10-1 Alcohols & Thiols - 10 Sources Structure, Nomenclature, Properties Acidity and Basicity Reaction with active metals Conversion to R-X, inorganic acid halides Reactions with HX S N 1/S N 2, sulfonates Dehydration of alcohols Oxidation of 1 o and 2 o alcohols Oxidation of glycols [Pinacol & Thiols/Sulfur chemistry - skip]

10-2 Preparation of alcohols - (review) Hydration C H H or H + /H 2 O CH 3 OH 1. Hg(OAc) 2 /H 2 O 2. NaBH 4 H C H H + H3BH3B HOOH NaOH C H OH H S N 1 / S N 2 Reduction

10-3 oxygen also sp 3 hybridized Structure - Alcohols Alcohol functional group: -OH group bonded to an sp 3 hybridized carbon bond angles ~ 109.5° CO H H H 3 C H

10-4 Nomenclature-Alcohols IUPAC names Longest chain that contains the -OH = root Give -OH group lowest number Change suffix -e to -ol (S)-2-methyl-1-butanol

10-5 Nomenclature of Alcohols Unsaturated alcohols: The double bond becomes infix -en- The hydroxyl group is the suffix -ol numbering give OH the lower number H 3 C C C H H C H H C HO CH 3 H (S,E)-4-hexen-2-ol

10-6 Physical Properties Hydrogen bonding: H bonded to an electronegative atom (F, O, or N) etc. R O H O H R O H R O H R Hydrogen bond weak (~ 5 kcal/mol) But have significant effects on properties and reactions

10-7 Physical Properties ethanol & dimethyl ether - constitutional isomers but weak hydrogen bonds (& dipole-dipole interactions) have dramatic effects: hydrogen bonds no hydrogen bonds

10-8 Acidity of Alcohols alcohols weak acids conjugate bases strong

10-9 Acidity of Alcohols RSH 8.5

10-10 Hydrophobic cage Acidity of Alcohols Acidity  on: solvation and stabilization bulky alkyl groups decreases solvation

10-11 Acidity of Alcohols Acidity  on: stabilization and solvation electron donation destabilize alkoxides decreases solvation

10-12 Basicity of Alcohols like water -Lewis base (-)

10-13 Alcohols + Li, Na, K (active metals) form metal alkoxides metal alkoxide sodium methoxide Reaction with Metals

10-14 Reaction with Metals sodium cyclohexoxide

° alcohols react very rapidly with HCl, HBr, HI. Conversion to R-X (with HX) Low-molecular-weight 1° and 2° alcohols are unreactive under these conditions

10-16 Reaction with HX 2° alcohols + HBr (or HI ) may afford racemization, rearrangement, olefins

o or 3 o ROH with HX - S N 1 -H + +X - -H 2 O good leaving group

o RX with HX - S N 2 X - displace + OH 2

10-19 Reaction with SOCl 2 1° and 2° alcohols 18 With amine -stereoselective

10-20 a good leaving group Reaction with SOCl 2 + Reaction of an 1 o /2 o alcohol w/ SOCl 2 in and a 3° amine is ‘stereoselective’; inversion.

10-21 Reaction with PBr 3 Synthesis of 1° and 2° alkyl bromides via alcohol + PBr 3 (less rearrangement)

10-22 Reaction with PBr 3 Good leaving group

10-23 Alkyl Sulfonates, good leaving group

10-24 alkyl sulfonates good leaving group for S N reaction S S DMF SR

10-25 Alkyl Sulfonates Alkyl Sulfonates - Commonly p-toluenesulfonyl chloride (Ts-Cl) is used pyridine

10-26 Alkyl Sulfonates OR

° ROH heated with acid catalyst, (H 2 SO 4 or H 3 PO 4 ) Dehydration of ROH 2° alcohols dehydrate at lower temperatures 3° alcohols at or slightly above room temperature

