Created by Professor William Tam & Dr. Phillis Chang Ch Chapter 12 Alcohols from Carbonyl Compounds Oxidation-Reduction & Organometallic Compounds

Ch About The Authors These PowerPoint Lecture Slides were created and prepared by Professor William Tam and his wife, Dr. Phillis Chang. Professor William Tam received his B.Sc. at the University of Hong Kong in 1990 and his Ph.D. at the University of Toronto (Canada) in He was an NSERC postdoctoral fellow at the Imperial College (UK) and at Harvard University (USA). He joined the Department of Chemistry at the University of Guelph (Ontario, Canada) in 1998 and is currently a Full Professor and Associate Chair in the department. Professor Tam has received several awards in research and teaching, and according to Essential Science Indicators, he is currently ranked as the Top 1% most cited Chemists worldwide. He has published four books and over 80 scientific papers in top international journals such as J. Am. Chem. Soc., Angew. Chem., Org. Lett., and J. Org. Chem. Dr. Phillis Chang received her B.Sc. at New York University (USA) in 1994, her M.Sc. and Ph.D. in 1997 and 2001 at the University of Guelph (Canada). She lives in Guelph with her husband, William, and their son, Matthew.

Ch Structure of the Carbonyl Group  Carbonyl compounds AldehydeKetone Carboxylic acidEsterAmide

Ch  Structure ●Carbonyl carbon: sp 2 hybridized ●Planar structure

Ch  Polarization and resonance structure

Ch A.Reactions of Carbonyl Compounds with Nucleophiles  One of the most important reactions of carbonyl compounds is nucleophilic addition to the carbonyl group

Ch  Two important nucleophiles: ●Hydride ions (from NaBH 4 and LiAlH 4 ) ●Carbanions (from RLi and RMgX)  Another important reactions:

Ch Oxidation-Reduction Reactions in Organic Chemistry  Reduction of an organic molecule usually corresponds to increasing its hydrogen content or decreasing its oxygen content carboxylic acid aldehyde oxygen content decreases hydrogen content decreases

Ch  The opposite reaction of reduction is oxidation. Increasing the oxygen content of on organic molecule or decreasing its hydrogen content is oxidation lowest oxidation state highest oxidation state

Ch  Oxidation of an organic compound may be more broadly defined as a reaction that increases its content of any element more electronegative than carbon

Ch A.Oxidation States in Organic Chemistry  Rules ●For each C–H (or C–M) bond  -1 ●For each C–C bond  0 ●For each C–Z bond  +1 (where M = electropositive element and is equivalent to H, e.g. Li, K, etc.; Z = electronegative heteroatom, e.g. OR, SR, PR 2, halogen, etc.)  Calculate the oxidation state of each carbon based on the number of bonds it is forming to atoms more (or less) electronegative than carbon

Ch  Examples Bonds to C: 4 to H = (- 1) x 4 = - 4 Total = - 4 Oxidation state of C = - 4

Ch  Examples Bonds to C: 3 to H = - 3 Total = - 2 Oxidation state of C = to O = +1

Ch  Examples Bonds to C: 2 to H = - 2 Total = 0 Oxidation state of C = 0 2 to O = +2

Ch  Examples Bonds to C: 1 to H = - 1 Total = +2 Oxidation state of C = +2 3 to O = +3

Ch  Overall order lowest oxidation state of carbon highest oxidation state of carbon oxidation state

Ch Alcohols by Reduction of Carbonyl Compounds (1 o alcohol)

Ch A.Lithium Aluminum Hydride  LiAlH 4 (LAH) ●Not only nucleophilic, but also very basic ●React violently with H 2 O or acidic protons (e.g. ROH) ●Usually reactions run in ethereal solvents (e.g. Et 2 O, THF) ●Reduces all carbonyl groups

Ch  Examples

Ch  Mechanism Esters are reduced to 1 o alcohols

Ch B.Sodium Borohydride  NaBH 4 ●less reactive and less basic than LiAlH 4 ●can use protic solvent (e.g. ROH) ●reduces only more reactive carbonyl groups (i.e. aldehydes and ketones) but not reactive towards esters or carboxylic acids

Ch  Examples

Ch  Mechanism Aldehydes are reduced to 1° alcohols & ketones are reduced to 2° alcohols

Ch C.Overall Summary of LiAlH 4 and NaBH 4 Reactivity ease of reduction reduced by NaBH 4 reduced by LiAlH 4

