyl halide • Tosylates made from alcohols using tosyl chloride (TsCl) in pyridine o higher yields than rxn w/ TsOH itself o mechanism: C-O bond of alcohol remains intact, alcohol retains stereochemical configuration o Pyridine = organic base, removes HCl formed in rxn prevents protonation of alcohol/side rxns • Ex: SN2 displacement of tosylate ion (OTs) from (S)-2-butyl tosylate, inversion of configuration o tosylate ion = stable b/c –charge distributed over 3 Os • Tosylate leaving group displaced by variety of nucleophiles (like halides) o S 2 mechanism (strong nucleophile) used more than S 1 in synthetic preparation N N o R must be unhindered primary/secondary alkyl group if want substitution, not elimination 11.6) Reduction ofAlcohols • Reducing alcohol alkane not common b/c removes functional group fewer options for further rxn o step 1: dehydrate alcohol alkene o step 2: hydrogenating alkene alkane • Another method: convert alcohol tosylate ester, then use hydride reducing agent to displace tosylate leaving group (works for most primary/secondary alcohols) 11.7) Reactions ofAlcohols with HydrohalicAcids • Alcohols  alkyl halide by tosylation of alcohol, then displacement of tosylate by halide ion o but not most common method for this b/c simple 1-step rxns available o ex: treat alcohol w/ hydrohalic acid (HBr, HCl, or HI) • Acidic sol’n: alcohol in eqbm w/ protonated form o protonation: hydroxyl group converted from poor leaving group ( OH) good leaving group (H O) 2 o after protonation, usual substitution/elimination rxns feasible, depending on alcohol structure (primary, secondary, tertiary) • Most good nucleophiles = basic become protonated, lose nucleophilicity in acidic sol’ns o but halide ions = exceptions b/c = anions of strong -cid-wea- base o HBr, HCl, and HI sol’ns contain nucleophilic Br , Cl, or I ions  commonly used to convert alcohols corresponding alkyl halides • Reactions with HydrobromicAcid o Concentrated hydrobromic acid converts tert-butyl alcohol tert-butyl bromide fast  strong acid protonates hydroxyl group good leaving group  hindered tertiary C can’t undergo S N displacement but can ionize tertiary carbocation  attack by bromide alkyl bromide  similar mechanism to S 1Nexcept that water = leaving group from protonated alcohol o Mechanism: Reaction of a TertiaryAlcohol w/ HBr (S 1) N  Step 1: Protonation: hydroxyl group good leaving group  Step 2: Water leaves carbocation  Step 3: Bromide ion attacks carbocation o Many other alcohols react w/ HBr, mechanism depends on alcohol structure  ex: butan-1-ol reacts w/ NaBr in concentrated sulfuric acid 1- bromobutane by S 2 Nisplacement  NaBr/sulfuric acid reagent generates HBr in sol’n o Protonation: hydroxyl group good leaving group, but ionization to primary carbocation = unfavorable  protonated primary alcohol good for S 2Ndisplacement  backside attack 1-bromobutane o Mechanism: Rxn of PrimaryAlcohol w/ HBr (S 2) N  Step 1: Protonation: hydroxyl group: good leaving group  Step 2: Bromide displaces water alkylbromide o Secondary alcohols react w/ HBr alkyl bromides by S 1 N  ex: cyclohexanol bromocyclohexane w/ HBr as reagent • Reactions w/ HydrochloricAcid o HCl reacts like HBr w/ alcohols  ex: concentrated aqueous HCl + tert-butyl alcohol tert-butyl chloride o Chloride ion weaker nucleophile than Br ion b/c smaller, less polarizable  additional lewis acid like zinc chloride (ZnCl2) promotes HCl + primary/secondary alcohol rxn  zinc chloride coordinates w/ O of alcohol same way proton does, but stronger o Lucas reagent: reagent composed of HCl and ZnCl 2  secondary/tertiary alcohols react w/ Lucas reagent by S N mechanism (fast) o When primary alcohol reacts w/ Lucas reagent, ionization not possible b/c primary carbocation too unstable  primary substrates react by SN2 mechanism (slower than S 1)N  ex: butan-1-ol + Lucas reagent
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