ORGANIC CHEMISTRY: PHYSICAL CHEMISTRY FOR MEDICAL, PHARMACEUTICAL, AND BIOLOGICAL STUDENTS
CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON INTERMEDIATES 1 1 1 GENERATION OF CARBANIONS BY DEPROTONATION 1 5 10 1 2 REGIOSELECTIVITY AND STEREOSELECTIVITY IN ENOLATE FORMATION 1 3 OTHER MEANS OF GENERATING ENOLATES 1 4 ALKYLATION OF ENOLATES 11 1 5 GENERATION AND ALKYLATION OF DIANIONS 20 1 6 MEDIUM EFFECTS IN THE ALKYLATION OF ENOLATES 20 1 7 OXYGEN VERSUS CARBON AS THE SITE OF ALKYLATION 23 1 8 ALKYLATION OF ALDEHYDES, ESTERS, AMIDES, AND NITRILES 28 1 9 THE NITROGEN ANALOGS OF ENOLS AND ENOLATES-ENAMINES AND IMINE ANIONS 31 1 10 ALKYLATION OF CARBON NUCLEOPHILES BY CONJUGATE ADDITION 39 GENERAL REFERENCES 47 PROBLEMS 47 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS 57 2 1 ALDOL ADDITION AND CONDENSATION REACTIONS 57 2 1 1 THE GENERAL MECHANISM 57 2 1 2 MIXED ALDOL CONDENSATIONS WITH AROMATIC ALDEHYDES 60 62 2 1 3 CONTROL OF REGIOCHEMISTRY AND STEREOCHEMISTRY OF MIXED ALDOL REACTIONS OF ALIPHATIC ALDEHYDES AND KETONES 89 96 2 1 4 INTRAMOLECULAR ALDOL REACTIONS AND THE ROBINSON ANNULATION 96 2 2 ADDITION REACTIONS OF IMINES AND IMINIUM IONS 2 2 1 THE MANNICH REACTION 100 2 2 2 AMINE-CATALYZED CONDENSATION REACTIONS 101 2 3 ACYLATION OF CARBANIONS 2 4 THE WITTIG AND RELATED REACTIONS OF PHOSPHORUS-STABILIZED CARBON NUCLEOPHILES 111 2 5 REACTIONS OF CARBONYL COMPOUNDS WITH A-TRIMETHYLSILYLCARBANIONS 120 2 6 SULFUR YLIDES AND RELATED NUCLEOPHILES 122 2 7 NUCLEOPHILIC ADDITION-CYCLIZATION 127 GENERAL REFERENCES 128 PROBLEMS 128 CHAPTER 3 FUNCTIONAL GROUP INTERCONVERSION BY NUCLEOPHILIC SUBSTITUTION 141 3 1 CONVERSION OF ALCOHOLS TO ALKYLATING AGENTS 141 3 1 1 SULFONATE ESTERS 141 3 1 2 HALIDES 142 3 2 INTRODUCTION OF FUNCTIONAL GROUPS BY NUCLEOPHILIC SUBSTITUTION AT SATURATED CARBON 147 147 3 2 1 GENERAL SOLVENT EFFECTS 150 3 2 2 NITRILES 150 3 2 3 AZIDES 152 3 2 4 OXYGEN NUCLEOPHILES 155 3 2 5 NITROGEN NUCLEOPHILES 158 3 2 6 SULFUR NUCLEOPHILES 158 3 2 7 PHOSPHORUS NUCLEOPHILES 159 3 2 8 SUMMARY OF NUCLEOPHILIC SUBSTITUTION AT SATURATED CARBON 159 3 3 NUCLEOPHILIC CLEAVAGE OF CARBON-OXYGEN BONDS IN ETHERS AND ESTERS 164 3 4 INTERCONVERSION OF CARBOXYLIC ACID DERIVATIVES 166 3 4 1 PREPARATION OF REACTIVE REAGENTS FOR ACYLATION 172 3 4 2 PREPARATION OF ESTERS 172 3 4 3 PREPARATION OF AMIDES 180 PROBLEMS 191 CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON-CARBON MULTIPLE BONDS 191 4 1 ADDITION OF