* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download File - Rasapalli Research Group
George S. Hammond wikipedia , lookup
Physical organic chemistry wikipedia , lookup
Enantioselective synthesis wikipedia , lookup
Discodermolide wikipedia , lookup
Marcus theory wikipedia , lookup
1,3-Dipolar cycloaddition wikipedia , lookup
Ring-closing metathesis wikipedia , lookup
Baylis–Hillman reaction wikipedia , lookup
Tiffeneau–Demjanov rearrangement wikipedia , lookup
Elias James Corey wikipedia , lookup
Stille reaction wikipedia , lookup
Ene reaction wikipedia , lookup
Wolff rearrangement wikipedia , lookup
Petasis reaction wikipedia , lookup
Wolff–Kishner reduction wikipedia , lookup
Asymmetric induction wikipedia , lookup
Kinetic resolution wikipedia , lookup
Strychnine total synthesis wikipedia , lookup
Hydroformylation wikipedia , lookup
Chapter 17: Alcohols and Phenols Dr. Sivappa Rasapalli Chemistry and Biochemistry University of Massachusetts Dartmouth Coverage and Objectives Coverage: 1. Structure and Bonding; Physical Properties of Alcohols 2. Acidity of Alcohols and Phenols 3. Formation of Alkoxides and Phenoxides 4. Preparation of Alcohols including Review Reactions and Ring-opening Reactions of Epoxides (+ Mechanisms). 5. Reactions of Alcohols + Mechanisms Objectives: 1. Know all mechanisms discussed in class. 2. Know how to predict the relative acidities of substituted alcohols and phenols. 3. Know reactions and reagents for preparation of alcohols including review reactions. 4. Know reactions of alcohols and mechanisms. Alcohols and Phenols H3C OH Methanol CO + 2H2 CH3OH H3C OH Ethanol Oldest known synthesis: fermentation Sugar + yeast ethyl alcohol + CO2 Role of Hydroxy group in Antitumor Agents Me HO N O O HO HO O HO O HO O O Tropine (toxic alkaloid present in several plant species) O O Taxus brevifolia Epothilone B inhibits tubulin aggregation Me Me O OH O O OH Me Me O O OH (high concetrations of this sugar in the tissue of certain insects and desert plants allows them to survive under conditions of water deficiency and cold) OH NH OH OH H Trehalose OH O Me O Me Me OH S Me Geraniol H (present in oil of geranium, roses and citronella) H Cholesterol HO OH N H O H O 21 O CH3O O O O O OH N H AcO H N 10 HO Azinomycin B Streptomyces sahachiroi OH OH O N CH3 O OH O OCH3 O OH O CH3 NH2 Doxorubicin (adriamycin) OH Binds to DNA and inhibits the enzyme topoisomerase II OH O Problem 1: Classify each of the following either as a phenol, or as a 1º, 2º, 3º, or vinyl alcohol IUPAC Rules for Naming Alcohols HO 7 5 6 4 2 1 3 6-methyl-3-propyl-2-heptanol 3-hydroxycyclohexanone 6 5 4 OH 3 2 1 OH 5-methyl-2,4-hexanediol Nomenclature of Phenols Problem 2: Name the following using IUPAC system Structure and Bonding of Alcohols 17.2 Physical Properties: miscible miscible 0.6% soluble Acidity of Alcohols and Phenols Acidity of Alcohols pKa ~15.5 ~15.5 ~19.0 H2O CH3OH H3C CH OH H2O H2O H2O ~12.4 CH3 CH2OH CF3 CH2OH stronger acid + H3O+ CH3O + H3O+ + H3O + + H3O+ + + H3C CH O CH3 ~15.9 HO donating groups destabilize anion CH3 H2O H2O CH3 CH2O CF3 CH2O H3O electron withdrawing (inductive) group stabilizes the anion . Acidity of Phenols weaker acid stronger acid HO HO O O O O Acidity of Phenols HO HO NMe2 HO CF3 increasing acidity Summary of EDG/EWG Substituents on p-Bonding Systems • donating and withdrawing ability measured relative to hydrogen increasing electron donating ability increasing electron withdrawing ability F3C N C HO3S O2N + R4N O R C O F RO C Cl O Br R2N C R H Ar CH CH2 O NH C R O O C R NH2 NR2 OH OR Problem 3: Write the products of the following reactions Preparation of Alcohols: an Overview 1. Hg(OAc)2 / H2O HO 2. NaBH4 (±) H CH3 . 