K peter c vollhardt, neil e schore organic chemistry structure and function w h freeman (2014)

Periodic Table of the Elements Relative atomic mass (atomic weight), 2013 IUPAC values; the IUPAC recommends atomic weight ranges for several elements but approves single “convenience” values for those elements as well; these values are used in the Table * for these radioactive elements, nuclidic mass of an important isotope 1.008 1, Ϫ1 2.2 H Oxidation states in compounds: important, most important 6.94 9.0121831 2 1.0 55.845 6, 3, 2, 0, Ϫ2 1.8 Electronegativity 26 Fe 1.6 Atomic number Li Be 22.989770 24.305 Element essential to at least one biological species 1.3 0.9 11 Na Element essential to all biological species investigated 12 Mg 39.0983 40.078 44.955908 47.867 50.9415 51.9961 54.938044 4, 5, 4, 3, 2, 6, 3, 2, 7, 6, 4, 3, 2, 0, Ϫ1 6, 3, 2, 0, Ϫ2 0.8 1.0 1.4 1.5 1.6 1.7 20 Ca 21 Sc 22 85.4678 87.62 88.90584 91.224 92.90637 95.95 5, 6, 5, 4, 3, 2, 19 K 0.8 37 Rb Sr 180.94788 183.84 6, 5, 4, 3, 2, 223.0197* 226.0254* 0.8 1.8 1.9 26 Fe 27 Co 98.9063* 101.07 102.90550 8, 6, 4, 3, 2, 0, Ϫ2 5, 4, 3, 2, 1, 2.3 44 Ru 45 Rh 186.207 190.23 192.217 7, 6, 4, 2, Ϫ1 8, 6, 4, 3, 2, 0, Ϫ2 6, 4, 3, 2, 1, 0, Ϫ1 43 Tc 2.4 2.2 72 Hf 73 Ta 74 W 75 Re 76 Os 77 267.12* 268.13* 271.13* 270.13* 277.15* 278.16* Ac–Lr 104 Rf 105 Db 106 Sg 107 Bh 108 Hs 109 Mt 138.90547 140.116 140.90766 144.242 146.9151* 150.36 151.964 4, 4, 3 3, La–Lu 0.9 42 Mo 1.3 57 to 71 3, 2, 0, Ϫ1 2.2 178.49 56 Ba Fr 1.3 58.933194 1.6 25 Mn 0.9 Y 24 Cr 137.327 39 55 Cs 87 1.2 V 41 Nb 0.8 23 40 Zr 38 132.9054520 1.0 Ti 55.845 Ir 89 to 103 88 Ra Lanthanides 1.1 1.1 1.1 1.1 1.2 3, 1.2 1.2 57 La 58 Ce 59 Pr 60 Nd 61 Pm 62 Sm 63 Eu 227.0278* 232.0377 231.03588 238.02891 237.0482* 244.0642* 243.0614* 5, 6, 5, 4, 6, 5, 4, 6, 5, 4, 6, 5, 4, Actinides 1.2 89 Ac 1.3 90 Th 1.3 91 Pa 1.4 92 U 1.4 93 Np 1.3 94 Pu 95 Am 18 4.002602 13 s Block elements d Block elements p Block elements f Block elements 14 10.81 12.011 4, 2, Ϫ4 15 14.007 5, 4, 3, 2, Ϫ3 2.0 2.6 B 26.9815385 28.085 4, Ϫ4 11 12 30.97376200 1.9 13 Al 14 Si 58.6934 63.546 65.38 69.723 72.630 2, 1.7 1.9 30 Zn 31 Ga 107.8682 112.414 2, 28 Ni 29 Cu 106.42 4, 2, 1.9 2.2 46 Pd 47 Ag 195.084 4, 2, 118.710 121.760 4, 5, 3, Ϫ3 1.8 196.966569 200.592 3, 2, F 10 Ne 32.06 35.45 6, 4, 2, Ϫ2 7, 5, 3, 1, Ϫ1 39.948 2.6 S 3.2 17 Cl 18 Ar 78.971 79.904 6, 4, Ϫ2 7, 5, 3, 1, Ϫ1 83.798 2.6 34 Se 2.0 4.0 O 2.2 114.818 49 2.5 2.0 33 As 1.7 3.4 16 5, 3, Ϫ3 32 Ge 48 Cd 2.3 P 74.921595 1.8 18.99840316 20.1797 Ϫ1 2.2 15 He 15.999 5, 3, Ϫ3 3, 2, 1.9 N 17 Ϫ2, Ϫ1 3.0 C 1.6 10 16 3.0 3.0 35 Br 36 Kr 127.60 126.90447 131.293 6, 4, Ϫ2 7, 5, 1, Ϫ1 8, 6, 4, 2.1 2.1 51 Sb 52 204.38 207.2 208.98040 208.9824* 209.9871* 222.0176* 3, 4, 5, 6, 4, 7, 5, 3, 1, Ϫ1 2.0 2.3 2.0 2.0 53 I 2.6 50 Sn In Te 2.7 54 Xe 2.0 Pt 79 Au 80 Hg 81 Tl 82 Pb 83 Bi 84 Po 85 At 86 Rn 281.17* 282.17* 285.18* 285.18* 289.19* 289.19* 293.2* 294.21* 294.21* 110 Ds 111 Rg 112 Cn 157.25 158.92535 162.500 164.93033 167.259 168.93422 173.054 174.9668 4, 3 3 3, 3, 78 1.2 1.2 113 Uut 114 Fl 1.2 1.2 1.2 64 Gd 65 Tb 66 Dy 67 Ho 68 247.0704* 247.0703* 251.0796* 252.083* 4, 4, 4, 3 96 Cm 97 Bk 98 Cf 99 Es 115 Uup Er 116 Lv 117 Uus 1.3 1.0 69 Tm 70 Yb 71 Lu 257.0951* 258.0984* 259.101* 262.11* 3 3, 100 Fm 101 Md 102 No 103 Lr 118 Uuo O RG A N I C C HE MISTRY About the Authors K PETER C VOLLHARDT was born in Madrid, raised in Buenos Aires and Munich, studied at the University of Munich, got his Ph.D with Professor Peter Garratt at the University College, London, and was a postdoctoral fellow with Professor Bob Bergman (then) at the California Institute of Technology He moved to Berkeley in 1974 when he began his efforts toward the development of organocobalt reagents in organic synthesis, the preparation of theoretically interesting hydrocarbons, the assembly of novel transition metal arrays with potential in catalysis, and the discovery of a parking space Among other pleasant experiences, he was a Studienstiftler, Adolf Windaus medalist, Humboldt Senior Scientist, ACS Organometallic Awardee, Otto Bayer Prize Awardee, A C Cope Scholar, Japan Society for the Promotion of Science Prize Holder, and recipient of the Medal of the University Aix-Marseille and an Honorary Doctorate from The University of Rome Tor Vergata He is the current Chief Editor of Synlett Among his more than 350 publications, he treasures especially this textbook in organic chemistry, translated into 13 languages Peter is married to Marie-José Sat, a French artist, and they have two children, Paloma (b 1994) and Julien (b 1997), whose picture you can admire on p 168 NEIL E SCHORE was born in Newark, New Jersey, in 1948 His education took him through the public school of the Bronx, New York, and Ridgefield, New Jersey, after which he completed a B.A with honors in chemistry at the University of Phennsylvania in 1969 Moving back to New York, he worked with the late Professor Nicholas J Turro at Columbia University, studying photochemical and photophysical processes of organic compounds for his Ph.D thesis He first met Peter Vollhardt when he and Peter were doing postdoctoral work in Professor Robert Bergman’s laboratory at Cal Tech in the 1970s Since joining the U.C Davis faculty in 1976, he has taught organic chemistry to more than 15,000 nonchemistry majors, winning seven teaching awards, publishing over 100 papers in various areas related to organic chemistry, and refereeing several hundred local youth soccer games Neil is married to Carrie Erickson, a microbiologist at the U.C Davis School of Veterinary Medicine They have two children, Michael (b 1981) and Stefanie (b 1983), both of whom carried out experiments for this book ORGANIC CHEMISTRY Structure and Function PETER VOLLHARDT University of California at Berkeley NEIL SCHORE University of California at Davis W.H Freeman and Company A Macmillan Higher Education Company SEVENTH EDITION Publisher: Jessica Fiorillo Acquisitions Editor: Bill Minick Development Editor: Randi Blatt Rossignol Marketing Manager: Debbie Clare Media and Supplements Editor: Dave Quinn Assistant Editor: Nick Ciani Photo Editor: Robin Fadool Photo Assistant: Eileen Liang Photo Researcher: Dena Digilio Betz Cover Designer: Blake Logan Text Designer: Patrice Sheridan Project Editing and Composition: Aptara®, Inc Illustrations: Network Graphics; Precision Graphics Illustration Coordinator: Dennis Free at Aptara®, Inc Production Coordinator: Susan Wein Printing and Binding: RR Donnelley Library of Congress Control Number: 2013948560 ISBN-13: 978-1-4641-2027-5 ISBN-10: 1-4641-2027-7 © 2003, 2007, 2011, and 2014 by W H Freeman and Company All rights reserved Printed in the United States of America First printing W H Freeman and Company 41 Madison Avenue New York, NY 10010 Houndmills, Basingstoke RG21 6XS, England www.whfreeman.com BRIEF CONTENTS PREFACE: A User’s Guide to ORGANIC CHEMISTRY: Structure and Function STRUCTURE AND BONDING IN ORGANIC MOLECULES xxv STRUCTURE AND REACTIVITY Acids and Bases, Polar and Nonpolar Molecules 49 REACTIONS OF ALKANES Bond-Dissociation Energies, Radical Halogenation, and Relative Reactivity 97 CYCLOALKANES 131 STEREOISOMERS 167 PROPERTIES AND REACTIONS OF HALOALKANES Bimolecular Nucleophilic Substitution 211 FURTHER REACTIONS OF HALOALKANES Unimolecular Substitution and Pathways of Elimination 247 HYDROXY FUNCTIONAL GROUP: ALCOHOLS Properties, Preparation, and Strategy of Synthesis 279 FURTHER REACTIONS OF ALCOHOLS AND THE CHEMISTRY OF ETHERS 325 10 USING NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY TO DEDUCE STRUCTURE 377 vi Brief Contents 11 ALKENES: INFRARED SPECTROSCOPY AND MASS SPECTROMETRY 433 12 REACTIONS OF ALKENES 483 13 ALKYNES The Carbon–Carbon Triple Bond 541 14 DELOCALIZED PI SYSTEMS Investigation by Ultraviolet and Visible Spectroscopy 579 INTERLUDE: A Summary of Organic Reaction Mechanisms 635 15 BENZENE AND AROMATICITY Electrophilic Aromatic Substitution 641 16 ELECTROPHILIC ATTACK ON DERIVATIVES OF BENZENE Substituents Control Regioselectivity 695 17 ALDEHYDES AND KETONES The Carbonyl Group 737 18 ENOLS, ENOLATES, AND THE ALDOL CONDENSATION ␣,␤-Unsaturated Aldehydes and Ketones 789 19 CARBOXYLIC ACIDS 833 20 CARBOXYLIC ACID DERIVATIVES 885 21 AMINES AND THEIR DERIVATIVES Functional Groups