Carbon-heteroatom single bonds basic C N C X. X= F, Cl, Br, I Alkyl Halide C O. epoxide Chapter 14 H. alcohols acidic H C S C. thiols.

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1 hapter 13: Alcohols and Phenols 13.1 Structure and Properties of Alcohols Alkanes arbon - arbon Multiple Bonds arbon-heteroatom single bonds basic Alkenes X X= F, l,, I Alkyl alide amines hapter 23 nitro alkane Alkynes phenol alcohols acidic ethers epoxide hapter 14 thiols S S sulfides (thioethers) S S disulfide Arenes 253 omenclature of alcohols 1. In general, alcohols are named in the same manner as alkanes; replace the -ane suffix for alkanes with an -ol for alcohols umber the carbon chain so that the hydroxyl group gets the lowest number 3. umber the substituents and write the name listing the substituents in alphabetical order. Many alcohols are named using non-systematic nomenclature benzyl alcohol (phenylmethanol) butane 1-butanol 2-butanol butan-1-ol butan-2-ol allyl alcohol (2-propen-1-ol) tert-butyl alcohol (2-methyl-2-propanol) ethylene glycol (1,2-ethanediol) glycerol (1,2,3-propanetriol)

2 Alcohols are classified according to the degree of substitution of the carbon bearing the - group primary (1 ) : one alkyl substituent secondary (2 ) : two alkyl substituents tertiary (3 ) : three alkyl substituents methanol 2 carbon secondary alcohol 1 carbon primary alcohol 3 carbon tertiary alcohol Physical properties of alcohols the - bond of alcohols has a significant dipole moment. + - l µ = 1.9 µ = Like water, alcohols can form hydrogen bonds: a non-covalent interaction between a hydrogen atom ( + ) involved in a polar covalent bond, with the lone pair of a heteroatom (usually or ), which is also involved in a polar covalent bond ( - ) ydrogen-bonds are broken when the alcohol reaches its bp, which requires additional energy

3 l MW=18 MW=58 MW=92.5 MW=74 bp= 100 bp= 0 bp= 77 bp= l 3 2 MW= 30.1 MW= 64.5 MW=60 bp = -89 bp= 12 bp= Acidity of Alcohols and Phenols Increasing stability of the conjugate base X pk a = Factors affecting the acidity of alcohols and phenols pk a ~ pk a ~ Inductive effects an atom s (or group of atoms) ability to polarize a bond through electronegativity differences (σ-bonds) 3 2 F 2 2 F 2 2 F 3 2 (F 3 ) 3 pk a ~ F 3 F 3 F 3 + Electron-withdrawing groups make an alcohol a stronger acid by stabilizing the conjugate base (alkoxide) A benzene ring is generally considered electron withdrawing and stabilizes the negative charge through inductive effects

4 esonance effect: the benzene ring stabilizes the the phenoxide ion by resonance delocalization of the negative charge Substituents on the phenol can effect acidity Electron-donating substituents make a phenol less acidic by destabilizing the phenoxide ion (resonance effect). Electron-withdrawing substituents make a phenol more acidic by stabilizing the phenoxide ion through delocalization of the negative charge and through inductive effects. X X= l pk a ~ The influence of a substituent on phenol acidity is also dependent on its position relative to the - X pk a X= -l X eagents for deprotonating an alcohol alcohols and phenols are deprotonated to alkoxides with a strong base such as sodium hydride (a)

5 13.3 Preparation of Alcohols via Substitution or Addition Substitution eactions (hapter 7) Addition eactions (hapter 9) ydration of alkenes (hapter 6) 1. Acid-catalyzed hydration (hapter 9.4) 2. xymercuration demercuration (hapter 9.5) 3. ydroboration oxidation (hapter 9.6) Preparation of Alcohols via eduction xidation State of arbon (-4 +4): is a group IV element l

6 eduction of ketone and aldehydes to alcohols adds the equivalent of 2 across the π-bond of the carbonyl (=) to yield an alcohol. ' reduction [] aldehyde ( or = ) 1 alcohol ketone ( and ) 2 alcohol atalytic hydrogenation is not typically used for the reduction of ketones or aldehydes to alcohols. Metal hydride reagents: equivalent to : (hydride) sodium borohydride lithium aluminium hydride (ab 4 ) (LiAl 4 ) ' a + B Li + Al electronegativity B Al ab 4 reduces aldehydes to primary alcohols 2 ab ab 4 reduces ketones to secondary alcohols ab ketones 2 alcohols ab 4 does not react with esters or carboxylic acids 3 2 ab

