Lecture 20. Herman Emil Fischer Nobel Prize 1902 Sugars, Esters and Purines. April 4, Chemistry 328N

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1 Lecture 20 April 4, 2019 Herman Emil Fischer Nobel Prize 1902 Sugars, Esters and Purines

2 Acid-catalyzed Esterification (also called Fischer esterification) CH CH 3 H H H 2 CCH 3 Please study the mechanism

3 Reaction of Esters with Grignard Reagents H 2 RCCH 3 NaH RC - Na CH 3 H

4 Nucleophilic Acyl Substitution R C X Y - R - Y C X R C X - Y

5 Reaction of Esters with H - Saponification H 2 RCCH 3 NaH RC - Na CH 3 H

6 Saponification of Esters Hydrolysis of an esters is aqueous base is called saponification Each mol of ester hydrolyzed requires 1 mol of base; for this reason, ester hydrolysis in aqueous base is said to be base-promoted (not catalyzed) H 2 RCCH 3 NaH RC - Na CH 3 H Hydrolysis of an ester in aqueous base involves Nucleophilic acyl substitution

7 Saponification of Fat R C CH 2 C C H CH 2 C R R CH 2 H NaH H C H CH 2 H R C - Na Fat glycerol Fatty Acid Salt "Soap" R = CH 3 (CH 2 ) 16 CH Stearic Acid CH 3 (CH 2 ) 7 CH CH(CH 2 ) 7 CH leic acid etc.

8 Physical Properties Water solubility decreases as the relative size of the hydrophobic portion of the molecule increases hydrophilic region; increases water solubility hydrophobic region; decreases water solubility

9 Soaps and Detergents Surface Active Agents = surfactants CH 3 (CH 2 ) 16 C - N a Soap CH 3 (CH 2 ) 11 S 'Na Anionic detergent CH 3 Cl CH 2 N (CH 2 ) 15 CH 3 CH 3 Cationic Detergent

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12 Hydrolysis of Amides Hydrolysis of amides is also irreversible. In acid solution the amine product is protonated to give an ammonium salt. RCNHR' H 2 H RCH R'NH 3

13 Hydrolysis of Amides In basic solution the carboxylic acid product is deprotonated to give a carboxylate ion. This makes the reaction irreversible! RCNHR' H RC R'NH 2

14 Hydrolysis of Amides in Acid Hydrolysis of amides in aqueous acid requires 1 mol of acid per mol of amide Ph 2-Phenylbutanamide CH 3 CH 2 CHCNH 2 H 2 HCl H 2 heat - CH 3 CH 2 CHCH NH 4 Cl Ph 2-Phenylbutanoic acid

15 Hydrolysis of Amides in Acid Acid-catalyzed hydrolysis of an amide is divided into three steps Step 1: protonation of the carbonyl oxygen R C NH 2 H H H R H C NH 2 R C NH 2 Resonance-stabilized cation H H 2

16 Hydrolysis of Amides in Acid Step 2: addition of H 2 to the carbonyl carbon followed by proton transfer H R C NH 2 H H R H H C NH 2 H proton transfer from to N R H C H NH 3 Tetrahedral carbonyl addition intermediate

17 Hydrolysis of Amides in Acid Step 3: collapse of the intermediate coupled with proton transfer to give the carboxylic acid and ammonium ion H R C NH 3 H R C H H NH 3 R C H NH 4

18 Hydrolysis of Amides in Base Hydrolysis of an amide in aqueous base requires 1 mole of base per mole of amide CH 3 CNH N-Phenylethanamide NaH H 2 heat CH 3 C - Na Sodium acetate H 2 N Aniline

19 Hydrolysis of Amides in Base Hydrolysis of an amide in aqueous base is divided into three steps Step 1: addition of hydroxide ion to the carbonyl carbon R C NH 2 - R C H Tetrahedral carbonyl addition intermediate - H NH 2

20 Hydrolysis of Amides in Base Step 2: collapse of the intermediate to form a carboxylic acid and ammonia R C - H NH 2 H H R C H NH 3 Tetrahedral carbonyl addition intermediate A very rare event Why??? - H

21 Hydrolysis of Amides in Base Step 3: proton transfer to form the carboxylate anion and water. Hydrolysis is driven to completion by this acid-base reaction R C H - -H R C - H H

22 Hydrolysis of Amides Hydrolysis of amides is irreversible. In acid solution the amine product is protonated to give an ammonium salt. RCNHR' H 2 H RCH R'NH 3