Containing Nitrogen 933 22 CHEMISTRY OF BENZENE SUBSTITUENTS Alkylbenzenes, Phenols, and Benzenamines 979 23 ESTER ENOLATES AND THE CLAISEN CONDENSATION Synthesis of ␤-Dicarbonyl Compounds; Acyl Anion Equivalents 1039 Index Naphthalene as aromatic, 658–660 deshielding and, 660 electrophilic reactivity of, 719 electrophilic substitution, 719–720 extended pi conjugation in, 659 molecular structure of, 659 NMR data for, 659, 660 orbital picture of, 659 resonance forms of, 658 spectral properties of, 658 Naproxen, 194 Natta, Giulio, 522n Natural pesticides, 1148–1149 Natural products, 151 alcohol and ether groups, 362 isoprene units, 153, 618 steroids, 154–157 structural characterization of, 419–420 taxol, 153–154 terpenes, 153 Natural rubber, 617–618 Nature absorption of photons by saturated aldehydes in, 808–809 alkynes in, 565–567 chemical warfare in, 1013 complex sugars in, 1098–1103 electrocyclization cascade in, 612–613 esters in, 903–905 oxidation-reduction processes in, 1013–1018 polycyclic carboxylic acids in, 868–869 polypeptides in, 1194–1196 sugars in, 1103–1110 Neo- prefix, 74 Neoprene, 616 Neurotransmitter, 837, 1100, 1126, 1135 Newman, Melvin S., 82n Newman projections, 82–83, 83, 86, 87 of chloroethane, 392 of E2 transition state, 264 substituted cyclohexane, 145 Nicotinamide adenine dinucleotide, 290, 1142–1143 Nicotine, 1126–1127, 1150 Nitration (trifluoromethyl)benzene and, 701 benzene and, 671–674 increasing rate of, 698 1-methoxynaphthalene and, 720 monosubstituted benzenes and, 709t N-phenylacetamide and, 703 Nitric acid, 15 as acid and as base, 65 activation by sulfuric acid, 672 Nitric oxide, 1170 Nitrile group, 915 C-N bond, 914–915 drug for breast cancer, 917 hydrolysis to carboxylic acids and, 846–847, 915–916 orbital picture of, 915 organometallic reagent attack, 916 reduction by hydride reagents, 916–917 -nitrile ending, 914 Nitro (meta director), interconversion with amino and, 713 Nitrobenzenamine, 717 Nitrogen alkanamine, 935–938 elimination in Wolff-Kishner reduction, 766 heterocyclic bases, 1196, 1196 inversion at, 938 modified sugars and, 1107–1110 Nitrogen nucleophiles, conjugate addition and, 813–814 Nitronium ion, 671–672 Nitrosation, 958–964 Nitrosyl cation, 15, 958, 958 Nitrous acid, 958 N-methyl-N-nitrosamides, 964 N-nitrosamines, 958, 960 N-nitrosodialkanamines, 959 Nodes, 24 Nonaromatic heterocycles, 1124–1128 Nonaromatic systems, 661 Nonconjugated dienes, 588–589 Nonconjugated isomers, 587 Nonequivalent neighboring hydrogens, 397–404 Nonequivalent resonance forms, 20–23 Non-first-order spectra, 404–406, 405 Norbornane, 150 Novoselov, Kostya S., 657n Noyori, Ryoji, 194n N-terminal amino acids, 1178 Nuclear magnetic resonance (NMR) spectroscopy, 377–432, 378 in acetic acid detection, 389 activity, 382t alkenes and, 441–447 alkynes and, 546–550 analyzing molecular structure and, 385–390 atom connectivity, 417–418 azacyclohexane and, 941 benzene derivatives and, 651–655 carbon-13, 411–421 chemical equivalence tests and, 390–394 chemical shifts and, 385, 387–390, 396 complex molecules, 447 conformational interconversion and, 391–393, 392 coupling constant and, 399 deshielding and, 386, 389t differentiating nuclei of same element and, 382–385, 384 doublets and, 397–399, 398 FT, advances in, 416–420 functional groups and, 387–390 glucose and, 1083 high field and, 386 high-resolution, 382, 384, 384 hydrogen nuclear magnetic resonance, 380–385 integration and, 394–396 integration mode, 395 local magnetic fields and, 385–386 low field and, 386 medical diagnosis and, 394 molecule excitation and, 378–379 multiplets and, 397 nonequivalent neighboring hydrogens and, 397–404 nuclear spins and, 380–382 nuclei responsive to, 382t, 383 nuclei undergoing magnetic resonance, 382 peak integration and, 396 peak position and, 386–387 quartets and, 397 recording a spectrum, 383 shielded nuclei and, 385–386, 386 signal position and, 385–386, 386 singlets and, 397 spectroscopy defined, 378–380 spin-spin splitting and, 397–404, 397 spin-spin splitting complications and, 404–411 time scale, 391–393 triplets and, 397 2-D, 416–420 upfield and, 386 Nuclear spins, 380–382 resonance, 381 spin states, 380, 381 Nucleic acids, 1196–1201 double helix and, 1200, 1201 heterocycles, 1196–1198 information storage in, 1198 sugars and bases, 1196 synthetic bases, 1199 Nucleophiles, 58 acids and bases and, 67–68 additions to aldehydes and ketones, 751t bromonium ion trapping and, 498 carbonyl carbon and, 848 conjugate addition and, 813–814 haloalkane reaction mechanisms, 269t reactivity of haloalkanes towards, 257, 257t relative reaction rates, 234t in SN1 reaction, 254–255 sterically hindered, 234, 267–268 strongly basic, 266–267 three-carbon, 586–587 weakly basic, 266 Nucleophilic, 58 Nucleophilic addition-protonation, 751 Nucleophilic aromatic substitution, 992 addition-elimination, 990–995 ipso substitution and, 991 mechanism of, 992 in phenol preparation, 990–1001 in synthesis, 993–994 Nucleophilic attack, 756–758 Nucleophilic carbon, 296–299 I-15 Nucleophilic ring opening of oxacyclopropanes, 352 Nucleophilic substitution, 67–68, 214–217 See also SN2 reactions by addition-elimination, 849 alcohol synthesis and, 287–288 of allylic halides, 584–586 benzylic, 982 bimolecular, 220–221 chloromethane with sodium hydroxide reaction and, 67, 215t, 219 diversity and, 214–216, 215t electrophilic centers, 214 of haloarenes, 996 kinetics and, 219–222 leaving groups and, 214 rate law, 219 as reversible, 234 R-X, reactivity of, 257t of substituted halocycloalkane, 227 substrates and, 214 unimolecular, 248–252 Nucleophilic trapping, 591 Nucleophilicity, 229–235 aprotic solvents and, 232–233, 232t basicity and, 230–231 increasing negative charges and, 229 increasing polarizability and, 233–234, 233 as kinetic phenomenon, 230 periodic table and, 230 reversible substitutions and, 234 solvation and, 231–232 sterically hindered nucleophiles and, 234 Nucleosides, 1197, 1199, 1208 Nucleotides, 1196, 1197, 1198, 1205 Nylon, 962–963 O O-acyl isourea, 1191 Observed optical rotation, 173 Octet rule, 7–13 covalent bonds and, 9–10 Lewis structures and, 14, 15–16 periodic table and, 7, 7t polar covalent bonds and, 10–12 pure ionic bonds and, 8–9 valence electron repulsion and, 12–13 Octets, -oic acid, 835 Oils, 903 -ol suffix, 280 Olah, George A., 671n Olefins, 433 Oleic acid, 433, 863, 866, 903–904 Olestra, 937, 1099 Oligomerization, 518–519 Oligomers, 518 -one ending, 739 1,2-additions, 814–816 1,2-dehydrobenzene, 996 1,3-diaxial interactions, 144–145 1,4-additions, 812–813, 814–816, 817 Open-chain form of glucose, 1083 Open-shell configuration, 28 I-16 Index Opium poppy, 362 Optical activity, 173 enantiomeric composition and, 174 optical rotation measurement, 173–174, 173 specific rotations, 173, 174t stereoisomers and, 172–175 Optical isomers, 173 Optical purity, 174 Optical rotation, 173–175 enantiomeric composition and, 173–174 measurement, 173–174, 173 observed, 173 specific, 173, 174t Optically active, 173 ORAC units (oxygen radical absorbance capacity), 1020 Orbital hybridization, 32, 39 Organic chemistry functional groups and, 2–3 learning and using of, mechanisms and, 4–5 reactions and, 4–5 scope of, 2–5 synthesis and, Organic conductors, 601 Organic esters, 336 Organic molecules constitutional isomers and, 37 elemental analysis and, 37 empirical formulas and, 37 fragmentation patterns of, 465–469 function of, infrared stretching wavenumber ranges of, 457, 458t molecular masses of, 461 rotational and mirror symmetry, 390, 390 structure and formulas of, 37–39 structure representations and, 38–39 Organocatalysis, 805, 1061, 1143 Organocuprates, 302–303, 814–815, 893 example preparation of, 814 lithium, 815 Organolithium, 296–298, 309, 326, 354, 521, 545, 552, 587, 769, 814, 944, 984, 1056, 1141 Organometallic reagents, 296–301 alcohol synthesis and, 299–301 aldehydes and ketones and, 750t allylic, 586–587 carboxylic acids and, 845–846 hydrolysis of, 298 nitrile attack to give ketones, 916 1,2-and 1,4-additions to, 814–816 in synthesis of alcohols, 299–301 Organometallics alkylation of, 302 carbonation of, 845 Orlistat, 937 Ortho and para directing, 699, 708 Ortho attack on benzenamine, 703 on benzoic acid, 706 on halobenzene, 707 on methylbenzene, 699 on (trifluoromethyl)benzene, 