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Alcohols and Phenols and Their Reac1ons More About the Families in Group II The families in Group II all have an electronega1ve atom or group that is a>ached to an sp3 carbon. Alcohols and Phenols Alcohols contain an OH group connected to a saturated C (sp3) They are important solvents and synthesis intermediates Phenols contain an OH group connected to a carbon in a benzene ring Methanol, CH3OH, called methyl alcohol, is a common solvent, a fuel addi1ve, produced in large quan11es • Ethanol, CH3CH2OH, called ethyl alcohol, is a solvent, fuel, beverage • Phenol, C6H5OH (“phenyl alcohol”) has diverse uses -­‐ it gives its name to the general class of compounds • OH groups bonded to vinylic sp2-­‐hybridized carbons are called enols • • • • Why this Chapter? • To begin to study oxygen-­‐containing func1onal groups • These groups lie at the heart of biological chemistry Classifica1on of Alcohols • General classifica1ons of alcohols based on subs1tu1on on C to which OH is a>ached • Methyl (C has 3 H’s), Primary (1°) (C has two H’s, one R), secondary (2°) (C has one H, two R’s), ter1ary (3°) (C has no H, 3 R’s) IUPAC Rules for Naming Alcohols • Select the longest carbon chain containing the hydroxyl group, and derive the parent name by replacing the -­‐e ending of the corresponding alkane with -­‐ol • Number the chain from the end nearer the hydroxyl group • Number subs1tuents according to posi1on on chain, lis1ng the subs1tuents in alphabe1cal order Naming Phenols • Use “phenol” (the French name for benzene) as the parent hydrocarbon name, not benzene • Name subs1tuents on aroma1c ring by their posi1on from OH Proper1es of Alcohols and Phenols • The structure around O of the alcohol or phenol is similar to that in water, sp3 hybridized. • Alcohols and phenols have much higher boiling points than similar alkanes and alkyl halides. • A posi1vely polarized ⎯OH hydrogen atom from one molecule is a>racted to a lone pair of electrons on a nega1vely polarized oxygen atom of another molecule. • This produces a force that holds the two molecules together • These intermolecular a>rac1ons are present in solu1on but not in the gas phase, thus eleva1ng the boiling point of the solu1on. Proper1es of Alcohols and Phenols: Acidity and Basicity • Weakly basic and weakly acidic • Alcohols are weak Brønsted bases • Protonated by strong acids to yield oxonium ions, ROH2+ Alcohols and Phenols are Weak Brønsted Acids • Can transfer a proton to water to a very small extent • Produces H3O+ and an alkoxide ion, RO-­‐, or a phenoxide ion, ArO-­‐ Acidity Measurements • The acidity constant, Ka, measures the extent to which a Brønsted acid transfers a proton to water [A-­‐] [H3O+] Ka = ————— and pKa = -­‐log Ka [HA] • Rela1ve acidi1es are more conveniently presented on a logarithmic scale, pKa, which is directly propor1onal to the free energy of the equilibrium • Differences in pKa correspond to differences in free energy • Table 17.1 presents a range of acids and their pKa values pKa Values for Typical OH Compounds Rela1ve Acidi1es of Alcohols • Simple alcohols are about as acidic as water • Alkyl groups make an alcohol a weaker acid • The more easily the alkoxide ion is solvated by water the more its forma1on is energe1cally favored • Steric effects are important Induc1ve Effects Also Important in Determining Acidity of Alcohols • Electron-­‐withdrawing groups make an alcohol a stronger acid by stabilizing the conjugate base (alkoxide) Genera1ng Alkoxides from Alcohols • Alcohols are weak acids – requires a strong base to form an alkoxide such as NaH, sodium amide NaNH2, and Grignard reagents (RMgX) • Alkoxides are bases used as reagents in organic chemistry Phenol Acidity • Phenols (pKa ~10) are much more acidic than alcohols (pKa ~ 16) because of resonance stabiliza1on of the phenoxide ion • Phenols react with NaOH solu1ons (but alcohols do not), forming salts that are soluble in dilute aqueous solu1on • A phenolic component can be separated from an organic solu1on by extrac1on into basic aqueous solu1on and is isolated amer acid is added to the solu1on Nitro-­‐Phenols • Phenols with nitro groups at the ortho and para posi1ons are much