HYDROGEN HALIDES 195 4 2 HYDRATION AND OTHER ACID-CATALYZED ADDITIONS OF OXYGEN NUCLEOPHILES 196 4 3 OXYMERCURATION 200 4 4 ADDITION OF HALOGENS TO ALKENES 209 4 5 ELECTROPHILIC SULFUR AND SELENIUM REAGENTS 216 4 6 ADDITION OF OTHER ELECTROPHILIC REAGENTS 216 4 7 ELECTROPHILIC SUBSTITUTION ALPHA TO CARBONYL GROUPS 222 4 8 ADDITIONS TO ALLENES AND ALKYNES 226 4 9 ADDITION AT DOUBLE BONDS VIA ORGANOBORANE INTERMEDIATES 226 4 9 1 HYDROBORATION 4 9 2 REACTIONS OF ORGANOBORANES 232 4 9 3 ENANTIOSELECTIVE HYDROBORATION 236 4 9 4 HYDROBORATION OF ALKYNES 239 GENERAL REFERENCES 240 241 PROBLEMS CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS 249 5 1 ADDITION OF HYDROGEN 249 5 1 1 CATALYTIC HYDROGENATION 249 5 1 2 OTHER HYDROGEN-TRANSFER REAGENTS 262 5 2 GROUP III HYDRIDE-DONOR REAGENTS 262 5 2 1 REDUCTION OF CARBONYL COMPOUNDS 262 5 2 2 STEREOSELECTIVITY OF HYDRIDE REDUCTION 273 5 2 3 REDUCTION OF OTHER FUNCTIONAL GROUPS BY HYDRIDE DONORS 280 5 3 GROUP IV HYDRIDE DONORS 286 5 4 HYDROGEN-ATOM DONORS 288 5 5 DISSOLVING-METAL REDUCTIONS 290 5 5 1 ADDITION OF HYDROGEN 292 5 5 2 REDUCTIVE REMOVAL OF FUNCTIONAL GROUPS 296 5 5 3 REDUCTIVE CARBON-CARBON BOND FORMATION 299 5 6 REDUCTIVE DEOXYGENATION OF CARBONYL GROUPS 307 310 5 7 REDUCTIVE ELIMINATION AND FRAGMENTATION 315 GENERAL REFERENCES 316 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS PROBLEMS 331 6 1 CYCLOADDITION REACTIONS 331 6 1 1 THE DIELS-ALDER REACTION: GENERAL FEATURES 332 6 1 2 THE DIELS-ALDER REACTION: DIENOPHILES 6 1 3 THE DIELS-ALDER REACTION: DIENES 339 345 6 1 4 ASYMMETRIC DIELS-ALDER REACTIONS 349 6 1 5 INTRAMOLECULAR DIELS-ALDER REACTIONS 353 6 2 DIPOLAR CYCLOADDITION REACTIONS 359 6 3 [2+2] CYCLOADDITIONS AND OTHER REACTIONS LEADING TO CYCLOBUTANES 367 6 4 PHOTOCHEMICAL CYCLOADDITION REACTIONS 370 6 5 [3,3] SIGMATROPIC REARRANGEMENTS 376 376 6 5 1 COPE REARRANGEMENTS 383 6 5 2 CLAISEN REARRANGEMENTS 394 6 6 [2,3] SIGMATROPIC REARRANGEMENTS 6 7 ENE REACTIONS 399 6 8 UNIMOLECULAR THERMAL ELIMINATION REACTIONS 403 6 8 1 CHELETROPIC ELIMINATION 403 6 8 2 DECOMPOSITION OF CYCLIC AZO COMPOUNDS 405 6 8 3 ? ELIMINATIONS INVOLVING CYCLIC TRANSITION STATES 408 GENERAL REFERENCES 414 PROBLEMS 414 CHAPTER 7 ORGANOMETALLIC COMPOUNDS OF THE GROUP I, II, AND III METALS 433 7 1 PREPARATION AND PROPERTIES 433 7 2 REACTIONS OF ORGANOMAGNESIUM AND ORGANOLITHIUM COMPOUNDS 445 7 2 1 REACTIONS WITH ALKYLATING AGENTS 445 7 2 2 REACTIONS WITH CARBONYL COMPOUNDS 446 7 3 