Ch Oxidation of Alcohols 4A.Oxidation of Primary Alcohols to Aldehydes  The oxidation of aldehydes to carboxylic acids in aqueous solutions is easier than oxidation of 1 o alcohols to aldehydes  It is, therefore, difficult to stop the oxidation of a 1 o alcohol to the aldehyde stage unless specialized reagents are used

Ch  PCC oxidation ●Reagent

Ch  PCC oxidation

Ch B.Oxidation of Primary Alcohols to Carboxylic Acids  Chromic acid (H 2 CrO 4 ) usually prepared by Jones reagent

Ch  Jones oxidation ●Reagent: CrO 3 + H 2 SO 4 ●A Cr(VI) oxidant

Ch D.Mechanism of Chromate Oxidations  Formation of the Chromate Ester

Ch  The oxidation step

Ch E.A Chemical Test for Primary and Secondary Alcohols

Ch F.Spectroscopic Evidence for Alcohols  Alcohols give rise to broad O-H stretching absorptions from 3200 to 3600 cm -1 in IR spectra  The alcohol hydroxyl hydrogen typically produces a broad 1 H NMR signal of variable chemical shift which can be eliminated by exchange with deuterium from D 2 O  Hydrogen atoms on the carbon of a 1 o or 2 o alcohol produce a signal in the 1 H NMR spectrum between  3.3 and  4.0 ppm that integrates for 2 and 1 hydrogens, respectively  The 13 C NMR spectrum of an alcohol shows a signal between  50 and  90 ppm for the alcohol carbon

Ch Organometallic Compounds  Compounds that contain carbon-metal bonds are called organometallic compounds

Ch Preparation of Organolithium & Organomagnesium Compounds 6A.Organolithium Compounds  Order of reactivity of RX ●RI > RBr > RCl  Preparation of organolithium compounds

Ch  Example

Ch B.Grignard Reagents  Order of reactivity of RX ●RI > RBr > RCl  Preparation of organomagnesium compounds (Grignard reagents)

Ch  Example

Ch Reactions of Organolithium and Organomagnesium Compounds 7A.Reactions with Compounds Con- taining Acidic Hydrogen Atoms  Grignard reagents and organolithium compounds are very strong bases

Ch  Examples ●As base

Ch  Examples ●As base A good method for the preparation of alkynylmagnesium halides

Ch B.Reactions of Grignard Reagents with Epoxides (Oxiranes)  Grignard reagents react as nucleophiles with epoxides (oxiranes), providing convenient synthesis of alcohols

Ch  Via S N 2 reaction

Ch  Also work for substituted epoxides

Ch C.Reactions of Grignard Reagents with Carbonyl Compounds

Ch  Mechanism

Ch Alcohols from Grignard Reagents

Ch  R, R’ = H (formaldehyde) ●1 o alcohol

Ch  R = alkyl, R’ = H (higher aldehydes) ●2 o alcohol

Ch  R, R’ = alkyl (ketone) ●3 o alcohol

Ch  Reaction with esters ●3 o alcohol

Ch  Mechanism

Ch  Examples

Ch  Examples

Ch  Examples

Ch  Examples

Ch A.How to Plan a Grignard Synthesis  Synthesis of

Ch  Method 1 ●Retrosynthetic analysis ●Synthesis

Ch  Method 2 ●Retrosynthetic analysis ●Synthesis

Ch  Method 3 ●Retrosynthetic analysis ●Synthesis

Ch B.Restrictions on the Use of Grignard Reagents  Grignard reagents are useful nucleophiles but they are also very strong bases  It is not possible to prepare a Grignard reagent from a compound that contains any hydrogen more acidic than the hydrogen atoms of an alkane or alkene

Ch  A Grignard reagent cannot be prepared from a compound containing an –OH group, an –NH– group, an –SH group, a –CO 2 H group, or an –SO 3 H group  Since Grignard reagents are powerful nucleophiles, we cannot prepare a Grignard reagent from any organic halide that contains a carbonyl, epoxy, nitro, or cyano (–CN) group

Ch  Grignard reagents cannot be prepared in the presence of the following groups because they will react with them:

Ch C.The Use of Lithium Reagents  Organolithium reagents have the advantage of being somewhat more reactive than Grignard reagents although they are more difficult to prepare and handle

Ch D.The Use of Sodium Alkynides  Preparation of sodium alkynides  Reaction via ketones (or aldehydes)

Ch Protecting Groups

Ch  Retrosynthetic analysis  However

Ch  Need to “protect” the –OH group first

Ch  Synthesis

Ch  END OF CHAPTER 12 