hapter 17: Alcohols and Phenols sp 3 alcohol phenol (aromatic alcohol) pka~ 16-18 pka~ 10 Alcohols contain an group connected to a saturated carbon (sp 3 ) Phenols contain an group connected to a carbon of a benzene ring enol keto chemistry dominated by the keto form 76 ' water alcohol ether peroxide S S S S ' thiols thioether disulfides Alcohols are classified as primary (1 ), secondary (2 ) or tertiary (3 ), which refers to the carbon bearing the hydroxy group methanol primary secondary tertiary 1 carbon 2 carbon 3 carbon 77 39
17.1: Nomenclature: 1. In general, alcohols are named in the same manner as alkanes; replace the -ane suffix for alkanes with an -ol for alcohols 3 2 2 3 3 2 2 2 butane 1-butanol 2-butanol 2. Number the carbon chain so that the hydroxyl group gets the lowest number 3. Number the substituents and write the name listing the substituents in alphabetical order. 4. For phenols, follow benzene nomenclature and use phenol as the parent name. The carbon bearing the - group gets number 1. 78 2-methyl-2-pentanol 3-phenyl-2-butanol N 2 N 2 3,4-dinitrophenol Many alcohols are named using non-systematic nomenclature benzyl alcohol (phenylmethanol) allyl alcohol (2-propen-1-ol) 3 3 3 tert-butyl alcohol (2-methyl-2-propanol) ethylene glycol (1,2-ethanediol) glycerol (1,2,3-propanetriol) 79 40
17.2: Properties of alcohols and phenols: ydrogen bonding: The structure around the oxygen atom of an alcohol or phenol is similar to that in water and is sp 3 hybridized Alcohols and phenols have much higher boiling points than similar alkanes and alkyl halides 2 3 2 2 3 3 2 2 2 l 3 2 2 MW=18 MW=58 MW=92.5 MW=74 bp= 100 bp= -0 bp= 77 bp= 116 6 6 6 6 6 6 3 6 6 2 MW=78 MW=94 MW=92 MW=108 bp= 80 bp= 182 bp= 110 bp= 203 80 Alcohols and phenols, like water, can form hydrogen bonds: non covalent interaction between a hydrogen atom (δ + ) involved in a polar covalent bond, with the lone pair of a heteroatom (usually or N), which is also involved in a polar covalent bond (δ - ) N!-!+!-!+ N!+!-!!!!!!!!!!!! ydrogen-bonds are broken when the alcohol reaches its bp, which requires additional energy 81 41
17.3: Properties of alcohols and phenols: acidity and basicity: Like water, alcohols are weak Brønsted bases and weak Brønsted acids. The nature of the group can significantly influence the basicity or acidity + X + oxonium ion alkoxide ion + + :X - 3 3 2 2 2 3 2 () 3 ( 3 )- MW = 32 MW = 74 MW = 74 MW = 74 bp= 65 bp = 116 bp = 99 bp = 82 pka ~ 15.5 pka ~ 16 pka ~ 17 pka ~ 18 The steric environment around the oxygen atom can influence the physical properties of an alcohol 82 Solvation: upon acid dissociation the alkoxide ion is stabilized by solvation through hydrogen bonding between water and the negatively charge oxygen. The steric environment around the negatively charge oxygen influences the solvation effect + + Acidity: methanol > 1 alcohol > 2 alcohol > 3 alcohol eflects the ability water to stabilized the resulting alkoxide though solvation 83 42
Electronic factors that influence acidity: inductive and resonance effect 3 2 F 2 2 F 2 2 F 3 2 (F 3 ) 3 2 pk a ~ 16.0 14.4 13.3 12.4 5.4 F 3 F 3 F 3! + Electron-withdrawing groups make an alcohol a stronger acid by stabilizing the conjugate base (alkoxide) X X= - -l -Br -N 2-3 - 3 -N 2 pk a ~ 9.9 9.38 9.35 7.15 10.16 10.21 10.46 X ~ pk a X= -l 9.38 8.85 -N 2 7.15 8.28-3 10.21 9.65-3 10.17 10.16 X 84 Phenols are much more acidic than aliphatic alcohols: a benzene ring is generally considered electron withdrawing (inductive effect) the benzene ring stabilizes the negative charge of the phenoxide ion through resonance (Fig. 17.3, p. 595) 85 43