701 Ortho substitution, 699, 702 Osazones, 1088 Osmium tetroxide, 511–513, 649 Overlap, atomic orbitals, 28–31 Overlap peptides, 1188 Overlapping p orbitals, 580–582 Oxa- prefix, 1123 Oxa-2-cycloalkanone, 896 Oxacycloalkane stem, 340 Oxacyclopentane synthesis, 565 Oxacyclopropanes, 361–362 acids-catalyzed ring opening, 355–356 formation, 354, 509 formation from alkene, 498 hydride and organometallic reagents and, 352–354 hydrolysis of, 510 hydrolytic kinetic resolution of, 354–355 inversion on opening, 353 nucleophilic ring opening of, 352 reactions of, 352–356 regioselectivity and, 352 ring opening by Grignard reagents and, 354 ring opening by lithium aluminum hydride and, 353 synthesis, 508–510 as the warhead of drugs, 356 Oxalic acid, 835 Oxaphosphacyclobutane, 770 Oxidation, 289 alcohol, utility in synthesis, 309 alcohols, “green,” 748 of aldoses, 1085–1086 of alkylboranes, 505–506 of alkyl-substituted benzenes, 984–986 allylic, 748 Baeyer-Villiger, 772–773 benzylic, 984–986 in the body, 290–291 carboxylic acids and, 845, 1084–1086 chromic esters as intermediates in, 295–296 of ethene, 523 hydroboration-oxidation and, 504–507 by peroxycarboxylic acids, 772–773 of primary alcohol, 295 of secondary alcohol, 294 of thiols, 358–359 Oxidation-reduction processes in nature, 1013–1018 Oxidative cleavage, 513–515, 1086–1087 Oximes, 762 Oxirane, 361 Oxonium ions, 269, 328, 739 Oxygen biological reduction to water, 1013–1014 lone electron pairs and alchols and, 286 peroxycarboxylic acids and, 509–510 in phenols, 1001–1002 transport by myoglobin and hemoglobin, 1194–1196, 1195, 1196 Oxygen nucleophiles, conjugate addition and, 813–814 Oxymercuration-demercuration, 501–504 demercuration and, 503 ether synthesis by, 503 mechanism of, 503 oxymercuration and, 503 Ozone layer, 121, 122 CFC substitutes and, 122–123 chemical destruction, 122 chlorofluorocarbons and, 121–122 hole in, 121 ozone decrease and, 122 ozone formation and, 121 Ozonide, 513 Ozonolysis, 513–515, 749 mechanism of, 514 reaction of alkenes, 514 P P orbitals, benzene ring and, 645–647 Paal, Karl, 1130n Paal-Knorr synthesis, 1130 Paired electrons, 26 Palmitic acid, 863, 903–904 Para attack on benzenamine, 703 on benzoic acid, 706 on halobenzene, 708 on methylbenzene, 699 on (trifluoromethyl)benzene, 701 Para substitution, 699, 702 Parent ion, 461 Parkinson’s disease, 488 Pascal, Blaise, 401n Pasteur, Louis, 187n Pauli, Wolfgang, 26n Pauli exclusion principle, 26 Pauling, Linus, 29n PCC (pyridinium chlorochromate), 295 Pd catalysis, 485, 553, 811, 949, 985, 1000–1001, 1092, 1190 Peak, spectroscopy, 379 Pedersen, Charles J., 342n Penicillamine, 1172 Penicillin, 908, 1147 Pentadiene, 587 Pentane fragmentation ions from, 465 isomeric, 73 mass spectrum of, 465, 465 Pentanoic acid mass spectrum of, 841 NMR spectrum of, 838 Pentoses, 1074 Peptic ulcers, 61 Peptide bonds, 1176 amino acids and, 1176–1178 formation with carboxy activation, 1191–1192 main chain, 1178 resonance in, 1177 side chains, 1178 Peptide hydrolysis, 1182–1183 Peptides, 1177 overlapping sequences, 1188 sequencing, 1186–1187 synthesis, 1190–1191 Performance-enhancing drug detection, 463 Perfumes, 153, 322, 361, 362, 554, 749, 828, 985, 1009, 1063 Pericyclic reactions, 639t Pericyclic transformations, 608 Periodic acid cleavage, 1087 Periodic acid degradation, 1087 Periodic table, 7, 7t, 230 Perkins, William Henry, 1022n Peroxides, 343, 349, 516, 517–521, 772, 867 Peroxycarboxylic acids epoxidation by, 508–510 oxidation of ketones by, 772–773 oxygen atom delivery, 509–510 Pesticides, natural, 1148–1149 Pethidine, 1147 Petroleum conversion of, 102–105 green chemistry and, 105 product distribution in distillation of, 104t as source of alkanes, 104–105 pH, 60 pH, isoelectric, 1169 Phase-transfer catalysis, 1177 Phenanthrene, 658, 660, 721 Phenobarbital, 1140 Phenol, 644, 695, 702, 716, 906–1020 Phenolic resin, 1006 Phenols, 986 acidity of, 988–989 alcohol chemistry of, 1001–1004 arenediazonium salts and, 998–999 benzoquinones and, 1011–1013 bisphenol A, 990–991 derivatives, oxidative damage and, 1014–1016 electrophilic substitution of, 1004–1008 Friedel-Crafts acylation of, 1004 “green” industrial synthesis and, 1001 haloarenes and, 1000–1001 halogenation of, 1004 hydroxyarenes and, 987–988 hydroxymethylation of, 1006 keto and enol forms of, 987 names and properties of, 986–990 nucleophilic aromatic substitution and, 990–1001 oxidation of, 1011–1013 oxygen in, 1001–1002 Pd-catalyzed synthesis, 1000 preparation of, 990–1001 recognizing as enols, 1007 resveratrol, 988, 990–991 retrosynthetic connection to arenes, 999 Phenoxide ions, 988 Index Phenoxy, 988 Phenoxy radicals, 1011 Phenyl, 644 Phenyl alkanoates, 1002 Phenyl cation, 1019 Phenylacetamide, 703 Phenylalkanones from Friedel-Crafts acylations, 681 Phenylethanamine, 936, 943 Phenylhydrazone formation, 1088 Phenylmethoxycarbonyl group, 1190 Phenylmethyl (benzyl), 644, 980–984, 981 Phenylmethyl protection, 986 Phenylosazone formation, 1088 2-Phenyl-2-propyl cation, 982 Pheromone, 81, 523–524, 555, 862–863, 897, 1149, 1173 Phospha- prefix, 1123 Phosphoglycerides, 903 Phospholipids, 903, 904 Phosphonium salts, 768–769 Phosphoric acid, 16 Phosphorous acid, 336, 337 Phosphorous trichloride, 16 Phosphorus betaine, 770 Phosphorus ylides, 768–771, 768–771 Photochemical reactions, 608 Photocyclization, 610 Photosynthesis, 360, 1094 Pi bonds, 29–30, 30, 437 alkynes and, 553–556 deshielding effect, 441–442, 442 electron movement in, 441, 442 energy ordering and, 439 in ethene, 35, 35, 437–440, 437, 438, 439 in ethyne, 35, 35 strength measurement, 438–440 thermal isomerization and, 438–440 Pi electrons, 441–442, 442 Pi systems See Delocalized pi systems Picric acid, 705 pKa values, 62, 62n alcohols and, 284–286, 284t, 286t aldehydes and ketones and, 790–792 alkanoic acids and, 843t alkynes and, 544–545 amines and, 947t amino acids and, 1166–1167, 1169–1171 ammonium ions and, 945 benzoic acids and, 843t beta-dicarbonyl compounds and, 843t, 1042, 1042t carboxylic acid derivatives and, 889–890, 911 carboxylic acids and, 841–844, 843t dioic acids and, 843t methyl- and phenyloxonium ion and, 1001 phenols and, 988–989 protonated alcohols, 286t pyrroles and, 1134 thiols and, 357 Planar benzene, 664 Planck, Max K E L., 24n Plane-polarized light, 173 Planes of symmetry, 172, 172 Plasticizers, 521 Platensimycin, 819 Pleated sheets, 1180–1181, 1181 Polar covalent bonds, 10–12, 57 Polar reaction mechanisms, 217–219 Polar reactions, types of, 637t–638t Polarimeters, 173 Polarizability, 212 Polarization, 11 aldehydes and, 741 in alkenes, 440 C-X bonds, 212 in dipole, 11 ketones and, 741 reverse, 298 Poly (p-phenylene vinylene), 601 Polyacrylates, 564 Polyalkylation, 678 Polyaniline, 601 Polycarbonate plastics, 991 Polychloroethene, 520 Polycyclic alkanes, 150–151 Polycyclic aromatic hydrocarbons (PAHs), 655–661 cancer and, 722–724 regioselectivity of, 721–722 Polycyclic benzenoid hydrocarbons, 719–722 Polycyclic carboxylic acids, 868–869 Polyenes, conducting, 600–601 Polyethene, 520 Polyethers solvate metal ions, 340–342 Polyethylene terephthalate, 845 Polyfunctional carbohydrates, 1073 Polyisoprene, 616, 617–618 Polymerase chain reaction (PCR), 1204, 1211–1212 Polymerases, 1204 Polymeric acetylene chain, 547 Polymeric chains, 1198 Polymerization alkenes, 518–519 anionic, 521 conjugated dienes, 615–619 difluoroethene, 483 metal-catalyzed, 522 radical, 519–521 Polymers, 518 common, 520t copolymers, 616 cross-linked, 615–616 environmental benefits, 520 monomers and, 520t synthesis of, 519–522 urethane-based, 906 Polypeptide chains, 1176 Polypeptides absolute configuration of, 195 affinity chromatography and, 1185 amino acid residues and, 1178–1180 amino end and, 1178 carboxy end and, 1178 cleavage and, 1187–1188, 1188t dialysis and, 1185 Edman degradation and, 1186–1187 electrophoresis and, 1185 enzymes and, 1187–1189, 1188t gel-filtration chromatography and, 1185 hydrogen bond between strands, 1180 information storage in, 1198 ion-exchange chromatography and, 1185 main chain and, 1178 Merrifield solid-phase peptide synthesis and, 1193–1194 in nature, 1194–1196 oxygen transport and, 1194–1196 peptide bonds and, 1176–1177 primary structure and, 1180, 1184–1186 protecting groups and, 1190–1191 purification and, 1184–1185 