Chapter 18 Additions to the Carbonyls Organic Chemistry II Fall 1999 Chapter 18 Additions to the Carbonyls substitution reaction leaving group (L-) nucleophile (Nu:-) electrophile (R-L) (Nu-R) d+ d- OrgChem-Chap18 Chapter 14

Mechanisms of Nucleophilic Additions Organic Chemistry II Fall 1999 Mechanisms of Nucleophilic Additions depends on the conditions:  741 Figure 18.1 basic conditions: strong Nu & no acidic H acidic conditions: weak Nu & strong acid RDS in nucleophilic additions: addition of Nu: RDS in electrophilic additions: addition of E+ ( 672) the equilibrium varies on the reaction conditions OrgChem-Chap18 Chapter 14

Nucleophilic Additions to Carbonyls Organic Chemistry II Fall 1999 Nucleophilic Additions to Carbonyls under basic conditions:  741 Figure 18.1 under acidic conditions:  741 Figure 18.1 OrgChem-Chap18 Chapter 14

Addition of H- & -CN: Alcohols Organic Chemistry II Fall 1999 Addition of H- & -CN: Alcohols hydride (H-): strong Nu, reduction;  742 top LiAlH4: reactive with ROH/RNH2,  742 middle NaBH4: mild (slow with esters, acids, amides, nitriles) aldehyde: 1o alcohol, ketone: 2o alcohol;  742-3 cyanide (-CN): good Nu, catalytic;  748 bottom equilibrium reaction: cyanohydrins; depends on the structure of the substrate,  749 middle OrgChem-Chap18 Chapter 14

Addition of Carbanions: Alcohols Organic Chemistry II Fall 1999 Addition of Carbanions: Alcohols organometallic Nu: R-M(metal)  Rd-Md+ Grignard reagents in ethers: M=MgX;  751 bottom organolithiums: M=Li, more reactive;  752 very strong Nu & bases: no acidic H;  753 top addition reactions: basic mechanism,  753 bottom formaldehyde: 1o alcohol, aldehyde: 2o alcohol, ketone: 3o alcohol, CO2: RCO2H;  755-756 retrosynthesis of alcohols:  757 top practice:  757, Pract. 18.2 &  758 Prob. 18.11 OrgChem-Chap18 Chapter 14

Addition of Phosphorus Ylide: Alkenes Organic Chemistry II Fall 1999 Addition of Phosphorus Ylide: Alkenes ylides: A+-B- (R3P+--CR1R2  Ph3P=CR1R2) preparation:  372  Ph3P+CH3 I-   759 Wittig reactions: regioselective alkenes mechanism: addition (betaine) & elimination (oxaphosphetane),  759 bot. &  760 Fig. 18.2 unstabilized vs stabilized ylides:  761 middle total synthesis: vitamin A;  763-5 Focus On practice:  762, Practice Problem 18.3 OrgChem-Chap18 Chapter 14

Addition of Water (H2O): Hydrates Organic Chemistry II Fall 1999 Addition of Water (H2O): Hydrates base- / acid-catalyzed reactions:  745 top equilibrium: depends on the structure inductive effects: dipolar repulsion,  746 top steric effects: ketones favor carbonyl forms,  746 bottom &  747 Table 18.1 practice:  747-8, Problem 18.3-18.5 OrgChem-Chap18 Chapter 14

Addition of ROH: (Hemi)Acetals Organic Chemistry II Fall 1999 Addition of ROH: (Hemi)Acetals acid-catalyzed addition:  775 top mechanism:  776 Figure 18.5 cyclic hemiacetals: favored with 5-/6-ring,  775-6 acetals with diols/dithiols:  777 middle as a protective group: stable under basic (nucleophilic) and neutral conditions,  779 top, Figure 18.6 practice:  779, Problem 18.24 OrgChem-Chap18 Chapter 14

Acetals: Protection of Carbonyls Organic Chemistry II Fall 1999 Acetals: Protection of Carbonyls OrgChem-Chap18 Chapter 14

Addition of Amine (RNH2): Imines Organic Chemistry II Fall 1999 Addition of Amine (RNH2): Imines addition-elimination (H2O): C=N,  765 bottom mechanism: optimum pH 4-6,  766 Figure 18.3 removal of water: azeotropic distillation / dehydrating agents structure elucidation: mp of solid derivatives,  767-8 oximes, semicarbazones, hydrazones (DNP: orange or red) reductive amination: amines,  771 bot. – 772 top Wolff-Kishner reduction:  770-1 Figure 18.4 imines in vivo:  773-4 Focus On 2o amines (RNHR’): enamines,  769 practice:  768-772, Problem 18.16-18.20 OrgChem-Chap18 Chapter 14

Conjugate Additions to Carbonyls Organic Chemistry II Fall 1999 Conjugate Additions to Carbonyls addition to electrophilic C=C double bonds a,b-unsaturated carbonyls:  780 top conjugate addition reactions:  781 middle 1,2- vs. 1,4-addition:  780 middle more reactive vs. less reactive LiAlH4 vs. NaBH4:  782 top RMgBr/RLi vs. R2CuLi/-CN/RNH2:  782 bot &  783 practice:  783 Problem 18.25 OrgChem-Chap18 Chapter 14

Conjugated Carbonyls: 1,2- vs 1,4-Addition Organic Chemistry II Fall 1999 Conjugated Carbonyls: 1,2- vs 1,4-Addition OrgChem-Chap18 Chapter 14

Synthesis: Addition to Carbonyls Organic Chemistry II Fall 1999 Synthesis: Addition to Carbonyls summary of additions:  788 Table 18.2 1,2-addition: alcohols & alkenes alcohols: Grignard/hydride;  785 middle alkenes: Wittig reactions;  784 bot. – 785 top 1,4-addition: carbonyls;  786 top practice:  786 Problem 18.26 &  789 bottom OrgChem-Chap18 Chapter 14