Electron-withdrawing substituents make a phenol more acidic by stabilizing the phenoxide ion through delocalization of the negative charge and through inductive effects Electron-donating substituents make a phenol less acidic by destabilizing the phenoxide ion (resonance effect) The location of the substituent relative to the phenol is important 86 17.4: Preparation of alcohols: 3 + Markovnikov addition a) B 2 6, TF b) Na, 2 2 B 2 Anti-Markovnikov verall syn addition of across the π-bond a) g(ac) 2, 2 b) NaB 4 gac Markovnikov a) s 4 b) NaS 3 s Syn addition of - groups ydration of alkenes (h. 7.4) xymercuration of alkenes (h. 7.4) ydroboration of alkenes (h. 7.5) Di-hydroxylation of alkenes (h. 7.8) 87 44
17.5: Alcohols from reduction of carbonyl compounds Figure 10.5 (hapter 10.10) Increasing oxidation state 2 l l l l l l l l l l N 2 N N 88 17.5: Alcohols from reduction of carbonyl compounds add the equivalent of 2 across the π-bond of the carbonyl to give an alcohol []: ' [] ' aldehyde ( or = ) 1 alcohol ketone ( and ) 2 alcohol sodium borohydride: NaB 4, ethanol reduces aldehydes to 1 alcohols and ketones to 2 alcohols lithium aluminum hydride (LA): LiAl 4, ether reduces aldehydes, carboxylic acids, and esters to 1 alcohols and ketones to 2 alcohols In general, NaB 4 and LiAl 4 will not reduce =. : M Et or ether M 3 + 89 45
17.6: Alcohols from reaction of carbonyl compounds with Grignard reagents Alkyl halides will react with some metals (M 0 ) in ether or TF to form organometallic reagents Grignard reagent- organomagnesium ether or TF -X + Mg (0) -Mg (II) -X X= l, Br, or I can be a variety of groups: 1 -, 2 -, 3 -alkyl, aryl or vinyl! -! + MgX _ arbanions: nucleophile reacts with electrophile -MgX : 90 Grignard reagents react with aldehydes or ketones to give alcohols! -! + : MgX ether MgX 3 + If, carbonyl = 2 = 1 alcohol = aldehyde 2 alcohol = ketone 3 alcohol Br Mg 0, ether MgBr 1) 2 = 2) 3 + Br MgBr Mg 0, ether 1) 2) 3 + 3 2 Br Mg 0, ether 3 2 MgBr 1) 2) 3 + 91 46
Grignard reagents react with esters to give 3 alcohols 3 _ 2 3 1) 2 3 MgBr 2) 3 + 3 3 3 MgBr the 3 + MgX _ 3 2 3 3 Some functional groups are incompatible with Grignard reagents Grignard reagents are very strong bases as well as highly reactive nucleophiles _ 3 MgBr _ MgX 3 + + 4 arboxylic acids are simply deprotonated by Grignard reagents and do not give addition products 92 Grignard reagents will deprotonate alcohols Br Mg 0 MgBr BrMg 3 + ther incompatible groups: - 2, -, -S, N 2, N (amides) eactive functional groups: aldehydes, ketones, esters, amides, halides, -N 2, -S 2, nitriles 93 47
17.7 Some reactions of alcohols A. eactions involving the - bond Dehydration to alkenes: E1 mechanism (reactivity: 3 > 2 >> 1 ) requires strong acid catalyst ( 2 S 4 ) water is a much better leaving group than - usually follows Zaitzev s rule 3 2 3 3 2 S 4 2, TF - 2 3 3 3 2 3 2 3 94 Dehydration to alkenes with Pl 3 E2 mechanism- requires an anti-periplanar conformation between leaving group and the hydrogen that is being lost mild conditions, requires a base (pyridine) 3 Pl 3, pyridine 3 Pl 3, pyridine 3 3 95 48
onversion of an alcohol to an alkyl halide (- -X) (hapter 10.7) 1. Substitution reaction of alcohols with X - + X -X + 2 Works better with more substituted alcohols << < < Methyl Primary (1 ) Secondary (2 ) Tertiary (3 ) increasing reactivity S N 1 mechanism involving a carbocation intermediate: rearrangements, stereochemistry (racemization) 96 2. Prepartion of alkyl chlorides by the treatment of alcohols with thionyl chloride (Sl 2 ) - + Sl 2 -l + S 2 + l 3. Preparation of alkyl bromides by the treatment of alcohols with phosphorous tribromide (PBr 3 ) - + PBr 3 -Br + P() 3 S N 2 mechanism: works best with 1 and 2 alcohols, but not with 3 alcohols. stereochemistry: inversion 97 49