secondary structure and, 1180 sequencing and, 1184–1186 side chains and, 1178 synthesis of, 1189–1192 tertiary structure and, 1182–1183 Polypropenenitrile, 521 Polypyrrole, 601 Polysaccharides, 1103–1110 Polystyrene, 1193 Polythiophene, 601 Poly(vinyl chloride), 565 Porphine, 1195, 1195 Porphyrin, 1194–1195 Potassium permanganate test, 511 Potential energy diagrams, 53, 53, 84, 86 benzene, 669 bromination of 2-methylpropane, 118 catalyzed and uncatalyzed process comparison, 104 CH3Cl formation from methane, 109 chair-chair interconversion, 142 E2 reactions of 2-bromo-2methylbutane, 451 fluorination of 2-methylpropane, 117 HCI addition to propene, 491 methane reaction with chlorine atom, 108 reaction of fluorine atom with CH4, 112 reaction of iodine atom with CH4, 112 SN1 hydrolysis of 2-bromo-2methylpropane, 251 SN2 reaction, 224 SN2 reaction of chloromethane with hydroxide, 251 Prelog, Vladimir, 176n Prescription drugs, 1122t Primary alcohols See also Alcohols ether synthesis from, 347–348 haloalkanes from, 328 organometallic compound reaction with formaldehyde and, 300 oxidation, carboxylic acids and, 845 oxidation to aldehydes, 748 I-17 PCC oxidation of, 295 rearrangement, 335–336 Primary amine, 934 Primary carbon, 74, 75 Primary haloalkanes, 267–268 Primary structure, proteins and, 1180, 1184–1186 Prodrugs chloramphenicol and, 899 prontosil and, 1023 Products, Progesterone, 157 Prontosil, 1023 Propadiene, 587 Propagation steps, 107–114, 111t, 122, 516–517, 520, 583, 981, 1014–1017 Propanal, 742 Propanedial (malondialdehyde), 1015, 1048 Propenenitrile, 963 Propenyl (allyl) system delocalization, 580–582 intermediate stabilization, 580 molecular orbital representation, 581–582, 581 partial electron density distribution, 582 Propranolol, 194 Propylene, 434 Propylhexedrine, 936 Prostaglandins, 447, 866–867 Protecting groups, 350–352 acetals as, 756–760, 1090–1091 dimethoxytrityl (DMT) as, 1208–1209 phenylmethyl esters as, 1190 phenylmethyl ethers as, 985–986 strategy, 350, 716–717 synthesis of polypeptides and, 1189–1192 tertiary butoxycarbonyl esters as, 1190 tertiary butyl ethers as, 350 in testosterone synthesis, 351 Protein Structure Initiative, 1207 Proteins, 1165 binding sites and, 1182 biosynthesis of, 1196–1201 cross-linking of, 1015 denaturation and, 1183 electrophoresis of, 1184 fibrous, 1182 globular, 1182 misfolded, “mad cow” disease and, 1183 nucleic acids and, 1196–1201 oxygen transport, 1194–1196, 1195, 1196 pleated sheets and, 1180–1181, 1181 primary structure and, 1180, 1184–1186 quaternary structure and, 1183–1184 recombinant DNA technology and, 1189 secondary structure and, 1180 sequencing, 1189 I-18 Index Proteins (continued) substrates or ligands and, 1182 superhelix and, 1182, 1182 synthesis, 1202–1204, 1202t tertiary structure and, 1182–1183 Proteomics, 1207 Protonation arenamines and, 946–947 of butadiene, 591 carboxamides and, 946–947 of carboxylic acid derivatives, 890 of carboxylic acids, 843–844 of double bonds, 59 electrophilic, 492 imines and, 946–947 of propene, 490–491 of pyrrole, 1133 reversibility, 493–494 Protons, benzene and, 668–670 electrophilic attack by, 488–489 fast exchange, 409–410, 410 spinning, 380 Psoralen, 1149 “Push-pull” transition states, 913 Pyramidal, 935 Pyranose, 1078, 1082, 1083, 1089 Pyridines, 1135 as aromatic, 1135–1137 chemical shifts, 1136 Chichibabin reaction and, 1141 condensation reactions and, 1137–1140 electrophilic aromatic substitution of, 1140–1141 electrostatic potential map of, 1136 Hantzsch synthesis and, 1137–1138 orbital picture of, 1136 reactions of, 1140–1144 resonance in, 1136 structure and preparation of, 1135–1140 as weak base, 1136 Pyridinium chlorochromate (PCC), 295 Pyrolysis, 103 Pyrroles, 1128 acidity, 1134 delocalized lone electron pairs, 1129–1130 electrophilic aromatic substitution, 1132–1134 orbital picture of, 1129 preparation from dicarbonyl compounds, 1130–1131 protonation of, 1133 resonance forms of, 1129 Pyruvate adduct formation, 1058 Q Quanta, 379 Quantized systems, 24 Quantum mechanics, 24 Quartets, NMR spectroscopy, 397 Quaternary carbon, 74, 75 Quaternary structure, proteins and, 1183–1184 Quetiapine (Seroquel), 1122t Quinine, 1022, 1150 Quinoline, 533, 1144–1147 Quinomethanes, 1006 R R,S sequence rules, 176–180 priority assignment and, 176–180 stereocenters, 176, 176 R symbol, 72 Racemic 2-bromobutane, 197–198 Racemic mixtures, 174 Racemization, 174, 795 Radical additions, 516–517 Radical allylic halogenation, 582–584 Radical allylic substitution, 582 Radical chain mechanism, 106–108, 109–115, 121–122, 516–517, 582–584, 1014–1016 Radical chain sequence, 516 Radical halogenation with fluorine and bromine, 117–118 Radical halogenations of methane, 111–113 Radical hydrobromination, 517 Radical polymerization, 519 of ethene, 520, 521 mechanism of, 520 Radical reactions, 97, 636t Radical-radical combination, 109 Radicals, 98 alkyl, structure of, 101–102 cycloalkyl, 132 enantiomers and, 193 formed by homolytic cleavage, 98–99 stability of, 100–101 stabilization by hyperconjugation, 102 Raney, Murray, 485n Rate constant, 55 Rate law, 219 Rate-determining step, 249–251, 260, 669, 699, 761, 796, 992–993 Rational drug design, 1109 Reactants, Reaction coordinates, 53 Reaction intermediates, Reaction mechanisms, 4–5 Reaction rates activation energy and, 53 activation-energy barrier and, 54 Arrhenius equation and, 56–57 first-order reaction and, 55, 56 rate constant and, 55 reactant concentration and, 54–55 second-order reaction and, 55 temperature and, 56–57 Recombinant DNA technology, 1189 Recording an NMR spectrum, 383 Redox reactions, 289 Reducing sugars, 1085 Reduction, 289 aldehydes and ketones to alcohols, 291–293 alkanes and, 554–556 amides and, 910–911 azides and, 987 in the body, 290–291 carboxylic acids and, 860–861 cyanide and, 948 esters to alcohols, 902 esters to aldehydes, 902 lithium aluminum hydride, 293 monosaccharides to alditols, 1087–1088 nature and, 1013–1018 nitriles to aldehydes and amines, 916–917 ozonide, 514 SN2 reactions, 238, 239 Wolff-Kishner, 766–767 Reductive animation, 950–953 amine synthesis by, 951 general, 950 of ketones, 951 Regioselectivity, 352 in benzylic halogenation, 980 in E2 reactions, 264, 450–452, 450, 451 in electrophilic additions, 490, 557 in electrophilic aromatic substitution, 696, 698–711, 720–721, 1132 enolate formation and, 791 halogen atom attack, 516 halonium ion opening, 498–500 in hydroboration, 505–506, 557, 560 in oxacyclopropane opening, 355 in oxymercuration, 501–503 in radical additions, 516–517, 520 Relative reactivities of alcohols with alkali metals, 327 of alcohols in dehydrations, 454 of aromatic heterocycles, 1130, 1133 of branched bromoalkanes with iodide, 237t, 239t of bromoalkanes with water, 248t of carbonyl group in aldehydes and ketones, 753 of carboxylic acid derivatives, 886–887 of competing nucleophiles in the SN1 reaction, 255 in hydrogen abstractions, 112–116, 118t of pi bonds in alkynes, 553–563 Replication, DNA, 1200–1201, 1201 Residues, 1177 Resolution catalytic kinetic, 354–355 of enantiomers, 199–201, 200 of racemate, 201 Resonance, 381, 696 See also Nuclear magnetic resonance (NMR) spectroscopy in acylium ion, 681, 744 in aldehydes, 838 in alkynyl cations, 549–550 in allyl, 468–469, 580–587 arenediazonium salts, 1018–1019, 1019 in annulenes, 661–667 in aromatic heterocycles, 1129, 1134–1136, 1171 in azo dyes, 1021 in benzene, 596, 642 in benzenoid hydrocarbons, 660 in benzyl, 980–981, 983–984 in benzyne, 997 in carbonyl group, 741, 838 in carboxylates, 842 in carboxylic acid derivatives, 886–887 in carboxylic acids, 838 C-L bond and, 888–889, 888t in conjugated carbonyl compounds, 598, 810, 812 in conjugated dienes, 588–590 in electrophilic aromatic substitution, 668–669, 697–708, 1132 in enamines, 799 in enolates, 790, 842 hybrids, 19 in hydroxycarbocations, 467 in imine derivatives, 763, 941 in indole, 1135 in ketones, 838 major contributors, 21 mixing colors analogy, 20 in naphthalene, 658 in nucleophilic aromatic substitution, 992–993 in pentadienyl radical, 1014–1015 in peptide bonds, 1177 in phenoxide ion, 988–989, 1012 in protonated imidazole, 1171 in pyridine, 1136 stabilization, 64 in sulfuric acid, 65 in thiazolium ion, 1057, 1060 Resonance energy, 647 Resonance forms, 18–23 