Oxidation-Reduction & Organometallic Chapter 12 Alcohols from Carbonyl Compounds Oxidation-Reduction & Organometallic Compounds © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. 1. Structure of the Carbonyl Group Carbonyl compounds Aldehyde Ketone Carboxylic acid Ester Amide © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Structure Carbonyl carbon: sp2 hybridized Planar structure © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Polarization and resonance structure © 2014 by John Wiley & Sons, Inc. All rights reserved.

1A. Reactions of Carbonyl Compounds with Nucleophiles One of the most important reactions of carbonyl compounds is nucleophilic addition to the carbonyl group © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Two important nucleophiles: Hydride ions (from NaBH4 and LiAlH4) Carbanions (from RLi and RMgX) Another important reaction: © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. 2. Oxidation-Reduction Reactions in Organic Chemistry Reduction of an organic molecule usually corresponds to increasing its hydrogen content or decreasing its oxygen content oxygen content decreases hydrogen content increases carboxylic acid aldehyde © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. The opposite reaction of reduction is oxidation. Increasing the oxygen content of an organic molecule or decreasing its hydrogen content is oxidation lowest oxidation state highest oxidation state © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Oxidation of an organic compound may be more broadly defined as a reaction that increases its content of any element more electronegative than carbon © 2014 by John Wiley & Sons, Inc. All rights reserved.

2A. 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, PR2, halogen, etc.) © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Calculate the oxidation state of each carbon based on the number of bonds it is forming to atoms more (or less) electronegative than carbon © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Examples Bonds to C: 4 to H = (- 1) x 4 = - 4 Total = - 4 Oxidation state of C = - 4 © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Examples Bonds to C: 3 to H = - 3 1 to O = +1 Total = - 2 Oxidation state of C = - 2 © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Examples Bonds to C: 2 to H = - 2 2 to O = +2 Total = 0 Oxidation state of C = 0 © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Examples Bonds to C: 1 to H = - 1 3 to O = +3 Total = +2 Oxidation state of C = +2 © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Overall order oxidation state lowest oxidation state of carbon highest oxidation state of carbon © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. 3. Alcohols by Reduction of Carbonyl Compounds (1o alcohol) © 2014 by John Wiley & Sons, Inc. All rights reserved.

3A. Lithium Aluminum Hydride LiAlH4 (LAH) Not only nucleophilic, but also very basic Reacts violently with H2O or acidic protons (e.g. ROH) Usually reactions run in ethereal solvents (e.g. Et2O, THF) Reduces all carbonyl groups © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Examples © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Mechanism Esters are reduced to 1o alcohols © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. 3B. Sodium Borohydride NaBH4 less reactive and less basic than LiAlH4 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 © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Examples © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Mechanism Aldehydes are reduced to 1° alcohols & ketones are reduced to 2° alcohols © 2014 by John Wiley & Sons, Inc. All rights reserved.

3C. Overall Summary of LiAlH4 and NaBH4 Reactivity reduced by LiAlH4 reduced by NaBH4 ease of reduction © 2014 by John Wiley & Sons, Inc. All rights reserved.

3D. Reduction of Alkyl Halides to Hydrocarbons: RX  RH © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. 4. Oxidation of Alcohols © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved.

4A. A Common Mechanistic Theme Alcohol oxidation by elimination A 1° or 2° alcohol reacts with a reagent that installs a leaving group (LG) on the alcohol oxygen atom In an elimination step, a base removes a hydrogen from the alcohol carbon, the bond forms, and the leaving group departs, resulting in the oxidized product © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Aldehyde Aldehyde hydrate Carboxylic acid © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. 4B. Swern Oxidation Swern oxidation of a 1° alcohol to an aldehyde Swern oxidation of a 2° alcohol to a ketone © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Mechanism of the Swern oxidation © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Mechanism of the Swern oxidation (Cont’d) © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. 4C. Chromic Acid (H2CrO4) Oxidation Chromic acid (H2CrO4) usually prepared by [CrO3 or Na2Cr2O7] + aqueous H2SO4 Jones reagent © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Jones oxidation Reagent: CrO3 + aqueous H2SO4 A Cr(VI) oxidant © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Mechanism of chromate acid oxidations Formation of the chromate ester © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. The oxidation step © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. A Chemical Test for Primary and Secondary Alcohols © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. 4D. Pyridinium Chlorochromate (PCC) PCC oxidation Reagent © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. PCC oxidation © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. 4E. Potassium Permanganate (KMnO4) © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. 5. Organometallic Compounds Compounds that contain carbon-metal bonds are called organometallic compounds © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. 6. Preparation of Organolithium & Organomagnesium Compounds 6A. Organolithium Compounds Preparation of organolithium compounds Order of reactivity of RX RI > RBr > RCl © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Example © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. 6B. Grignard Reagents Preparation of organomagnesium compounds (Grignard reagents) Order of reactivity of RX RI > RBr > RCl © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Example © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. 7. Reactions of Organolithium and Organomagnesium Compounds 7A. Reactions with Compounds Containing Acidic Hydrogen Atoms © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Grignard reagents and organolithium compounds are very strong bases © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Examples As base © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Examples As base A good method for the preparation of alkynylmagnesium halides © 2014 by John Wiley & Sons, Inc. All rights reserved.

7B. Reactions of Grignard Reagents with Epoxides (Oxiranes) Grignard reagents react as nucleophiles with epoxides (oxiranes), providing convenient synthesis of alcohols © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Via SN2 reaction © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Also works for substituted epoxides © 2014 by John Wiley & Sons, Inc. All rights reserved.

7C. Reactions of Grignard Reagents with Carbonyl Compounds © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Mechanism © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. 8. Alcohols from Grignard Reagents © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. R, R’ = H (formaldehyde) 1o alcohol © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. R = alkyl, R’ = H (higher aldehydes) 2o alcohol © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. R, R’ = alkyl (ketone) 3o alcohol © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Reaction with esters 3o alcohol © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Mechanism © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Examples © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Examples © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Examples © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Examples © 2014 by John Wiley & Sons, Inc. All rights reserved.

8A. How to Plan a Grignard Synthesis Synthesis of © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Method 1 Retrosynthetic analysis Synthesis © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Method 2 Retrosynthetic analysis Synthesis © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Method 3 Retrosynthetic analysis Synthesis © 2014 by John Wiley & Sons, Inc. All rights reserved.

8B. 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 © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. A Grignard reagent cannot be prepared from a compound containing an –OH group, an –NH– group, an –SH group, a –CO2H group, or an –SO3H 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 © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Grignard reagents cannot be prepared in the presence of the following groups because they will react with them: © 2014 by John Wiley & Sons, Inc. All rights reserved.

8C. 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 © 2014 by John Wiley & Sons, Inc. All rights reserved.

8D. The Use of Sodium Alkynides Preparation of sodium alkynides Reaction via ketones (or aldehydes) © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. 9. Protecting Groups © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Retrosynthetic analysis However © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Need to “protect” the –OH group first © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. Synthesis © 2014 by John Wiley & Sons, Inc. All rights reserved.