10-28 Dehydration of ROH where isomeric alkenes are possible, the alkene having the greater number of substituents on the double bond (the more stable alkene) usually predominates (Zaitsev rule)

10-29 ROH dehydration is often accompanied by rearrangement 80% 20% rearrangement & ease of dehydration (3°>2°>1°) suggest: E1 mechanism for 2° and 3° ROH [R + formed in the rate-limiting step]

10-30 Dehydration of ROH Dehydration and alkene hydration compete

10-31 Dehydration of ROH  Based on evidence of ease of dehydration (3° > 2° > 1°) prevalence of rearrangements  Chemists propose a three-step mechanism for the dehydration of 2° and 3° alcohols because this mechanism involves formation of a carbocation intermediate in the rate- determining step, it is classified as E1

10-32 Dehydration of ROH Step 1: proton transfer to the -OH group gives an oxonium ion Step 2: loss of H 2 O gives a carbocation intermediate

10-33 Dehydration of ROH Step 3: proton transfer from a carbon adjacent to the positively charged carbon to water; the sigma electrons of the C-H bond become the pi electrons of the carbon-carbon double bond

10-34 Dehydration of ROH  Acid-catalyzed alcohol dehydration and alkene hydration are competing processes  Principle of microscopic reversibility:  Principle of microscopic reversibility: the sequence of transition states and reactive intermediates in the mechanism of a reversible reaction must be the same, but in reverse order, for the reverse reaction as for the forward reaction

10-35 Pinacol Rearrangement This section out [rearrangement under dehydration conditions]

10-36 Oxidation

10-37 Oxidation: 1° ROH Pyridinium chlorochromate (PCC): pyridine + CrO 3 [Cr(VI)] + HCl PCC converts 1° alcohols to aldehydes and 2 o alcohols to ketones

10-38 Oxidation aldehyde acid ketone NR (no reaction)

10-39 Oxidation: 2° ROH eliminate chromate ester (leaving group)

10-40  -elimination of H and chromate + 3 o alcohols - NR - no “  -hydrogen”

10-41 R C O H H H R C O H R C O OH [O] [O] = CrO 3 PCC Oxidation: 1° ROH aldehyde acid

10-42 Oxidation: 1° ROH PCC oxidation of a 1° alcohol => aldehyde H 2 CrO 4 But…... (also K 2 CrO 7 )

10-43 Rxn: Oxidation: 1° ROH chromate ester  -elimination

10-44 Oxidation: 1° ROH hydrate

10-45 Oxidation 1 o and 2 o ROH K 2 Cr 2 O 7 and many other reagents

10-46 Oxidation of Glycols with H 5 IO 6 (or HIO 4 2H 2 O) acyclic or cis-1,2 cyclic diols

10-47 OsO 4 / HIO 4 equivalent to O 3 /reduction OsO 4 source of diols

10-48 mechanism Oxidation of Glycols with H 5 IO 6 (or HIO 4 2H 2 O)

10-49 Oxidation of Glycols with H 5 IO 6 (or HIO 4 2H 2 O)

10-50 Oxidation of Alcohols by NAD + biological systems do not use chromic acid or the oxides of other transition metals to oxidize 1° alcohols to aldehydes or 2° alcohols to ketones what they use instead is a NAD + the Ad part of NAD + is composed of a unit of the sugar D-ribose (Chapter 25) and one of adenosine diphosphate (ADP, Chapter 28)

10-51 Oxidation of Alcohols by NAD + when NAD + functions as an oxidizing agent, it is reduced to NADH in the process, NAD + gains one H and two electrons; NAD + is a two-electron oxidizing agent

10-52 Oxidation of Alcohols by NAD + NAD + is the oxidizing in a wide variety of enzyme-catalyzed reactions, two of which are

10-53 Oxidation of Alcohols by NAD + mechanism of NAD + oxidation of an alcohol hydride ion transfer to NAD + is stereoselective; some enzymes catalyze delivery of hydride ion to the top face of the pyridine ring, others to the bottom face