See also Resonance carbonate ion and, 18–20 drawing, 19 major resonance contributors, 21 nonequivalent, 20–23 recognition and formulation of, 19–20 Resonance-stabilized cations, 549–550 Restriction endonucleases, 1204 Resveratrol, 988, 990–991 Retention of configuration, 225 Retina, 789 Retro-Claisen condensations, 1042–1043 Retrosynthetic analysis, 306 alcohol construction and, 307–309 Claisen condensation and, 1046–1048 strategic disconnection and, 306 of synthesis of 4-ethyl-4nonanol, 308 synthesis problem simplification and, 305–307 of 3-hexanol, 307 Reverse polarization, 298 Reversible sulfonation, 672–673, 716 Rhizobium bacteria, 934 Ribonucleic acids (RNA), 1196 messenger (mRNA), 1202–1203, 1203 nucleotides of, 1198 protein synthesis through, 1202–1204 Index Ribonucleic acids (RNA) (continued) structures of, 1196–1198 transcription and, 1202 transfer (tRNA), 1202–1203, 1203 translation and, 1202 Ribose, 1074 Ribosomes, 1202 Rickets, 1145 Ring current, 652, 652 Ring size, 345–346 Ring strain, 135–138 in cyclopropane, 136 presence of, 135–136 smaller cycloalkanes and, 137–138 Ring-fusion carbons, 150 Ring-fusion substituents, 150 Robinson, Robert, 818n Robinson annulation, 818, 819, 1054–1055 Rodbell, Martin, 808n Rosuvastatin (Crestor), 1122t Rotational energy, 83 Rotations in ethane, 81–82, 82 Fischer projection, 182 single bonds and, 81–84 steric hindrance and, 84–85 in substituted frames, 84–88 Rotundone, 810 Rowland, R Sherwood, 121n RU-486, 158 Rubber, 615–619 Ruff, Otto, 1093–1095 Ruff degradation, 1093–1095 S Saccharic acid, 1086 Saccharides, 1073 Saccharin, 3, 1101 Sandmeyer, Traugott, 1019n Sandmeyer reactions, 1019 Sanger, Frederick, 1204 Sanger DNA sequencing method, 1205–1206, 1206 Saponification, 863 Saturated compounds, 433 Saytzev, Alexander M., 451n Saytzev rule, 451 Scanning tunneling microscope (STM), 36, 485 Schiff, Hugo, 760n Schiff base See Imines Schmitt, Rudolf, 1007n Schrock, Richard R., 525n Schrödinger, Erwin, 23n S-cis, 589, 590 Scissoring motion, 939 Secondary alcohols See also Alcohols ether synthesis from, 348 formation from Grignard reagent and aldehyde, 300 oxidation of, 294 Secondary amine, 934 Secondary carbon, 74, 75 Secondary C-H bonds, 114–115 Secondary haloalkanes, 247–248, 269 Secondary structure, proteins and, 1180 Second-order reactions, 55 Semicarbazones, 763 Semiquinone radical anion, 1012 Sequencing, amino acid, 1184–1186 Sequencing, peptide, 1186–1187 Sequencing, protein, 1189 Serotonin, 1149 Sex hormones, 155–157 “Sexual swindle,” 81 Sharpless enantioselective oxacyclopropanation and dihydroxylation, 512–513 Sharpless, K Barry, 194n Shielded nuclei, 385–386, 386 Shirakawa, Hideki, 600n Short tandem repeats (STR), 1212–1213 Sialic acid, 1108–1109 Side chains (polypeptides), 1178 Sigma bonds, 29–30, 30 Sildenafil citrate (Viagra), 1123 Simmons, Howard E., 508n Simmons-Smith reagent, 508 Simple sugars, 1074 Single bonds, 10 covalent, rotation about, 81–84 Singlets, NMR spectroscopy, 397 Skew conformations, 82 Skew-boat cyclohexane, 141, 141 Skin color, 1145 Smalley, Richard E., 656n Smith, Ronald D., 508n Smoking, 1126–1127 SN1 reactions, 249 allylic halides and, 584–586 anticancer drug synthesis and, 259 carbocation stability and, 256–259 green criteria, 258 hydride shifts and, 330–333, 331 hyperconjugation and, 256, 257 leaving groups and, 254 nucleophile strength and, 254–255 polar solvents and, 254 rearrangement by alkyl shift in, 334 secondary systems and, 256–258, 257t stereochemical consequences of, 252–253 stereoselective displacement and, 259 transition states, 254 visual demonstration, 258 water as leaving group in, 328–330 SN2 reactions allylic halides and, 586 aprotic solvents and, 232–233, 232t backside displacement mechanism, 222 branching at reacting carbon and, 237–238 carbon lengthening and, 238–239, 239 in enantiomer synthesis, 225–227 ether preparation by, 342–344 green criteria, 258 inversion consequences in, 224–227 inversion of configuration, 222 leaving-group ability and, 227–229 of molecules with two stereocenters, 226 nucleophilic ring opening of oxacyclopropanes and, 352 nucleophilicity and, 229–235 potential energy diagram, 224 reduction of, 238, 239 retention of configuration and, 225 secondary systems and, 256–258, 257t stereochemistry of, 222–224 stereospecificity and, 222–223 structure and, 227–229 summary, 240 transition states and, 224, 224, 233, 237, 240 water as leaving group in, 328 SNF 4435 isomer formation, 613 Soaps and detergents, 864–865 Sodium amide, 944 Sodium borohydride, 40–41 aldehydes and ketones reduction by, 289–293 alkylmercuric acetate reduction by, 501 aldoses reduction by, 1087–1088 disulfides reduction by, 358–359 Sodium cation, Sodium chloride, Sodium cyanoborohydride, 951 imine reduction in reductive amination, 951–952 Sodium nitrite, 959 Sodium reduction of alkynes, 555 Solanine, 1148 Solvated molecules, 232 Solvation drug activity and, 231 nucleophilicity and, 231–232, 232 Solvents aprotic, 232–233, 232t coordinated, 297 ether, 340 SN1 reactions and, 254 SN2 reactions of iodomethane with chloride ion in, 233t Solvolysis, 247 carbocation formation and, 249–252 of 2-chloro-2-methylpropane, 248 first-order kinetics and, 249 rate-determining step and, 249, 249 rearrangement in, 333 of tertiary and secondary haloalkanes, 247–248 Sondheimer, Franz, 663n Sonogashira, Kenkichi, 562n Sonogashira coupling reaction, 563 Sorbose, 1091 Sp hybrids, 32–33, 33 Sp2 hybrids, 33–34, 33, 438 Sp3 hybrids, 34, 34 Space-filling model, 78 Specific rotation, 173, 174t Spectinabilin, 613 Spectrometers, 379, 380 I-19 Spectroscopy, 378–380, 380–381 baseline and, 379 correlation (COSY), 417 Fourier transform (FT) and, 379 heteronuclear correlation (HETCOR), 418 infrared, 456–460 molecular excitations and, 378–379 nuclear magnetic resonance (NMR), 380–421 peak and, 379 radiation absorption and, 379–380, 379 spectrum and, 379, 380 ultraviolet, 619–624 visible, 619–624 Spectrum, 379, 380, 382, 383 Speier, Arthur, 854 Spider pheromone, 1173 Spin, 26 Spin states, 380, 381 Spin-spin coupling, 397–404, 397, 547–548, 547 Spin-spin splitting, 397–404, 397 in common alkyl groups, 402t complications, 404–411 coupling constant and, 398, 398 fast proton exchange and, 409–410, 410 geminal coupling, 399 multiple hydrogens and, 399–400, 399 N 1 rule and, 400–402, 401 nonequivalent neighbor coupling and N 1 rule, 406–409, 406, 408 non-first-order spectra and, 404–406, 405 Pascal’s triangle and, 400t rapid magnetic exchange and, 410–411 sequential N ϩ rule, 406–409, 444–445 temperature dependence of, 410, 410 vicinal coupling, 399 Staggered conformations, 81 Starch, 1103–1104 State of equilibrium, 50 Statistical product ratio, 114 Stem chain, 75 Stereocenters, 170 chlorination of (S)-2-bromobutane and, 191–197, 196 molecules incorporating several, 185–188 more than two, 188 R,S configuration, 176, 176 substituted, 189–190 two, 185–186 Stereochemistry in chemical reactions, 191–199 cyclic bromonium ions and, 496–497 of SN2 reaction, 222–224 Stereoisomerism, 2, 168, 169 Stereoisomerization, 793–796 I-20 Index Stereoisomers, 133, 167–210, 189–190 absolute configuration and, 175–180 chiral molecules, 169 diastereomers, 186–188, 188 Fischer projections and, 180–185 meso compounds and, 188–191 more than two stereocenters and, 188 optical activity and, 172–175 R,S sequence rules, 175–180 resolution of enantiomers and, 199–201, 200 stereochemical relations of, 189 stereochemistry in chemical reactions, 191–199 stereoperception and, 179 stereoselectivity and, 198 substituted stereocenters and, 189–190 tartaric acid and, 187 two stereocenters and, 185–186 Stereoperception, 179 Stereoselective aldol reactions, 805 Stereoselective displacement, 259 Stereoselective products, 198 Stereoselectivity aldol reaction, 805 Diels-Alder reaction, 604–606, 606 drug synthesis, 193–194, 259 E2, 453–454, 487–488 hydroboration, 505 hydrogenation, 194, 487–488, 553 norepinephrine from dopamine,198 steroid, 290–291 Wittig reaction and, 770 Stereospecific intramolecular Williamson synthesis, 346–347 Stereospecificity, 222 catalytic hydrogenation, 487 Diels-Alder reaction, 602–604 in E2 reactions, 453–454 electrocyclic reactions, 609–615 in SN2 reaction, 222–227 Steric disruption, 285–286 Steric hindrance, 84–85 Sterically