ORGANIC DERIVATIVES OF GROUP IIB AND GROUP IIIB METALS 458 7 3 1 ORGANOZINC COMPOUNDS 459 7 3 2 ORGANOCADMIUM COMPOUNDS 463 7 3 3 ORGANOMERCURY COMPOUNDS 464 7 3 4 ORGANOINDIUM REAGENTS 465 7 4 ORGANOLANTHANIDE REAGENTS 467 GENERAL REFERENCES 468 PROBLEMS 468 CHAPTER & REACTIONS INVOLVING THE TRANSITION METALS 477 8 1 ORGANOCOPPER INTERMEDIATES 477 8 1 1 PREPARATION AND STRUCTURE OF ORGANOCOPPER REAGENTS 477 8 1 2 REACTIONS INVOLVING ORGANOCOPPER REAGENTS AND INTERMEDIATES 481 8 2 REACTIONS INVOLVING ORGANOPALLADIUM INTERMEDIATES 499 501 8 2 1 PALLADIUM-CATALYZED NUCLEOPHILIC SUBSTITUTION AND ALKYLATION 503 8 2 2 THE HECK REACTION 507 8 2 3 PALLADIUM-CATALYZED CROSS COUPLING 521 8 2 4 CARBONYLATION REACTIONS 525 8 3 REACTIONS INVOLVING ORGANONICKEL COMPOUNDS 529 531 8 4 REACTIONS INVOLVING RHODIUM AND COBALT 535 8 5 ORGANOMETALLIC COMPOUNDS WITH A BONDING 536 GENERAL REFERENCES PROBLEMS CHAPTER 9 CARBON-CARBON BOND-FORMING REACTIONS OF COMPOUNDS OF BORON, SILICON, AND TIN 547 9 1 ORGANOBORON COMPOUNDS 547 9 1 1 SYNTHESIS OF ORGANOBORANES 547 9 1 2 CARBON-CARBON BOND-FORMING REACTIONS OF ORGANOBORANES 549 563 9 2 ORGANOSILICON COMPOUNDS 9 2 1 SYNTHESIS OF ORGANOSILANES 563 9 2 2 CARBON-CARBON BOND-FORMING REACTIONS 567 9 3 ORGANOTIN COMPOUNDS 576 9 3 1 SYNTHESIS OF ORGANOSTANNANES 576 9 3 2 CARBON-CARBON BOND-FORMING REACTIONS 579 GENERAL REFERENCES 585 PROBLEMS 586 CHAPTER 10 REACTIONS INVOLVING CARBOCATIONS, CARBENES, AND RADICALS AS REACTIVE INTERMEDIATES 595 10 1 REACTIONS INVOLVING CARBOCATION INTERMEDIATES 595 10 1 1 CARBON-CARBON BOND FORMATION INVOLVING CARBOCATIONS 10 1 2 REARRANGEMENT OF CARBOCATIONS 602 596 10 1 3 RELATED REARRANGEMENTS 609 10 1 4 FRAGMENTATION REACTIONS 612 10 2 REACTIONS INVOLVING CARBENES AND NITRENES 614 10 2 1 STRUCTURE AND REACTIVITY OF CARBENES 617 10 2 2 GENERATION OF CARBENES 620 10 2 3 ADDITION REACTIONS 625 10 2 4 INSERTION REACTIONS 634 10 2 5 GENERATION AND REACTIONS OF YLIDES BY CARBENOID DECOMPOSITION 637 10 2 6 REARRANGEMENT REACTIONS 639 10 2 7 RELATED REACTIONS 641 10 2 8 NITRENES AND RELATED INTERMEDIATES 642 10 2 9 REARRANGEMENTS TO ELECTRON-DEFICIENT NITROGEN 646 651 10 3 REACTIONS INVOLVING FREE-RADICAL INTERMEDIATES 652 10 3 1 SOURCES OF RADICAL INTERMEDIATES 654 657 10 3 2 INTRODUCTION OF FUNCTIONALITY BY RADICAL REACTIONS 660 674 10 3 3 ADDITION REACTIONS OF RADICALS TO SUBSTITUTED ALKENES 679 10 3 4 CYCLIZATION OF FREE-RADICAL INTERMEDIATES 680 10 3 5 FRAGMENTATION