17.2 How Aldehydes and Ketones React (Part I) 1 ++ R = alkyl or aryl (C) Y = alkyl, aryl or H (class II) (No leaving group) -- Electron rich (Lewis base, Nu) Electron deficient (Lewis acid, E + ) Main Menu

Class I vs. Class II Carbonyl Compounds 2 Class II Y = NR’ 2 (amide) = OR’ (ester, carboxylic acid) = OCOR’ (acid anhydride) = X (acyl halide) Class I Y = H (aldehyde) = R’’ (ketone) H-H (pKa = 35) R-H (pKa = 50) Hydride (H - ) and carboanion are not leaving groups

Relative Reactivity of Class I and Class II Carbonyl Compounds 3 acyl halide >> >> >> acid anhydride ketone aldehyde esteramide Esters and amides are more stable than ketones and aldehydes due to their resonance stabilization. H R’

Nucleophilic Addition (Class II) 4 1. General mechanism in basic condition: 2. General mechanism in acidic condition:

Important pKa to Remember 5 Names Acids H-Z Approx. pKa Conjugate Base, :Z General Roles of :Z Alkane (2°)51 Base as Li + salt Nucleophile as Grignard reagent Amine38Base and Nucleophile Hydrogen35 Base in NaH, CaH 2 Nucleophile in LiAlH 4, NaBH 4 Alcohol water Often as a base but can be a nucleophile Ammonium10-11 Weak base, but can be a nucleophile Thiol10-11Nucleophile Carboxylic Acid 4-5Weak base, poor leaving group Hydrochloric Acid -7Leaving group, poor nucleophile

Types of Nucleophile for Class II Carbonyl Groups 6 1. Carbon as the nucleophilic atom pKa = 50 Basic condition 2. Hydrogen as the nucleophilic atom carboanion hydride Mostly basic condition 3. Nitrogen as the nucleophilic atom 1° and 2° amines Mostly acidic condition 4. Oxygen as the nucleophilic atom Acidic condition 1° alcohols pKa = 25 Acetylide ion

Carbon as the Nucleophilic Atom: Grignard Reagents 7 Carboanions are highly reactive. pKa = 50 Hard to find a base to do the deprotonation. carboanion Formation of Grignard reagent X = Cl, Br or I THF or Et 2 O THF: tetrahydrofuran Et 2 O: diethyl ether The carbonanions can be stabilized.

Reactions of Grignard Reagents 8

9 3° alcohols 2° alcohols

Reactions of Grignard Reagents 10 1° alcohols (one extra carbon) Carboxylic acid 1° alcohols (two extra carbons)

Reactions of Grignard Reagents with Esters 11 1 mol. 0.5 mol. 2 mol. 1 mol.

Reactions of Grignard Reagents with Esters 12 Why two equivalents of Grignard reagent are needed? A ketone (more reactive than ester)

Carbon as the Nucleophilic Atom: Acetylide Ions 13 pKa = 50 carboanion pKa = 25 Acetylide ion Why the pKa of acetylide is much lower? 2P x 2P z 2P y 2S The radius of 2S orbital is smaller than the radius of 2P orbitals. Order for the radius of hybridized orbitals: SP 3 > SP 2 > SP Order for the electronegativity of hybridized orbitals: SP 3 < SP 2 < SP Order for the acidity of H’s of hybridized orbitals: SP 3 < SP 2 < SP pKa = 40

Reactions of Carbonyl Groups with Acetylide Ions 14 pKa = 25 Acetylide ion pKa = 38

Carbon as the Nucleophilic Atom: Cyanide 15 Hydrogen cyanide is weakly acidic. pKa = 9.1 Cyanide is highly poisonous. cyanide Addition of cyanide to aldehydes or ketones: HCl Stable in acidic condition but unstable in basic condition. H +, H 2 O heat H 2, Pt/C  -hydroxy carboxylic acid

Hydrogen as the Nucleophilic Atom: Hydride Reagents 16 Reagents that can provide hydrides as nucleophiles: Theoretically, one molecule of LiAlH 4 or NaBH 4 can provide four hydrides. Lithium aluminum hydride LiAlH 4 NaBH 4 NaHCaH 2 Sodium boroydride Reagents that can provide hydrides as bases: Diisobutylaluminum hydride (DIBAL)

Reactions of Aldehydes and Ketones with Hydride Reagents 17 General Reactions: Examples: 1)LiAlH 4 or NaBH 4 2)H 2 O

General Mechanism for the Reduction of Aldehydes and Ketones Using Hydride Reagents 18 -- -- The three H’s can still act as hydrides. Repeat 3 times H2OH2O

Comparison of LiAlH 4, DIBAL and NaBH 4 19 Relative Reactivity > LiAlH 4 DIBALNaBH 4 > AmideEster Carboxylic acid KetoneAldehyde LiAlH 4 yes DIBALnoyes? NaBH 4 no yes NaBH 3 CN > Stable in weak acid Unstable in weak acid

Reduction of Ester with LiAlH 4 20 General reaction 1)LiAlH 4 2)H 2 O Mechanism H2OH2O Reduction cannot stop at the stage of aldehyde

Reduction of Carboxylic Acids with LiAlH 4 21 General reaction 1)LiAlH 4 2)H 2 O Mechanism H2OH2O Reduction cannot stop at the stage of aldehyde

Reduction of Amides with LiAlH 4 22 General reaction 1)LiAlH 4 2)H 2 O Mechanism H2OH2O

Reduction of Ester with DIBAL 23 General reaction 1)DIBAL, -78°C 2)H 2 O, -78°C 1)DIBAL, -78° - 0°C 2)H 2 O, 0°C Reduction can stop at the stage of aldehyde Control of temperature is important for the reduction to stop at the stage of aldehyde.

Examples 24

Examples 25

Examples 26 No reaction

Selective Reduction 27 In most of the cases, hydride reducing reagents cannot reduce C=C.

28 Learning Check 1. What could be the reagent needed for this transformation? 2. What could be reagent needed for this transformation?

29 Learning Check 3. What could be the product for the following reaction? 4. What could be the product for the following reaction?

30 Learning Check 6. What could be the product for the following reaction? 5. What could be the reagent needed for the following reaction?

31 Learning Check 7. What could be the product for the following reaction?

32 Learning Check Main Menu 8. What could be the product for the following reaction?