hindered bases, 267–268 Steroids, 131, 154–157 See also Cycloalkanes angular fusion and, 154 bile acids, 865 cholesterol and, 156 crystalline epiandrosterone, obtaining, 154 detection by mass spectrometry, 465 as hormones, 154–157 hydroxylation, 291 as performance enhancing drugs, 131, 156 synthesis, 351 Stevioside, 1101 Stille, John K., 562n Stille coupling reaction, 562 Stomach acid, 61 Straight-chain alkanes, 72 names, 74t physical constants of, 79 physical properties, 74t S-trans, 589, 590 Strategic disconnection, 306 Strecker, Adolf, 1174n Strecker synthesis, 1174 Strong acids See also Acids carboxylic acids as, 841–842 reactions of alcohols with, 327–330 Strong bases See also Bases bimolecular elimination (E2) and, 262–263 in deprotonating alcohols, 326 hydrazone conversion, 766–767 Strong nucleophiles, 266–267 Structural isomers, 37 Strychnine, 301, 1150 Styrene, 643 Substituents, 38, 75 activation or deactivation on benzene ring, 696–698 benzene, 979–1037 cis, 133 electron-withdrawing, 842–843 in electrophilic aromatic substitution, 708t equatorial positions and, 146–147 exchanging in Fischer projection, 182–183 halogen, 707–709 keto-enol equilibria and, 793 priority assignment to, 176–180 ring-fused, 150 trans, 133 Substituted benzenes alkyl, 984–986 arene, 644 arenediazonium salts conversion into, 1019–1020 directing effects of, 702–709 directing power of, 713–715 Friedel-Crafts electrophiles and, 715 groups that donate electrons and, 702–704 groups that withdraw electrons and, 706–707 halogen substituents, 707–709 infrared bending vibrations for, 651 protection strategies and, 716–719 reversible sulfonation and, 716 synthetic strategies toward, 713–719 Substituted cyclohexanes, 144–149 axial and equatorial methylcyclohexanes and, 144–146, 146t competition for equatorial position and, 146–147 Newman projection of, 145 1,3-diaxial interaction and, 144–145 Substitution, See also Electrophilic aromatic substitution; Nucleophilic substitution curved arrows and, 58, 67 Substrates, 4, 214, 1182 leaving groups, 235 with multiple stereocenters, 226 nucleophilic attack and, 237–240 Succinic acid, 835 Sucralose, 1101 Sucrose characteristics of, 1098 as disaccharide, 1098–1102 heat of combustion, 123t inversion of, 1099 Maillard reaction, 1194 octaester Olestra, 937 sweetness, 1100–1101 temperature stability and, 1099 Sugars acetals and, 1089–1092, 1102–1103 as aldoses and ketoses, 1074 amino acids and, 1167 anomers of, 1083–1084 biological synthesis, 1094–1095 as chiral and optically active, 1075–1076 complex, 1074, 1098–1103, 1102–1103 conformations and cyclic forms of, 1078–1082 cyanohydrin formation and reduction and, 1092–1093 cyclic, 1081–1082 D and L designations, 1075 esterification, 1089–1091 Fehling’s test and, 1084–1085 Fischer projections and, 1075 Haworth projections and, 1081–1082 intramolecular hemiacetals and, 1078–1081 invert, 1099 methylated, 1089–1091 modified, nitrogen and, 1107–1110 in nature, 1098–1110 neighboring hydroxy groups in, 1091–1092 nucleic acids, 1196 oxidative cleavage of, 1086–1087 periodic acid degradation of, 1087 polyfunctional chemistry of, 1084–1086 reducing, 1085 Ruff degradation and, 1093–1095 simple, 1074 step-by-step buildup and degradation of, 1092–1095 Tollens’s test and, 1084–1085 Sulfa drugs, 362, 673, 674, 1023 Sulfides, 357 by alkylation of thiols, 358 reactions of, 357–358 valence-shell expansion and, 358–359 Sulfonamides, 362, 673 Sulfonates, 864–865 Sulfonation, 672–673, 716 Sulfonation, of benzene, 673 Sulfones, 359 Sulfonyl chlorides, 673 Sulfosalicylic acid, 711 Sulfoxide, 359 Sulfur analogs, 357–359 garlic and, 363 valence-shell expansion of, 358–359 Sulfuric acid, 16 nitric acid activation by, 672 resonance effect in, 65 Sunglasses, 621 Sunscreen SPF value, 650 Superhelix, 1182, 1182 Superoxide, 1014 Sustainability, 105 Suzuki, Akira, 562n Suzuki coupling reaction, 562–563 Sweetness, 1100–1101 Symmetrical ethers, 72 Symmetry, chiral molecules and, 171–172 Syn addition, 487 Synthesis, 3, 338 acetals and, 755, 758 acetoacetic ester, 1050–1051 acyl halide, 851 alcohols, 289–296, 506 aldehydes and, 747–749, 747t alkenyl organometallics in, 561 alkyl sulfonate, 338 alkylbenzene, 767 alkynes and, 551 alpha-hydroxyketones and, 1056 amines and, 947–954 amino acids and, 1171–1174 antibacterial, 819 anticancer drug, 259 antitumor drugs, 512–513 aromatic detergent, 673 benzene derivatives, 668–670 biomimetic, 613 bromoalcohol, 498 bromoalkane, 328, 337 butylbenzene and, 715 carboxylic acid, 844–845 chloroalkane, 337–338 chloroethene, 522 cis alkenes, 553–554 conjugate addition in, 815–816 convergent, 310 cyclic ether, 344, 345 cyclopropane, 507–508 dialkylated acetic acid and, 1051 dibromobenzene and, 1020 dinucleotide, 1209 DNA, 1207–1211 enantiomers, 225–227 enantioselective, 194, 1174–1175, 1176–1177 ether, 347–349 formic acid, 844 goal of, haloalkane, 336–339 Hantzsch, 1137–1138 hexanol, 307 hydrazone and, 766 iodoalkane, 328 ketones and, 300, 747–749, 747t linear, 310 malonic ester, 1051–1053 Mannich reaction in, 957 natural ruber, 617–618 nitrobenzenamine and, 717 Index Synthesis (continued) nucleophilic aromatic substitution in, 993–994 oxacyclopentane, 565 oxacyclopropane, 508–510 Pd-catalyzed phenol, 1000–1001 peptide, 1190–1191 phenolic resin, 1006 phosphonium salt, 769 polymers and, 519–522 polypeptides and, 1189–1192 protected aldehyde in, 757 proteins, 1202–1204, 1202t Strecker, 1174 strychnine, 301 sugar, biological, 1094–1095 testosterone, 351 total, 302 utility of alcohol oxidations in, 309 varenicline, 1127 vicinal haloether, 498 Williamson ether, 342–347, 1002 Wöhler’s synthesis of urea, 3, Synthesis gas, 287 Synthetic dyes, 1022–1023 Synthetic rubbers, 616–617 Synthetic strategy, 301–311, 302–304 mechanisms in predicting outcome of reactions, 302–304 new reactions lead to new methods, 304–305 retrosynthetic analysis and, 305–310 syntheses planning pitfalls and, 310–311 Systematic nomenclature, 73 T Tartaric acid, 187 diethyl ester in enantioselective oxacyclopropanation, 512 resolution and, 199 tetroses and, 1096 Tautomerism, 558 Tautomerize, 558 Tautomers, 558 Taxol, 153–154 Temperature, reaction rates and, 56–57 Temperature units, 51n Terminal alkenes, 435 Terminal alkynes, 542, 544–545 acidity of, 544–545 deprotonation of, 545 hydration of, 558 hydroboration of, 560 hydroboration-oxidation of, 560 infrared absorptions and, 548–549, 549 Termination steps, 109, 113, 516, 520 Terpenes, 153 Tert-butoxycarbonyl, Boc, 1190 Tertiary alcohols ether synthesis from, 348 ketones and, 301 Tertiary amine, 934 Tertiary butyl ethers, 350–352 Tertiary carbon, 74, 75 Tertiary C-H bonds, 115–116 Tertiary haloalkanes, 247–248, 269, 311 Tertiary structure, proteins and, 1182 Tesla, Nikola, 381n Testosterone, 156, 157 detection, 463 synthesis, 351 Tetracene, 658 Tetrahedral structures due to valence electron repulsion, 12 Tetrahedral carbon, Tetrahedral carbon compounds, 34, 34 Tetrahedral intermediate, 849, 856, 859 Tetrahydroisoquinoline, 1150 Tetroses, 1074 Theobromine, 903, 1150 Thermal dehydration, 1189 Thermal isomerization, 438–440, 439 Thermodynamic control, 50, 492–494, 593 See also Kinetic control changing product ratios and, 592–594 electrophilic attack on conjugated dienes and, 591–595 kinetic control verus, 593 thermodynamic control versus, 593 Thermodynamic feasibility, 483–485 Thermodynamics catalysts and, 104 of simple chemical processes, 50–57 Thia- prefix, 1123 Thiamine, 1058–1059 Thiamine pyrophosphate, 1095 Thiazolium salts, 1057 acidity of, 1060 aldehyde coupling and, 1057–1061 catalysis mechanism, 1060 thiamine, 1058–1059 Thioacetal hydrolysis, 759 Thioacetals, 759–760 Thiol esters, 863 Thiol-disulfide redox reaction, 359 Thiols, 72, 357–359 acidity of, 357 boiling points, 357t oxidation of, 358–359 radical addition to alkene, 517 reactions of, 357–358 sulfides by alkylation of, 358 valence-shell expansion and, 358–359 Thionyl chloride, 853 Thiophenes, 1128 delocalized lone electron pairs, 1129–1130 electrophilic aromatic substitution, 1132–1134 orbital picture of, 1129 preparation from dicarbonyl compounds, 1130–1131 3’ end, 1198 Threose, 1076 Thymine, 1196 Tigecycline, 909 TNT, 705 Tollens, Bernhard C G., 773n Tollens’s test, 773, 1084–1085 Toluene, 643 Torsional angle, 83 Torsional energy, 