stronger acids Prepara1on of Alcohols • Alcohols are derived from many types of compounds • The alcohol hydroxyl can be converted to many other func1onal groups • This makes alcohols useful in synthesis Review: Prepara1on of Alcohols by Regiospecific Hydra1on of Alkenes • Hydrobora1on/oxida1on: syn, an0-­‐Markovnikov hydra1on • Oxymercura1on/reduc1on: Markovnikov hydra1on 1,2-­‐Diols • Review: Cis-­‐1,2-­‐diols from hydroxyla1on of an alkene with OsO4 followed by reduc1on with NaHSO3 • Trans-­‐1,2-­‐diols from acid-­‐catalyzed hydrolysis of epoxides Alcohols from Carbonyl Compounds: Reduc1on • Reduc1on of a carbonyl compound in general gives an alcohol • Note that organic reduc1on reac1ons add the equivalent of H2 to a molecule Reduc1on of Aldehydes and Ketones • Aldehydes gives primary alcohols • Ketones gives secondary alcohols Reduc1on Reagent: Sodium Borohydride • NaBH4 is not sensi1ve to moisture and it does not reduce other common func1onal groups • Lithium aluminum hydride (LiAlH4) is more powerful, less specific, and very reac1ve with water • Both add the equivalent of “H-­‐” Mechanism of Reduc1on • The reagent adds the equivalent of hydride to the carbon of C=O and polarizes the group as well Reduc1on of Carboxylic Acids and Esters • Carboxylic acids and esters are reduced to give primary alcohols • LiAlH4 is used because NaBH4 is not effec1ve Alcohols from Carbonyl Compounds: Grignard Reagents • Alkyl, aryl, and vinylic halides react with magnesium in ether or tetrahydrofuran to generate Grignard reagents, RMgX • Grignard reagents react with carbonyl compounds to yield alcohols Reac1ons of Grignard Reagents with Carbonyl Compounds Reac1ons of Esters and Grignard Reagents • Yields ter1ary alcohols in which two of the carbon subs1tuents come from the Grignard reagent • Grignard reagents do not add to carboxylic acids – they undergo an acid-­‐base reac1on, genera1ng the hydrocarbon of the Grignard reagent Grignard Reagents and Other Func1onal Groups in the Same Molecule • Cannot be prepared if there are reac1ve func1onal groups in the same molecule, including proton donors Mechanism of the Addi1on of a Grignard Reagent • Grignard reagents act as nucleophilic carbon anions (carbanions = : R-­‐) in adding to a carbonyl group • The intermediate alkoxide is then protonated to produce the alcohol Strongly Basic Leaving Groups Cannot Be Displaced Acid Converts the Poor Leaving Group into a Good Leaving Group Alcohols have to be “ac1vated” before they can react. Only weakly basic nucleophiles can be used. Strongly basic nucleophiles would react with the proton. Reac1ons of Alcohols • Conversion of alcohols into alkyl halides: -­‐ 3˚ alcohols react with HCl or HBr by SN1 through carboca1on intermediate -­‐ 1˚ and 2˚ alcohols converted into halides by treatment with HCl, HBr, or HI -­‐ 1˚ and 2˚ alcohols converted into halides by treatment with SOCl2 or PBr3 via SN2 mechanism Conver1ng Alcohols to Alkyl Halides Primary and Secondary alcohols require heat; ter1ary alcohols do not. The Reac1ons of Primary Alcohols with Hydrogen Halides are SN2 Reac1ons Recall that Br– is a good nucleophile in a pro1c solvent. Alcohols undergo SN1 reac1ons unless they would have to form a primary carboca1on. An SN1 Reac1on Creates a Carboca1on Intermediate, So Watch Out for Carboca1on Rearrangements Cl– is the Poorest Nucleophile of the Halide Ions ZnCl2 increases the rate of the reac1on by crea1ng a be>er leaving group than water. The Mechanism for the Reac1on with PBr3 or PCl3 A bromophosphite (chlorophosphite) group is a be>er leaving group than a halide ion. Pyridine is the solvent and acts as a base. The Mechanism for the Reac1on with SOCl2 A chlorosulfite group is a be>er leaving group than a halide ion. Pyridine is the solvent and acts as a base. Why is It Important to Be Able to Convert Alcohols to Alkyl Halides? Alcohols are readily available but unreac1ve. Alkyl halides are less available but reac1ve and can be used to synthesized a wide variety of compounds. Primary and Secondary Alcohols Can Be Ac1vated by Being Converted to Sulfonate Esters Common Sulfonyl Chlorides tosyl chloride = TsCl The Mechanism A Sulfonate Ester Reacts with Nucleophiles Conversion of Alcohols into Tosylates • Reac1on with p-­‐toluenesulfonyl chloride (tosyl chloride, p-­‐