7 Lithium Aluminium ydride (LiAl 4, LA) - much more reactive than ab 4. Incompatible with protic solvents (alcohols, 2 ). LiAl 4 (in ether) reduces aldehydes, carboxylic acids, and esters to 1 alcohols and ketones to 2 alcohols. 1) LiAl 4, ether 2) 3 + or 2 1) LiAl 4, ether 2) 3 + or 2 arboxylic Acids and esters are reduced to 1 alcohols by LiAl 4 (but not ab 4 or catalytic hydrogenation). 3 1) LiAl 4, ether 2) 3 + or 2 1) LiAl 4, ether 2) 3 + or 2 ester 1 alcohol carboxylic acid Preparation of Diols (hapters 9.9 & 9.10) Vicinal diols have hydroxyl groups on adjacent carbons (1,2-diols, vic-diols, glycols). 1) 3 2) 3 + s 4 anti chapter 9.9 chapter 9.10 syn other diols 13.6 Preparation of Alcohols via Grignard eagents Mg -X (0) -MgX (Grignard reagent) TF + + X MgX MgX + alkyl halide = electrophile carbanion = nucleophile reacts with electrophiles

8 -X can be an alkyl, vinyl, or aryl halide (chloride, bromide, or iodide) Mg(0), ether Mg Mg(0), ether Mg Mg(0), ether Mg Solvent: diethyl ether (Et 2 ) or tetrahydrofuran (TF) diethyl ether (Et 2 ) tetrahydrofuran (TF) Grignard reagents react with aldehydes, ketones, and esters to afford alcohols - + : MgX ether MgX Grignard reagents react with... formaldehyde ( 2 =) to give primary alcohols Mg 0, ether Mg 1) 2 = 2) 3 + aldehydes to give secondary alcohols Mg Mg 0, ether 1) ketones to give tertiary alcohols esters to give tertiary alcohols 2) 3 + Mg 0, ether 1) Mg 2) Mg 0, ether 2 3 -Mg 1) 2)

9 Tertiary alcohols from esters and Grignard reagents - mechanism: Mg 1) TF 2) then rganolithium eagents can generally be used interchangeably with Grignard reagents - + Li -X 2 Li (0) -Li + LiX diethyl ether _ very strong bases very strong nucleophiles Protection of Alcohols Grignard eagents are highly basic; therefore the solvent or reactant can not contain functional groups that are acidic or electrophilic. These are incompatible with the formation and/or reactivity of the Grignard reagent. Mg 0 Mg Mg 3 + ther incompatible groups: - 2, -, -S, 2, (amides) eactive functional groups: aldehydes, ketones, esters, amides, halides, - 2, -S 2, nitriles 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)

10 Trimethylsilyl ethers as a protecting group for alcohols Mg 0 Mg Mg 3 + ( 3 ) 3 Sil ( 3 2 ) 3 protect alcohol 3 Si 3 3 Mg 0, TF 3 Si 3 3 _ Mg then Si or 3 F + remove protecting group 13.8 Preparation of Phenols (please read) eaction of Alcohols: Substitution and Elimination Substitution reaction of alcohols with X works well for 3 alcohols + X X and 2 alcohols react with thionyl chloride (Sl 2 ) or phosphorous tribromide (P 3 ) to afford 1 and 2 alkyl chlorides and bromides, respectively + Sl 2 + base l + S 2 + l + P P()

11 Elimination reaction of alcohols (hapter 8.9) E1 mechanism 3 alcohol undergo E1 elimination under strongly acidic conditions ( 2 S 4, Δ) E2 mechanism - 1 and 2 alcohols must be converted to a better leaving group (halide or sulfonate) to be reactive toward E2 elimination eactions of Alcohols: xidations oxidation [] reduction [] [] alcohols ketone [] 1 1 alcohols aldehyde carboxylic acids [] 1 hromic acid (a 2 r 2 7, 3 + ) oxidize secondary alcohols to ketones, and primary alcohols to carboxylic acids

12 xidation of primary alcohols to aldehydes Pyridinium hlorochromate (P) r 3 + 6M l + pyridine lr 3 - P is soluble in anhydrous organic solvent such as 2 l 2. The oxidation of primary alcohols with P in anhydrous 2 l 2 stops at the aldehyde. 2 2 r , acetone P 2 l 2 arboxylic Acid 1 alcohol Aldehyde : Biological edox eactions (please read) Ethanol metabolism: 3 2 alcohol dehydrogenase 3 aldehyde dehydrogenase 3 ethanol acetaldehyde acetic acid icotinamide Adenine Dinucleotide (AD) 2 2 P P 2 P P 2 reduced form = AD, AD + = P 3 2- ADP, ADP + oxidized form Vitamin B 3, nicotinic acid, niacin

13 13.12 xidation of Phenols (please read) Synthetic Strategies 3, DMS 1) 2, hν 2) base (E2) 1) 2, 2) a 2 alkane 2, Pd 1) Tsl 2) base (E2) alkene 1) B 3 2) 2 2, a 2 2, Lindlar's or a(0), 3 alkyne P, 2 l 2 1) B 3 2) 2 2, a 2 a) 3 - Mg TF b) 2 or 3 + 1) g(ii), 2 2) ab 4 ab 4 or LA P, 2 l 2 g(ii), 3 + ab 4 or LA 277 xidation states of functional groups oxidation l l l l l l l l l l 2 2 reduction