Chapter 20: Introduction to Carbonyl Chemistry; Organometallic Reagents; Oxidation and Reduction

I. II. III. IV. V. VI. VII. VIII. IX. X. XI. XII. XIII. XIV. XV. XVI. Introduction (20.1) General Reactions of Carbonyl Compounds (20.2) Preview of Oxidation and Reduction (20.3) Reduction of Aldehydes and Ketones (20.4) Stereochemistry of Carbonyl Reduction (20.5) Enantioselective Carbonyl Reductions (20.6) Reduction of Carboxylic Acids and Their Derivatives (20.7) Oxidation of Aldehydes (20.8) Organometallic Reagents (20.9) Reactions of Organometallic Reagents with Aldehydes and Ketones (20.10) Retrosynthetic Analysis of Grignard Products (20.11) Protecting Groups (20.12) Reaction of Organometallic Reagents with Carboxylic Acid Derivatives (20.13) Reaction of Organometallic Reagents with Other Compounds (20.14) E,F-Unsaturated Carbonyl Compounds (20.15) Synthesis (20.17)
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I. Introduction
O C
carbonyl group

Two classes of organic molecules contain the carbonyl group.

O C R H R
aldehyde
O R C OH R O C Cl R O C

O C R'
ketone
O OR' R C NRR'

carboxylic acid

acid chloride

ester

amide

Carboxylic acid derivatives have good leaving groups.
2

‡ Carbonyl carbon is electrophilic, susceptible to nucleophilic attack. ‡ Trigonal, planar geometry makes nucleophilic attack at carbonyl carbon sterically feasible.
3

II. General Reactions of Carbonyl Compounds
A. Nucleophilic Addition to Aldehydes and Ketones

Aldehydes are more susceptible to nucleophilic attack than ketones.

4

Nucleophilic Substitution of RCOZ ‡ Nucleophilic substitution of Nu for Z ‡ Nucleophilic acyl substitution reaction 5 .B.

Aldehydes and ketones do not undergo nucleophilic substitution: R L u- R u L X + L R u - L = H.Nucleophilic acyl substitution reactivity parallels leaving group ability. R 6 .

7 . Reduction: decrease in the number of C-Z bonds or increase in the number of C-H bonds. ‡ Aldehydes and ketones can be either oxidized or reduced. ‡ Carboxylic acids and derivatives are already highly oxidized.III. Preview of Oxidation and Reduction Oxidation: increase in the number of C-Z bonds or decrease in the number of C-H bonds.

Oxidation of aldehydes O R C [O] O R C O 8 aldehyde carboxylic acid .Three useful oxidation and reduction reactions: 1. Reduction of carboxylic acid derivatives O C R Z R aldehyde 1o alcohol [ ] O C O + R C 3. Reduction of aldehydes and ketones O C R (R') O [ ] R C (R') aldehyde or ketone 1o or 2o alcohol 2.

IV. Reduction of Aldehydes and Ketones A. Reductions with Metal Hydrides O C C 3C 2 NaB C 3O O 4 C 3C 2 C propionaldehyde 1-propanol 9 .

10 .+ H+) to C= Tbond.O C C 3 1) iAl O 4 C C 3 2) 2O 3 C C 3 B. Mechanism of Hydride Reduction Net Result: addition of H (H:.

C. Catalytic Hydrogenation of Aldehydes and Ketones O 2 O Pd/C C C 3C 2 C 3C 2 C 2 O Pd/C O 11 .

Stereochemistry of Carbonyl Reduction O C C 3 NaB O 4 C 2C 3 C 3O C C 3 C 2C 3 + (R)-2-butanol When a chiral alcohol results from reaction of achiral reactants. O C C 3 C 2C 3 (S)-2-butanol Why? 12 .V. the product is a racemic mixture.

13 . CBS Reagents ‡ (S)-CBS reagent generally gives alcohol as major product.VI. Enantioselective Carbonyl Reductions A. ‡ ( )-CBS reagent generally gives S alcohol as major product.

B. Biological Reductions Biological reductions are 100% enantioselective and most use NADH as reducing agent. C R H C H H H(R') enzyme R C H(R') H H C H R R NADH NAD+ 14 .

OH R C R' H NAD NADH O R C R' 15 .O C H 3C CO2H L H C H 3C OH CO2H pyruvic acid (S)-lactic acid DH = lactate dehydrogenase NAD+ is a biological oxidizing agent that converts alcohols into carbonyl compounds.

Reduction of Carboxylic Acids and Their Derivatives A. Reducing Agents O Li -AlH4 Al H Li H Al. Reduction of Acid Chlorides and Esters 16 .O O lithium aluminum hydride most reactive diisobutylaluminum hydride (DIBA -H) less reactive lithium tri-t-butoxyaluminum hydride less reactive B.VII.

+ CH3OH + CH3OH 17 .

Mechanism for Reduction of Acid Chlorides and Esters by Metal Hydride Reagents 18 .

C. Reduction of Carboxylic Acids and Amides Carboxylic acids are reduced only by iAlH4. 19 . Amides are reduced to amines by iAlH4.