Sl 2 l S + l S N 2 l ()-2-hlorohexane (S)-2-hexanol PBr 3 PBr 2 + Br S N 2 B. eaction involving the - bond onversion of an alcohol to a tosylate (Tos) Br ()-2-Bromohexane eaction of an alcohol with with p-toluenesulfonyl chloride (tosyl chloride, p-tosl) in pyridine gives a tosylates l S pyridine + S 3 3 tosylate 98 Formation of the tosylate does not involve the bond so the stereochemistry of the carbon attached to the alcohol is not affected Tosylates are good leaving groups and their reactivity is similar to alkyl halides PBr 3 Br N N S N 2 ()-2-Bromohexane S N 2 (S)-2-methylhexanenitrile (S)-2-hexanol Tosl Tos N N S N 2 (S)-2-hexyl-p-toluene sulfonate ()-2-methylhexanenitrile 99 50
17.8 xidation of Alcohols 100 xidation of primary alcohols with r(vi) exact structure of the chromium reagent depends on solvent and p 2 - r(vi) 3 Base: r chromate ester pyridinium chlorochromate (P)- oxidizes 1 alcohols to aldehydes; and 2 alcohols r to ketones. Solvent: 2 l 3 l 2 chromic acid (Jones reagent): r 3 (or Na 2 r 2 7 ) + 2 + 2 S 4 2 r 4 2 2 r 4 2 r 2 7 + 2 oxidizes 1 alcohols to carboxylic acids; and 2 alcohols to ketones. Solvent: 3 + and acetone E 2 N + r(iv) r(iii) 101 51
2-1 alcohol 2 r 2 7 3 +, acetone 2 hydration 2 r 2 7 3 +, acetone P 2 l 2 2 r 2 7 3 +, acetone 2 Aldehyde 1 alcohol arboxylic Acid 102 17.9 Protection of Alcohols ydroxyl groups are weak protic acids and can transfer a proton to a basic reagent, which may prevent a desired reaction. Protecting group: Temporarily convert a functional group that is incompatible with a set of reaction conditions into a new functional group (with the protecting group) that is compatible with the reaction. The protecting group is then removed giving the original functional group (deprotection). 103 52
Trimethylsilyl ethers as a protecting group for alcohols Br Mg 0 MgBr BrMg 3 + ( 3 ) 3 Sil ( 3 2 ) 3 N protect alcohol 3 Si 3 3 Br Mg 0, TF 3 Si 3 3 _ MgBr then 3 + 3 Si 3 3 3 + remove protecting group 104 17.10 Preparation of phenols alkali fusion reaction (hapter 16.2) hapter 24.8: anilines (Ar-N 2 ) phenols (Ar-) 17.11 eactions of Phenols: electrophilic aromatic substitution (hapter 16.5-16.7) phenols are highly activated toward electrophilic aromatic substitution and are o,p-directors 105 53
xidation of phenols to quinones (please read) phenols can be oxidized by strong oxidants to give hydroquinones and quinones (KS 3 ) 2 N, 2 (Fermy's salt) hydroquinone (reduced) Ubiquinones (n= 1-10): oenzyme Q 3 3 - e -, - + 3 - e -, - + + e -, + + 3 semiquinone - e -, - + + e -, + + - e -, - + 3 quinone (oxidized) 3 3 hydroquinone (reduced) α tocopherol (vitamin E) n + e -, + + 3 semiquinone n + e -, + + 3 quinone (oxidized n 3 3 3 3 - e -, - + + e -, + + 3 3 3 3 106 17.12 Spectroscopy of Alcohols and Phenols: Infrared (I): haracteristic stretching absorption at 3300 to 3600 cm 1 Sharp absorption near 3600 cm -1 except if -bonded: then broad absorption 3300 to 3400 cm 1 range Strong stretching absorption near 1050 cm 1 107 54
1 NM: protons attached to the carbon bearing the hydroxyl group are deshielded by the electron-withdrawing nature of the oxygen, δ 3.5 to 4.0!= 3.64, br, 1!= 3.8, s, 1!= 1.0, d, 6 108 Usually no spin-spin coupling between the proton and neighboring protons on carbon due to exchange reaction A + A The chemical shift of the - proton occurs over a large range (2.0-5.5 ppm). This proton usually appears as a broad singlet. It is not uncommon for this proton not to be observed. 109 55
13 NM: The oxygen of an alcohol will deshield the carbon it is attached to. The chemical shift range is 50-80 ppm!= 63.5!= 25 145.2 DMS-d 6 (solvent) 110 9 12 5 1 1 2 3 13: 138.6 129.0 128.0 126.1 79.0 31.8 7.5 8 10 2 2 1 2 3 13: 153.7 132.1 129.2 115.8 32.4 14.6 111 56