TosCl) in pyridine yields alkyl tosylates, ROTos • Forma1on of the tosylate does not involve the C–O bond so configura1on at a chirality center is maintained • Alkyl tosylates react like alkyl halides Stereochemical Uses of Tosylates • The SN2 reac1on of an alcohol via an alkyl halide proceeds with two inversions, giving product with same arrangement as star1ng alcohol • The SN2 reac1on of an alcohol via a tosylate, produces inversion at the chirality center Dehydra1on of Alcohols to Yield Alkenes • The general reac1on: forming an alkene from an alcohol through loss of O-­‐H and H (hence dehydra1on) of the neighboring C–H to give π bond • Specific reagents are needed Acid-­‐ Catalyzed Dehydra1on • Ter1ary alcohols are readily dehydrated with acid • Secondary alcohols require severe condi1ons (75% H2SO4, 100°C) -­‐ sensi1ve molecules do not survive • Primary alcohols require very harsh condi1ons – imprac1cal • Reac1vity is the result of the nature of the carboca1on intermediate Dehydra1on is a Reversible Reac1on To prevent the alkene from adding water and reforming the alcohol, the water is removed as it is formed. Dehydra1on of Secondary and Ter1ary Alcohols are E1 Reac1ons Dehydra1on is a Regioselec1ve Reac1on The major product is the more stable alkene. The More Stable Alkene Has the More Stable Transi1on State Leading to Its Forma1on Ter1ary Alcohols are the Easiest to Dehydrate The rate of dehydra1on reflects the ease of carboca1on forma1on. An E1 Reac1on Creates a Carboca1on Intermediate, So Watch Out for Carboca1on Rearrangements Dehydra1on of a Primary Alcohol is an E2 Reac1on Both E2 and SN2 products are obtained. Alcohols undergo E1 reac1ons unless they would have to form a primary carboca1on. Dehydra1on is Stereoselec1ve The major product is the stereoisomer with the largest groups on opposite sides of the double bond. Dehydra1on (at milder condi1on) with POCl3 • Phosphorus oxychloride in the amine solvent pyridine can lead to dehydra1on of secondary and ter1ary alcohols at low temperatures • An E2 reac1on via an intermediate ester of POCl2 The Mechanism The E1 dehydra1on has been changed to an E2 dehydra1on. Another Way to Do an E2 Dehydra1on Incorpora1on of Alcohols into Esters Oxida1on of Alcohols • Can be accomplished by inorganic reagents, such as KMnO4, CrO3, and Na2Cr2O7 or by more selec1ve, expensive reagents Oxida1on of Primary Alcohols • To aldehyde: pyridinium chlorochromate (PCC, C5H6NCrO3Cl) in dichloromethane • Other reagents produce carboxylic acids Oxida1on of Primary Alcohols Oxida1on of Secondary Alcohols • Effec1ve with inexpensive reagents such as Na2Cr2O7 in ace1c acid • PCC is used for sensi1ve alcohols at lower temperatures Oxida1on of Secondary Alcohols Mechanism of Chromic Acid Oxida1on • Alcohol forms a chromate ester followed by elimina1on with electron transfer to give ketone • The mechanism was determined by observing the effects of isotopes on rates Oxida1on by Hypochlorous Acid (HOCl) Protec1on of Alcohols • Hydroxyl groups can easily transfer their proton to a basic reagent • This can prevent desired reac1ons • Conver1ng the hydroxyl to a (removable) func1onal group without an acidic proton protects the alcohol Methods to Protect Alcohols • Reac1on with chlorotrimethylsilane in the presence of base yields an unreac1ve trimethylsilyl (TMS) ether • The ether can be cleaved with acid or with fluoride ion to regenerate the alcohol Protec1on-­‐Deprotec1on • An example of TMS-­‐alcohol protec1on in a synthesis Phenols and Their Uses • Industrial process from readily available cumene • Forms cumene hydroperoxide with oxygen at high temperature • Converted into phenol and acetone by acid Mechanism of Forma1on of Phenol Reac1ons of Phenols • The hydroxyl group is a strongly ac1va1ng, making phenols substrates for electrophilic halogena1on, nitra1on, sulfona1on, and Friedel–Crams reac1ons • Reac1on of a phenol with strong oxidizing agents yields a quinone • Fremy's salt [(KSO3)2NO] works under mild condi1ons through a radical mechanism Quinones in Nature • Ubiquinones mediate electron-­‐transfer processes involved in energy produc1on through their redox reac1ons