17.4 How Aldehydes and Ketones React (Part III) Main Menu 17.4 How Aldehydes and Ketones React (Part III) Electron rich (Lewis base, Nu) d- d+ Electron deficient (Lewis acid, E+) R = alkyl or aryl (C) Y = alkyl, aryl or H (class II) (No leaving group)

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

Important pKa to Remember Names Acids H-Z Approx. pKa Conjugate Base, :Z General Roles of :Z Alkane (2°) 51 Base as Li+ salt Nucleophile as Grignard reagent Amine 38 Base and Nucleophile Hydrogen 35 Base in NaH, CaH2 Nucleophile in LiAlH4, NaBH4 Alcohol water 15-16 Often as a base but can be a nucleophile Ammonium 10-11 Weak base, but can be a nucleophile Thiol Nucleophile Carboxylic Acid 4-5 Weak base, poor leaving group Hydrochloric Acid -7 Leaving group, poor nucleophile

Types of Nucleophile for Class II Carbonyl Groups 1. Carbon as the nucleophilic atom Basic condition pKa = 25 Acetylide ion pKa = 50 carboanion 2. Hydrogen as the nucleophilic atom 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

Oxygen as the Nucleophilic Atom pKa of alcohol. pKa = 15-16 pKa = -2 1° and 2° Alcohols function as weak acids, weak bases or nucleophiles. 3° Alcohols function as weak acids or weak bases.

Reactions of Aldehydes and Ketones with Alcohols 2° and 3° Alcohols are too hindered to react. General reaction with primary alcohols: H+ 2 1° Alcohols Ketal or acetal General reaction with water: H+ Geminal diol (gem-diol)

Reactions of Aldehydes and Ketones with Water Example: H+ Mechanism:

Reactions of Aldehydes and Ketones with Alcohols Examples: H+ 2 H+ 2 H+ 1

Reactions of Aldehydes and Ketones with Alcohols Mechanism: hemiacetal acetal

Application of Ketal or Acetal Synthesis using protecting group ? LiAlH4 or DIBAL will reduce the ketone as well. Ketal as the protecting group for ketone: Ketals like ethers are relatively stable in basic condition.

Mechanism for the Formation of Cyclic Ketal

More Examples on the Use of Protecting Groups ? SOCl2 (PBr3 or PCl3) will convert carboxylic acids into acyl halides as well. Ester as the protecting group for carboxylic acid: Ester will not react with SOCl2 (from compound 3 to compound 4).

More Examples on the Use of Protecting Groups Amines under acidic condition may turn into an EWG in the form of ammoniim ions. Amide as the protecting group for amine: Amide in compound 3 will act as EGD..

Formation of Cyclic Hemiacetals or Ketals Intramolecular reaction: formation of 5 or 6-membered rings

Cyclic Hemiacetals in Carbohydrates Intramolecular formation of 5 or 6-membered rings D-Glucose

Learning Check 1. What could be the reagent and reaction condition for the following transformation? (a) ethanol, NaOH (b) ethanol, H+ (c) methanol, NaOH (d) methanol, H+ (e) None of the above 2. What should be the product from the following reaction?

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

Learning Check 4. Which hydroxy group when added to the aldehyde functional group (C-1) of open chain glucose will produce the cyclic hemiacetal form shown below? (a) The one that locates on C-2. (b) The one that locates on C-3. (c) The one that locates on C-4. (d) The one that locates on C-5. (e) None of the above

Learning Check Main Menu 5. Which hydroxy group when added to the aldehyde functional group (C-1) of open chain glucose will produce the cyclic hemiacetal form shown below? (a) The one that locates on C-2. (b) The one that locates on C-3. (c) The one that locates on C-4. (d) The one that locates on C-5. (e) None of the above