1. BH3 THF Syn Addition HO H - 2. OH/H2O2 (±) trans-2-methylcyclohexanol OsO4 / H2O2 or HO – dil. KMnO4 / OH 1. MCPBA + 2. H3O O H2 Pd/C H HO OH H H H OH cis-diol OH (±) Racemic Retrosynthesis R H C R OH C H:– H H R H C R' O R OH H:– C R' O Oxidation-Reduction Reactions in Organic Chemistry 19 Alcohols by Reduction of Carbonyl Compounds Reducing agents both reagents act as donors of hydride (H-) donors H Na + H B i-Butyl H – H Sodium borohydride H Li + H Al – H H Lithium aluminum hydride H Al iButyl Diisobutyl aluminum hydride Sodium borohydride Aldehydes are reduced to 1° alcohols Ketones are reduced to 2° alcohols The reagent adds the equivalent of hydride to the carbon of C=O and polarizes the group as well NaBH4 Vs LiAlH4 synthons R1 C R2 R1 C R2 OH H OH precursors + R1 = H: C O + NaBH4 R2 NaBH4 reduces aldehydes to primary alcohols O O2N H NaBH4 H H O2N OH HOCH2CH3 NaBH4 reduces ketones to secondary alcohols O H NaBH4 OH HOCH2CH3 ketones 2° alcohols NaBH4 does not react with esters or carboxylic acids HO H O NaBH4 H3CH2CO HOCH2CH3 O H3CH2CO O 23 NaBH4 Vs LiAlH4 Preparation of Diols Preparation of Diols Recap of the reduction and examples Alcohols via Grignard Grignard reactions Grignard reaction of Aldehydes and Ketones Mechanism Organometallics Order of the reactivity Grignard + Ester Grignard attacks the carbonyl and OEt ion leaves. Ketone intermediate Grignard + Acid Chloride Grignard attacks the carbonyl and Chloride ion leaves. Ketone intermediate How would you synthesize... Using an aldehyde or ketone. Using an acid chloride or ester. Grignard with epoxides Draw the mechanism and the products for the following? Problems Propose a synthetic route Grignard Reagents and Other Functional Groups in the Same Molecule Which Solvents (if any) Would be OK for Handling RMgBr?, Which substrates could be converted into RMgBr, and Subsequently reacted with CH3CHO? Combining Grignard Reactions with Other Reactions Some Reactions of Alcohols Two general classes of reaction – At the carbon of the C–O bond – At the proton of the O–H bond Dehydration of Alcohols Conversion to halides Solve the following? Tosylates are Pseudohalides! R O Cl H O S O CH3 R O H O S O O R O S O CH3 Base HO + TsO TsCl + - Na Br +- Na Br N C CN Na NH3 H2N +- OCH3 H3CO CH3 Oxidation of Alcohols Can be accomplished by inorganic reagents, such as KMnO4, CrO3, and Na2Cr2O7 or by more selective, expensive reagents Oxidation of Alcohols Typical Oxidizing Agents High-oxidation state metal salts are useful oxidizing agents, which are soluble in water. Mn(VII) Cr(VI) Chromic acid is formed when chromate (CrO4-) or dichromate (Cr2O72-) are exposed to aqueous acid which is an oxidizing agent Mechanism of Chromic Acid Oxidation Alcohol forms a chromate ester followed by elimination with electron transfer to give ketone The mechanism was determined by observing the effects of isotopes on rates Why doesn’t it stop aldehyde stage? Non-aqueous Sources of Cr(VI) Oxidation of Primary Alcohols with PCC or PDC To aldehyde: pyridinium chlorochromate (PCC, C5H6NCrO3Cl) in dichloromethane Other reagents produce carboxylic acids Oxidation of Secondary Alcohols Oxidation of Alcohols-Review Identify the products? Synthesis problems? Recognizing Oxidizing versus Reducing Agents Oxidizing Agents: Often have: Highly Oxidized Metals or Nonmetals Extra Oxygen OsO4 (+8) KMnO4 (+7) CrO4 (+6) H2CrO4 (+6) HNO3 (+5) H2O2 H2O RCO3H RCO2H O3 O2 Reducing Agents: Often involve: Hydrides in Formulas Highly Reduced Metals Metals + H2 Metals + acid LiAlH4 