83 Torsional strain, 83 Total synthesis, 302 trans alkene production, 554–556 trans coupling, 442–444 Trans fatty acids, 866 trans isomers, 448–449 trans substituents, 133 Transcription in protein synthesis, 1202 Trans-decalin, 150–151, 151 Trans-dehydromatricaria ester, 566 Transesterification, 899–900 Transfer DNA (tRNA), 1202–1203, 1203 Transition states, 53 aromatic, 649 bimolecular elimination (E2), 264 diastereomeric, 196 Diels-Alder reaction, 601 of inversion, 938 “push-pull,” 913 SN1 reactions, 254 SN2 reactions, 224, 224, 237, 240, 254 symbol, 221 Translation in protein synthesis, 1202 Tremetone, 1148 Triamantane, 152 Tricarboxylic acid (TCA) cycle, 1058 (Trifluoromethyl)benzene, 701 Triglycerides, 903 Trigonal structures due to valence electron repulsion, 12 Trihydroxybutanals, 1076 -trione ending, 739 Trioses, 1074 Tripeptides, 1177, 1178 Triple bonds, 10, 14 additions use of curved arrows, 59 in alkynes, 69, 543, 547–550 in benzyne, 996 in drugs, 158, 917, 566–567 anti-Markovnikov additions to, 559–560 in ethyne, 35, 543 hydration, 749 infrared spectroscopy, 458t, 549 in nitriles, 915 priority rules, 178 reduction, 553–556 Triplets, NMR spectroscopy, 397 Trivial names, 73 Trypsin, 1187 Tryptamine, 1135 Tscherning, Kurt, 154 Twist-boat conformation, 141, 141 U Ubiquinones, 1013–1014 Ultraviolet spectroscopy, 619–624 electronic excitations and, 620–621, 621 viniferone characterization and, 623 Ultraviolet spectrum, of benzene, 650, 650 I-21 Unimolecular elimination (E1), 259–262 alcohol dehydration by, 329 alkene-forming step in, 261 carbocation rearrangements and, 333 product mixtures and, 261 reaction mechanism, 261 SN1 ratio to, 262t water as leaving group in, 328–330 Unimolecular nucleophilic substitution, 248–252, 249 See also SN1 reactions carbocation formation and, 249–252 first-order kinetics and, 249 leaving groups and, 254 nucleophile strength and, 254–255 polar solvents and, 254 “Unnatural products,” structural characterization of, 419–420 Unsaturated aldehydes base-catalyzed hydration of, 813 conjugated, 810–811 conjugate additions to, 812–814 in nature, 808–809 properties of, 810–812 reactions of, 811–812 Unsaturated carbonyl compounds, 810–811, 812 Unsaturated compounds, 433 Unsaturated fatty acids, 866–887 Unsaturated ketones base-catalyzed hydration of, 813 conjugated, 810–811 conjugate additions to, 812–814 properties of, 810–812 reactions of, 811–812 Upfield, NMR spectroscopy, 386 Uracil, 1196 Urea, Wöhler’s synthesis of, 3, Urethane-based polymers, 906 V Valence electrons, in drawing Lewis structures, 13 as electron dots, repulsion, 12–13 Valence-shell electron-pair repulsion (VSEPR) method, 12–13 Valence-shell expansion, 16 van der Waals forces, 79 van der Waals, Johannes D., 79n Vancomycin, 909 Vanillin, 641 van’t Hoff, Jacobus H., 187n Varenicline, 1127 Vegetable oil, green fuels from, 905 Vibrational excitation, 456–457, 457 Vicinal anti dihydroxylation, 510 Vicinal coupling, 399, 443 Vicinal diols cyclic acetal formation from, 1091 oxidative cleavage of, 1086 periodic acid cleavage of, 1087 Vicinal haloether synthesis, 498 Vicinal syn dihydroxylation, 511–513 Villiger, Victor, 772n I-22 Index Viniferone, 623 Visible spectroscopy, 619 Visible spectrum, 620, 624 Vision, 808–809 Vitamin B6, 1123 Vitamin B12, 1123 Vitamin C, 1016 Vitamin D, 1145 Vitamin E, 1015–1016 reactions with lipid hydroperoxy and alkoxy radicals, 1016 regeneration by vitamin C, 1016 synthetic analogs of, 1017–1018 Volhard, Jacob, 861n Von Baeyer, Johann Friedrich Wilhelm Adolf, 772n Von Fehling, Hermann C., 773n Vulcanization, 616 W Wacker, Alexander, 522n Wacker process, 522 Water, 10 acidity of alcohols and, 284–285 alcohols structural similarity to, 281–282, 282 arenediazonium salts decomposition in, 998 bonding and electron repulsion, 35, 35 carbonyl group and, 752–754 clusters in gas phase, 282 as leaving group, 328–330 nucleophilic attack by, 250 Watson, James D., 1200n Wave equations, 23–24 Wave functions, 24 Waves, 24 Waxes, 903 Weak acids, 943–944 Weak nucleophiles, 266 Weight control, amines and, 936–937 Williams, Evan R., 1179n Williamson, Alexander W., 342n Williamson ether synthesis, 342–344 alkoxybenzene synthesis by, 1002 cyclic ether synthesis and, 344–345 intramolecular, 346–347 ring size and, 345–346 SN2 reactions and, 342–344 stereospecific, 346–347 Willstätter, Richard, 662n Wittig, Georg, 768 Wittig reaction, 768–771 carbon-carbon double bonds and, 769–771 highly trans-selective, 771 mechanism of, 770 Wöhler, Frederick, Wöhler’s synthesis of urea, Wolff, Ludwig, 766n Wolff-Kishner reduction, 766–767 in alkylbenzene synthesis, 767 of Friedel-Crafts acylation product, 767 nitrogen elimination in, 766 Wong, Richard L., 1179n Woodward, Robert B., 614n Woodward-Hoffmann rules, 614 X X-ray diffraction, 175–176 Xylene, 643 Xylitol, 1101 Y -ylene suffix, 434 -yne suffix, 542 Z Zanamivir (Relenza), 1109 Zelinsky, Nicolai D., 861n Zerumbone, 815 Zidovudine (AZT), 1123 Ziegler, Karl, 522n Zingiber zerumbet, 815 Zwitterions, 770, 1168–1169 Structure and Bonding Ionic bonds: Formed by transfer of electrons from one atom to another (1-3) Covalent bonds: Formed by electron sharing between two atoms; polar covalent bonds: Between atoms of differing electronegativity (1-3) Lewis structures: Electron dot descriptions of molecules; resonance forms: Multiple Lewis structures for a molecule; octet rule: Preferred valence electron total for atoms (2 for H) (1-4, 5) Alkanes: CnH2n12 hydrocarbons; straight-chain or branched; acyclic; nearly non-polar; weak intermolecular London forces (2-7) Conformations: “Free” rotation about single bonds; staggered 2.9 kcal mol21 more stable (lower energy) than eclipsed (2-8, 9) Cycloalkanes: CnH2n hydrocarbons; n 3, 4: Cyclopropane, cyclobutane (strained bond angles); n 6: Cyclohexane (most stable, chair conformation); axial (less stable) & equatorial (more stable) substituent positions (4-2, 3) VSEPR: Governs molecular shape and geometry around atoms (1-8) Stereoisomers: Same atom connectivity, different threedimensional arrangement; cis: Two substituents on same ring face; trans: Opposite faces (4-1) Hybrid orbitals: Explain geometry; sp3: Tetrahedral (1098, CH 4); sp2: Trigonal planar (1208, BH3 and H2CPCH2); sp: Linear (1808, BeH2 and HCqCH) (1-8) Reactions: Few (nonpolar, lack functional groups); combustion, halogenation (3-3 to 11) S bonds: From end-to-end orbital overlap; P bonds: From side-by-side orbital overlap (1-8) Constitutional isomers: Different connectivity (1-9) Halogenation: Radical chain mechanism with initiation, propagation, termination steps (3-4) C H ϩ X2 h␯ or Δ C X ϩ HX X ϭ Cl, Br Structure and Reactivity; Acids and Bases Thermodynamics: Govern equilibria; DG8 2RT ln K 21.36 log K (at 258C) (2-1) Gibbs free energy: DG8 DH8 TDS8; enthalpy: DH8; exothermic if , 0; endothermic if 0; entropy: DS8; measures energy dispersal (disorder) (2-1) Kinetics: Govern rates; first order: Rate k[A]; second order: Rate k[A][B] (2-1) Reaction coordinate: Graph of energy vs structural change; transition state: Maximum-energy point on reaction coordinate; activation energy: Ea E (transition state) E (starting point) (2-1, 7, 8) Brønsted acids: Proton donors; Brønsted bases: Proton acceptors (2-3) Strong acids HA: Have weak conjugate bases A2; acid dissociation constant Ka: pKa 2log Ka; HA acid strength: h for A larger, more electronegative, resonancedelocalized negative charge; g pKa stronger acid (2-3) Lewis acids/electrophiles: Electron pair acceptors; Lewis bases/nucleophiles: Electron pair donors (2-2, 3) (DHЊC H ϩ DHЊX X) Ϫ (DHЊC X ϩ DHЊH X) ϭ ΔHЊ Reactivity: F2 Cl2 Br2 (I2 none); selectivity: Br2 Cl2 F2 (3-8) Reactivity: Tert sec prim methane COH; follows radical stability due to hyperconjugation (3-7) Bond-dissociation energy: DH8; bond dissociation gives radicals or free atoms (3-1) Stereoisomers Chiral: Handed; not superimposable on mirror image; enantiomers: Mirror-image stereoisomers; stereocenter: Center of chirality in a molecule, such as a carbon with different groups attached (5-1); nomenclature: R/S system (5-3) Optical activity: Rotation of the plane of polarized light by an enantiomer; racemate (racemic mixture): Optically inactive 1:1 mixture of two enantiomers (5-2) Diastereomers: Non-mirror