AND REARRANGEMENT REACTIONS GENERAL REFERENCES CHAPTER 11 AROMATIC SUBSTITUTION REACTIONS 693 PROBLEMS 11 1 ELECTROPHILIC AROMATIC SUBSTITUTION 693 11 1 1 NITRATION 693 11 1 2 HALOGENATION 695 11 1 3 FRIODEL-CRAFTS ALKYLATIONS AND ACYLATIONS 699 11 1 4 ELECTROPHILIC METALATION 711 11 2 NUCLEOPHILIC AROMATIC SUBSTITUTION 714 11 2 1 ARYL DIAZONIUM IONS AS SYNTHETIC INTERMEDIATES 714 11 2 2 SUBSTITUTION BY THE ADDITION-ELIMINATION MECHANISM 722 11 2 3 SUBSTITUTION BY THE ELIMINATION-ADDITION MECHANISM 724 11 2 4 TRANSITION-METAL-CATALYZED SUBSTITUTION REACTIONS 728 11 3 AROMATIC RADICAL SUBSTITUTION REACTIONS 731 11 4 SUBSTITUTION BY THE SRN1 MECHANISM 734 GENERAL REFERENCES 736 CHAPTER 12 OXIDATIONS 736 PROBLEMS 747 12 1 OXIDATION OF ALCOHOLS TO ALDEHYDES, KETONES, OR CARBOXYLIC ACIDS 747 12 1 1 TRANSITION-METAL OXIDANTS 747 12 1 2 OTHER OXIDANTS 752 12 2 ADDITION OF OXYGEN AT CARBON-CARBON DOUBLE BONDS 12 2 1 TRANSITION-METAL OXIDANTS 757 12 2 2 EPOXIDES FROM ALKENES AND PEROXIDIC REAGENTS 757 12 2 3 TRANSFORMATIONS OF EPOXIDES 767 12 2 4 REACTION OF ALKENES WITH SINGLET OXYGEN 772 782 12 3 CLEAVAGE OF CARBON-CARBON DOUBLE BONDS 12 3 1 TRANSITION-METAL OXIDANTS 786 12 3 2 OZONOLYSIS 786 12 4 SELECTIVE OXIDATIVE CLEAVAGES AT OTHER FUNCTIONAL GROUPS 788 12 4 1 CLEAVAGE OF GLYCOLS 790 12 4 2 OXIDATIVE DECARBOXYLATION 790 12 5 OXIDATION OF KETONES AND ALDEHYDES 792 12 5 1 TRANSITION-METAL OXIDANTS 794 794 12 5 2 OXIDATION OF KETONES AND ALDEHYDES BY OXYGEN AND PEROXIDIC COMPOUNDS 798 12 5 3 OXIDATION WITH OTHER REAGENTS 802 12 6 ALLYLIC OXIDATION 803 12 6 1 TRANSITION-METAL OXIDANTS 803 805 12 6 2 OTHER OXIDANTS 807 12 7 OXIDATIONS AT UNFUNCTIONALIZED CARBON 809 GENERAL REFERENCES 809 PROBLEMS 821 CHAPTER 13 PLANNING AND EXECUTION OF MULTISTEP SYNTHESES 13 1 PROTECTIVE GROUPS 822 13 1 1 HYDROXYL-PROTECTING GROUPS 822 13 1 2 AMINO-PROTECTING GROUPS 831 13 1 3 CARBONYL-PROTECTING GROUPS 835 13 1 4 CARBOXYLIC ACID-PROTECTING GROUPS 837 13 2 SYNTHETIC EQUIVALENT GROUPS 839 845 13 3 SYNTHETIC ANALYSIS AND PLANNING 846 13 4 CONTROL OF STEREOCHEMISTRY 848 13 5 ILLUSTRATIVE SYNTHESES 848 13 5 1 JUVABIONE 859 13 5 2 LONGIFOLENE 869 13 5 3 PRELOG-DJERASSI LACTONE 881 890 13 5 4 TAXOL 897 13 5 5 EPOTHILONE A 897 13 6 SOLID-PHASE SYNTHESIS 13 6 1 SOLID-PHASE SYNTHESIS OF POLYPEPTIDES 900 13 6 2 SOLID-PHASE SYNTHESIS OF OLIGONUCLEOTIDES 903 GENERAL REFERENCES 13 7 COMBINATORIAL SYNTHESIS 909 PROBLEMS 910 REFERENCES FOR PROBLEMS 923