NaBH4 Li, Na, K, Mg, Zn, Al, etc. Pd/H2, Pt/H2, Ni/H2 etc. Zn/HCl, Fe/HCl, Zn/Hg/HCl, etc.. Protection of Alcohols Methods to Protect Alcohols Reaction with chlorotrimethylsilane in the presence of base yields an unreactive trimethylsilyl (TMS) ether The ether can be cleaved with acid or with fluoride ion to regenerate the alcohol Protection-Deprotection An example of TMS-alcohol protection in a synthesis Reactions of Phenols Ar-OH Reactions: alcohols phenols 1. HX NR 2. PX3 NR 3. dehydration NR 4. as acids more acidic 5. ester formation similar 6. oxidation NR 1. as acids 2. ester formation 3. ether formation 4. EAS Preparation and Uses of Phenols Special Reactions of Phenols Summary - Phenols Much more acidic (pKa 10) than alcohols Substitution of the aromatic ring by an electron-withdrawing group increases phenol acidity Substitution by an electron-donating group decreases acidity Oxidized to quinones Quinones are reduced to hydroquinones Spectroscopy of Alcohols and Phenols Summary - Alcohols Synthesis: – Reduction of aldehydes and ketones – Addition of Grignard reagents to aldehydes and ketones Protection of OH as TMS) ether: Reactions: – Conversion to alkyl halides – Dehydration – Oxidation Reactions of Alcohols: A Review Conversion to alkyl halides 1. Reaction with hydrogen halides 2. Reaction with thionyl chloride 3. Reaction with phosphorous trihalides Acid-catalyzed dehydration to alkenes Conversion to p-toluenesulfonate esters Conversion to ethers Conversion to esters Esters of inorganic acids Oxidation to carbonyl compounds Cleavage of vicinal diols to ketones and aldehydes Important Reactions Important Reactions Design the synthesis for the following? Retrosynthesis Problems Draw the mechanisms for the following? Important Concepts 1. 2. Alcohols are alkanols (IUPAC) - Names derived from stem prefixed by alkyl and halo substitutents. Alcohols Have Polar and Short O-H Bond • Hydroxy group is hydrophilic (hydrogen bonding) • Unusually high boiling points • Appreciable water solubility • Alkyl part is hydrophobic 3. Alcohols Are Amphoteric – • Deprotonation by bases whose conjugate acids are weaker than the alcohol. • Protonation yields alkyloxonium ions • Acidity: primary > secondary > tertiary alcohol • Electron withdrawing substituents increase acidity. 4. Reverse Polarization - ie – Conversion of the alkyl group in a haloalkane, Cδ+-Xδ-, into its nucleophilic analog in an organometallic compound, C δ--Mδ+. 5. Aldehyde and Ketone Carbonyl Carbons are Electrophilic - C=O carbon is subject to attack by hydride hydrogens or organometallic alkyl groups. Aqueous workup yields alcohols. 6. Oxidation of Alcohols – Yields aldehydes and ketones (Chromium IV reagents). 7. Protection of alcohols is required in order to mask them participating in unwanted reactions. 8. Phenols are acidic in nature, and can be oxidized to quinones. 9. Alcohols upon reaction with HX provide alkyl halides. 10. An alkyl halide = an alkyl group with a halogen 11. Haloalkane Properties – Strongly affected by the C-X bond polarization and the polarizability of X. 12. Alcohols and alkyl halides are produced via each other, and also they participate in some common type of reactions . 13. Nucleophilic substitution and eliminations – When a lone pair of electrons on a reagent attacks a positively polarized (or electrophilic) center. If a substituent is replaced, the reaction is termed a nucleophilic substitution. The substituent replaced is called the leaving group. If the neucleophile picks up a proton and leads to elimination of leaving group on adjacent atom it is called elimination.