23 Hydrolysis of Amides In basic solution the carboxylic acid product is deprotonated to give a carboxylate ion. This makes the reaction irreversible! RCNHR' H RC R'NH 2

24 Chemistry of Nitriles Nitriles and carboxylic acids both have a carbon atom with three bonds to an electronegative atom, and both contain a bond Both both are electrophiles Nitrile Carboxylic Acid

25 Naming Nitriles Name the parent alkane (include the carbon atom of the nitrile as part of the parent) followed with the word -nitrile. The carbon in the nitrile is given the #1 location position. It is not necessary to include the location number in the name because it is assumed that the functional group will be on the end of the parent chain. Cycloalkanes are followed by the word -carbonitrile. Cyclopentane carbonitrile

26 Preparation of Nitriles Sandmeyer rection of diazonium salts Sn2 reactions with Cyanide anion Cyanohydrin formation Dehydration of Amides There are many more.

27 Preparation of Nitriles by Dehydration Reaction of primary amides RCNH 2 with SCl 2 (or other dehydrating agents) Not limited by steric hindrance or side reactions (as is the reaction of alkyl halides with NaCN)

28 Mechanism of Dehydration of Amides Nucleophilic amide oxygen atom attacks SCl 2 followed by deprotonation and elimination

29 Addition of HCN to Carbonyls Mechanism of cyanohydrin formation CH 3 CH 2 CH 3 CH 2 CH 3 CH 2 CH 2 CH 2 N C - H 3 CH 2 C N C C - N C C H Mg 2 THF dil. CH 3 CH 3 CH 3

30 Cyanohydrins The value of cyanohydrins is for the new functional groups into which they can be converted acid-catalyzed dehydration of the 2 alcohol gives a valuable monomer H CH 3 CHC N acid catalyst CH 2 =CHC N H 2 2-Hydroxypropanenitrile (Acetaldehyde cyanohydrin) Propenenitrile (Acrylonitrile)

31 Cyanohydrins acid-catalyzed hydrolysis of the cyano group gives an a-hydroxycarboxylic acid H CHC N H 2 acid catalyst H CHCH Benzaldehyde cyanohydrin (Mandelonitrile) 2-Hydroxy-2-phenylethanoic acid (Mandelic acid)

32 Cyanohydrins catalytic reduction of the carbon-nitrogen triple bond converts the cyano group to a 1 amine H CHC N 2 H 2 Ni H CHCH 2 NH 2 Benzaldehyde cyanohydrin 2-Amino-1-phenylethanol LiAlH 4 also works well... But what about Pd/C and H 2

33 Hydrolysis: Conversion of Nitriles into Carboxylic Acids Hydrolyzed in with acid or base gives a carboxylic acid and ammonia

34 Reaction of Nitriles with rganometallic Reagents Grignard reagents add to give an intermediate imine anion that is hydrolyzed by addition of water to yield a ketone

35 Reduction: Conversion of Nitriles into Amines Reduction of a nitrile with LiAlH 4 gives a primary amine

36 Some loose ends before we go on Spectrosopy of acid derivatives A selective reduction for your tool box

37 Reduction of Acid Derivatives Acids (page ) Esters (page ) Please work through the example in section 18.9 Amides (page ) Nitriles (page 800) Selective reductions with NaBH 4 Esters to aldehydes by DiBAlH (page )

38 DIBAlH Diisobutylaluminum hydride (DIBAlH) at -78 C selectively reduces esters to aldehydes at -78 C, the tetrahedral intermediate does not collapse and it is not until hydrolysis in aqueous acid that the carbonyl group of the aldehyde is liberated Stable at low temperature

39 Infrared Spectroscopy C= stretching frequency depends on whether the compound is an acyl chloride, anhydride, ester, or amide. C= stretching frequency n CH 3 CCl CH 3 CCCH 3 CH 3 CCH 3 CH 3 CNH cm and 1815 cm cm cm -1

40 Infrared Spectroscopy Anhydrides have two peaks due to C= stretching. ne from symmetrical stretching of the C= and the other from an antisymmetrical stretch. C= stretching frequency n CH 3 CCCH and 1815 cm -1

41 Infrared Spectroscopy Nitriles are readily identified by absorption due to carbon-nitrogen triple bond stretching that is all alone in the cm -1 region.

42 t-butyl esters

43 t-butyl esters

44 t-butyl ester hydrolysis Note which bond is broken in this hydrolysis!!