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

CO + 2H 2  CH 3 OH Oldest known synthesis: fermentation Sugar + yeast  ethyl alcohol + CO 2

Role of Hydroxy group in Antitumor Agents

Problem 1: Classify each of the following either as a phenol, or as a 1 º, 2 º, 3 º, or vinyl alcohol

IUPAC Rules for Naming Alcohols 3-hydroxycyclohexanone

Nomenclature of Phenols Problem 2: Name the following using IUPAC system

Structure and Bonding of Alcohols

17.2 Physical Properties: miscible 0.6% soluble

Acidity of Alcohols and Phenols

Acidity of Alcohols

Acidity of Phenols

Summary of EDG/EWG Substituents on  -Bonding Systems donating and withdrawing ability measured relative to hydrogen

Problem 3: Write the products of the following reactions

Preparation of Alcohols: an Overview

Retrosynthesis H: – CRH OHOHOHOH H C R H O CRH OHOHOHOH R' C R R' O

Oxidation-Reduction Reactions in Organic Chemistry 19

Alcohols by Reduction of Carbonyl Compounds

Sodium borohydride Na + – B HHHH Lithium aluminum hydride Li + – Al HHHH both reagents act as donors of hydride (H-) donors Diisobutyl aluminum hydride Al iButyli-ButylH Reducing agents

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

NaBH 4 Vs LiAlH 4 23 synthonsprecursors = NaBH 4 reduces aldehydes to primary alcohols NaBH 4 reduces ketones to secondary alcohols NaBH 4 does not react with esters or carboxylic acids

NaBH 4 Vs LiAlH 4

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

Two general classes of reaction – At the carbon of the C–O bond – At the proton of the O–H bond Some Reactions of Alcohols

Dehydration of Alcohols

Conversion to halides

Solve the following?

Tosylates are Pseudohalides!

Oxidation of Alcohols Can be accomplished by inorganic reagents, such as KMnO 4, CrO 3, and Na 2 Cr 2 O 7 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. Chromic acid is formed when chromate (CrO 4 - ) or dichromate (Cr 2 O 7 2- ) are exposed to aqueous acid which is an oxidizing agent Mn(VII) Cr(VI)

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, C 5 H 6 NCrO 3 Cl) 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 Reducing Agents: Often involve: Hydrides in Formulas Highly Reduced Metals Metals + H2 Metals + acid OsO4 (+8) KMnO4 (+7) CrO4 (+6) H2CrO4 (+6) HNO3 (+5) H2O2 H2O RCO3H RCO2H O3 O2 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: alcoholsphenols 1.HXNR 2.PX 3 NR 3.dehydrationNR 4.as acidsmore acidic 5.ester formationsimilar 6.oxidationNR Reactions of Phenols Ar-OH 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 (pK a  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

Design the synthesis for the following?

Retrosynthesis Problems

Draw the mechanisms for the following?

Important Concepts 1.Alcohols are alkanols (IUPAC) - Names derived from stem prefixed by alkyl and halo substitutents. 2. 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, C δ + -X δ -, into its nucleophilic analog in an organometallic compound, C δ - -M δ +. 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.