Mechanism for Reduction of an Amide with LiAlH4 20 .

Oxidation of Aldehydes O C CH3CH2 O C H AgO 2 NH4OH CrO3 O C CH3CH2 O C OAg OH Cr3 H H2SO 4 H2O NH4 Additional oxidizing reagents: N 2Cr2O7 in aqueous H2SO4 K2Cr2O7 in aqueous H2SO4 KMnO4 in aqueous HO- 21 .VIII.

‡ Organometallic reagents are nucleophilic.IX. 22 . Organometallic Reagents R-Li organolithium reagents R-M -X Grignard reagents R Cu.Li+ organocuprates C M C M C H- M H+ ‡ Polar carbon-metal bond ‡ Anionic carbon ‡ Organometallic reagents are basic.

Grignard Reagents CH CH Cl + M Et CH CH M Cl Ether solvents stabilize Grignard reagents. Preparation of Organometallic Reagents 1.A. 23 . Organolithium Reagents CH CH Cl + Li CH CH Li + LiCl 2.

Acetylide Anions 24 . Organocuprates B.3.

7 CH M r + H CH CH pKa = 55 + CH M r pKa = 15.5 O CH C C Na + H CCH +CH C CH + Na 2CCH pKa = 4.8 pKa = 25 CH CH2CH2CH2-Li 2O CH CH2CH2CH2- + Li+ -OD 25 . Organometallic Reagents as Bases Li + H H pKa = 50 H + Li+ .C.H pKa = 15.

Reactions with Carboxylic Acid Derivatives 3.C. Organometallic Reagents as Nucleophiles 1. Reactions with Aldehydes and Ketones 2. Reactions with Other Electrophiles 26 .

General Features Mechanism: ‡ Net addition of R + H to C=O ‡ Similar mechanism for organolithium reagents and acetylide anions. ‡ Used to prepare 1°. 2° and 3° alcohols. 27 . Reactions of Organometallic Reagents with Aldehydes and Ketones A.X.

28 . Synthesis of Alcohols ‡ Chiral 2° and 3° alcohol products are racemic mixtures.B.

XI. Retrosynthetic Analysis of Grignard Products A. Retrosynthetic Analysis OH C CH CH H 2 1 O CH CH M X + C H O M X + CH CH C H Disconnect at bonds to C-OH to identify carbonyl and Grignard reactants. Synthesis 1: O CH CH M X + C H OC CH CH H H O OH C CH CH H 29 .

O O H + CH M r O O+ +M pKa = 18 + CH r pKa = 55 30 .Synthesis 2: O M X + CH CH C H OC CH CH H H O OH C CH CH H XII. Protecting Groups Addition of organometallic reagents to carbonyl compounds fails when carbonyl reactant also contains OH or NH bonds.

31 .Use a protecting group to circumvent this problem: O OH CH3 Cl Si C(CH3)3 CH3 NH N O OSiR3 1) CH3 gBr 2) H2O HO OH CH3 TBAF H2O HO OSiR3 CH3 ‡ Step 1: Put on protecting group. ‡ Step 3: Remove the protecting group. ‡ Step 2: Do the desired reaction.

Reaction of Organometallic Reagents with Carboxylic Acid Derivatives A. Reaction of RLi and RMgX with Esters and Acid Chlorides 32 .XIII.

Mechanism: 33 .

Reaction of R2CuLi with Acid Chlorides Acid chlorides react with organocuparates: O C Cl 1) (CH ) CuLi ) H O O C CH Esters do not react: O C OCH 1) (CH ) CuLi ) H O No Reaction 34 .B.

35 .IV. Grignard Reagents with CO2 B. RMgX. R2Cu i) open epoxide rings to form alcohols. Reaction with Epoxides Organometallic reagents (R i. Reaction of Organometallic Reagents with Other Compounds A.

36 . E.SN2 reaction of organometallic reagents occurs at less substituted carbon: XV.F-unsaturated carbonyl compounds are electrophilic at carbonyl carbon and F-carbon.F-Unsaturated Carbonyl Compounds OH C H + - C C H + resonance hybrid E.

2-Addition Mechanism: 37 .A. 1.

B.4-Addition Mechanism: 38 . 1.

Reactions of E.F-Unsaturated Carbonyl Compounds with Organometallic Reagents RLi and RM X react by 1.2 addition: OH CH3 + enantiomer O 1) CH3M Br 2) H2O OH O CH3 1) 2) H2O Li CH3 + enantiomer 39 .C.

Retrosynthetic Analysis OH OH O CH3CH2 gBr CH3CH2OH 40 .4 addition: 1) (CH )2CuLi O 2) H2O O H C XVII. cyclohexanol. and appropriate reagents.Organocupratres react by 1. Synthesis Synthesize ethylcyclohexane from ethanol. A.

Synthesis CH CH2OH 1) PBr 2) M /Et2O OH PCC O 1) CH CH2M Br 2) H2O   OH CH2CH H2SO4 H2 Pd/C PCC: pyridinium chlorochromate O O Cr Cl O N H 41 .B.

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