image stereoisomers (5-5) Meso compound: Achiral molecule with multiple stereocenters (5-6) Resolution: Separation of enantiomers (5-8) 2-3-4 Alkanes and Cycloalkanes 6-7 Haloalkanes IUPAC Nomenclature: Longest continuous chain; numbering: Lowest for first substituent (2-6) Functional group: d1COXd2; electrophilic C, leaving group X2 (6-1, 2) Reactions: Nucleophilic substitution (6-2 to 11, 7-1 to 5, 7-8, 9), elimination (7-6 to 9) H C C Nu Subst ϪXϪ NuϪ ϩ H C C X Elim ϪHX i i CP C f f SN2: R Me prim sec, backside displacement; SN1: R tert sec, racemization; E2: Nu2 strong base; E1: Side rxn to SN1, rates of SN1, E1 both follow carbocation stabilization by hyperconjugation 8-9 Alcohols and Ethers Nomenclature: Alkanol—longest chain containing OH; numbering: Lowest for OH (8-1) d2 Functional group: d1CO OOHd1; Lewis basic O; acidic H (pKa 16–18, like H2O), hydrogen bonding (8-2, 3) Preparation: Hydride/Grignard addn to CPO; prim: RCHO LiAlH4 or H2CPO RMgX; sec: RR9CPO LiAlH4 or RCHO R9MgX; tert: RR9CPO R0MgX (8-6, 8) LiAlH4 Hϩ, H2O H C OH i CP O f RMgX Hϩ, H2O R C OH Infrared spectroscopy: Gives bonds and functional groups (11-8) Wavenumber Bond 3650– 3200 3150– 3000 3000– 2840 2260– 2100 1760– 1690 1680– 1620 1500 OOH (s, br) NOH (m, br) qCOH (s) PCOH (m) OCOH (s) CqC (w) CqN (m) CPO (s) CPC (m) Fingerprint w weak; m medium; s strong; br broad Nuclear magnetic resonance: Gives hydrogen and carbon signals; chemical shift: Structural environment; integration: Number of H for each signal; splitting: Number of H neighbors (N 1 rule) (10-3 to 9) Chem shift 9.9–9.5 H type O B OC OH 4.0–3.0 9.5–6.0 H 2.6–1.6 H i D C f G O,Br,Cl H A A C 5.8–4.6 H i i CP C f f 1.7–0.8 variable alkyl COH OOH NOH C,O 11-12 Alkenes Nomenclature: Longest chain containing CPC (OH takes precedence); stereochemistry: Cis/trans or E/Z systems (11-1) Functional group: CPC, p bond electron pair nucleophilic, electrophiles add (11-2, 12-3 to 13) Oxidation: Cr(VI) reagents; RCH2OH (prim) PCC n RCHO (aldehyde); prim Na2Cr2O7 n RCO2H (carboxylic acid); RR9CHOH (sec) Na2Cr2O7 n RR9CPO (ketone) (8-6) Stability: h with increased substitution (R2CPCR2 most stable; H2CPCH2 least stable); trans disubstituted cis disubstituted Substitution: Prim, sec SOCl2, PBr3, P/I2 n RX; tert HX n RX (9-2 to 4) Preparation: Haloalkane strong base (bulky for prim RX), E2, anti stereospecific, most stable alkene favored (Saytzev rule) except with bulky base (Hofmann rule) (7-7, 11-6) Dehydration: Conc H2SO4 prim (1808C), sec (1008C), tert (508C) n alkene; carbocations rearrange (9-2, 3, 7) Preparation: Alcohol conc H2SO4, product mixtures (Saytzev rule) (9-2, 11-7) Ether synthesis: Williamson, RO2 R9X (R9 Me, prim) n ROR9 (9-6) Hydrogenation: H2 with catalytic Pd or Pt, syn addition n alkane (12-2) Ether cleavage: ROR9 HX (X Br, I) n RX R9X (9-8) 10-11 Spectroscopy Electrophilic addition mechanism: Electrophile adds to less substituted alkene carbon, nucleophile to more substituted alkene carbon (12-3) CH3CHPCH2 High-resolution mass spectrometry: Gives molecular formula (11-9, 10) Degree of unsaturation: Gives number of rings number of p bonds; degree of unsaturation (Hsat Hactual)/2, where Hsat 2n C 2 nX nN (11-11) E O Nu more highly substituted ϩ CH3CHOCH2E Ϫ Nu CH3CHOCH2E A Nu Hydrohalogenation: Markovnikov regioselectivity, except HBr peroxides (ROOR) (12-3, 13) CH3CHPCH2 ϩ H OX CH3CHPCH2 ϩ HO Br Reduction: H2, Pt n alkane; H2, Lindlar’s n cis alkene; Na, NH3 n trans alkene; (13-6) CH3CHOCH3 A X X ϭ Cl, Br, l ROOR CH3CHOCH2Br A H Hydration: Markovnikov with aq acid or oxymercuration; anti-Markovnikov with borane (12-4, 7, 8) CH3CHPCH2 BH3; H2O2, ϪOH Addition: HX, X2 add twice (13-7) Hydration: Hg21, H2O (Markovnikov) or R2BH, then 2OH, H2O2 (anti-Markovnikov) n enol n ketone or aldehyde via tautomerism (13-7, 8; 18-2) 14 Dienes Hϩ, H2O* or Hg2ϩ, H2O; NaBH4 *may rearrange CH3CHPCH2 Alkynyl anions: RCqCH NaNH2 n RCqC:2, then R9X (R9 Me, prim) n RCqCR9 (13-5) CH3CHOCH3 A OH CH3CHOCH2OH A H 1,2- and 1,4-addition to 1,3-dienes: Via delocalized allylic intermediate; kinetic product forms fastest; thermodynamic is more stable (14-6) H2CPCHO CHP CH2 Halogenation: Anti stereochemistry of addition via cyclic halonium ion (12-5) E O Nu 1,2-addn product (usually kinetic) ϩ H2CPCH O CHO CH2E Ϫ Nu ϩ @ 1,4-addn product (often thermodynamic) X Dihydroxylation: Anti using peroxycarboxylic acid; syn using OsO4 (12-10, 11) COC ; @ HO Hϩ,H2O @ C OC @ ; ; Diels-Alder reaction: Concerted, stereospecific cycloaddition (14-8) & O RCO3H ≥ i i CP C f f O OsO4 @ C ; HO O C @ ; H2S B C D A ´[ B ≥ D C OH @ COC @ ; ; 15-16-22 Benzene and Aromaticity Ozonolysis: Cleavage using ozone followed by reduction (12-12) i i CP C f f A ϩ OH O2 Os i i CP C f f ϩ Nu A H2COCH P CHO CH2E [ COC ; H2C OCH P CHO CH2E & X ≥ i i C P C ϩ X2 f f X ϭ Cl, Br Nu A H2CPCHOCHO CH2E O3; Zn, CH3CO2H i CPO f 13 Alkynes Functional group: CqC, two p bonds; qCOH bond acidic (pKa 25) (13-2) Preparation: Alkene halogen n 1,2-dihaloalkane (12-5), then double elimination (NaNH2) n alkyne (13-4) Nomenclature: Special common names, ortho/o (1,2), meta/m (1,3), para/p (1,4) for disubstituted (15-1) OH CH3 H2N Br 1-Bromo-2-methylbenzene (o-Bromotoluene) CH2OH Phenylmethanol (Benzyl alcohol) NO2 3-Nitrobenzenol (m-Nitrophenol) CHO Benzenecarbaldehyde (Benzaldehyde) l 4-Iodobenzenamine ( p-Iodoaniline) COOH Benzenecarboxylic acid (Benzoic acid) Aromaticity: Special stability, properties, and reactions, based on Hückel’s rule, 4n 2p electrons in a circle of p orbitals (15-2 to 7) Benzenamines: Preparation (16-5); diazotization (22-4, 10, 11) NO2 Electrophilic aromatic substitution mechanism: Electrophile adds to position favored by groups previously present (directing effects, below), followed by loss of H1 (15-8) N2ϩ H2O, Δ N2ϩ NH2 Zn(Hg), HCl or H2, Ni or Fe, HCl HNO2, 0ЊC OH Go,p N N CuX, Δ X ϭ Cl,Br,CN E Eϩ X Go,p Azo dyes E H ϩ Five electrophilic aromatic substitutions below, clockwise from bottom right: Sulfonation, nitration, halogenation, Friedel-Crafts (F-C) alkylation, Friedel-Crafts acylation (15-9 to 13) X2, FeX3 X (X ϭ Cl,Br) CH3Cl, AlCl3 CH3 HNO3, H2SO4 NO2 O CH3COCl, AlCl3 Hϩ, H2O CCH3 SO3, H2SO4 SO3H Directing effects: Ortho/para-directing Go,p include alkyl, aryl, halogen, OOR, ONR2; meta-directing Gm include OSO3H, ONO2, CPO, OCF3, ONR41 (16-2, 3) Activation/deactivation: All Go,p except halogen are activating; halogen and all Gm are deactivating (16-1 to 3) Go,p Go,p Go,p E ϩ E 17-18 Aldehydes and Ketones Nomenclature: Alkanal and alkanone—longest chain containing CPO; common: Formaldehyde (methanal), acetaldehyde (ethanal), acetone (propanone) (17-1) Preparation: ROH oxidation (8-6); CPC O3 (12-12); CqC hydration (13-7, 8): F-C acylation (15-13) Functional group: d1CPOd2; electrophilic C, Nu2 adds (17-2) Addition: H2O n hydrate, ROH n hemiacetal (both unstable); ROH, H+ n acetal (17-6 to 8) G Addition: RNH2 n CP NR; R2NH n enamine (17-9) D Deoxygenation: CPO n CH2, Clemmensen (16-5); dithioacetal Raney Ni (17-8); hydrazone base, D (17-10) Wittig: CPO CH2PPPh3 n CPC (17-12) faster than benzene ϩ Eϩ (except Go,p ϭ halogen) ϩ Phenols: Acidic (pKa 10; more acidic with deactivating substituents); phenoxide R9X (R9 Me, prim) n ether (22-4, 5) Aldol: Aldehydes, aldehyde ketone, intramolecular n a,b-unsaturated aldehyde/ketone (18-5 to 7) E Gm Gm O ϩ slower than benzene ϩ Eϩ E RCH2 ϩ RCH2 E Alkylbenzenes: F-C alkylation (may rearrange); F-C acylation, then reduction (16-5) Benzylic reactivity: Halogenation (22-1); oxidation to benzoic acid (22-2) ER H2C ON ER C X2, h␯ or Δ P Cl, Br Xϭ CHX KMnO4, HOϪ, Δ RCH2 CH C H O O H C CH Δ ϪH2O RCH2 C H R O HC CO2H OH C CH R 1,2- vs 1,4-addition: RLi n alcohol (1,2); H2O, ROH, RNH2, R2CuLi (cuprate) n 3-substituted carbonyl product (1,4); Michael addition: Enolate n 1,5-dicarbonyl (1,4); Robinson annulation: Intramolecular aldol n 6-membered ring (18-8 to 11) R Zn(Hg), HCl Clemmensen reduction HO Ϫ CH O O CR Ϫ OH O H2C ϩ H3C CCH3 Michael H2C R CR H2CD H2C Ϫ CH3 C O OH, Δ Robinson O 19-20-23 Carboxylic Acids and their Derivatives Nomenclature: Alkanoic acid—longest chain ending with CO2H; common: Formic (methanoic), acetic (ethanoic), benzoic (benzenecarboxylic) (19-1) Claisen condensation: Esters n b-ketoester; 1,7-diester n cyclic b-ketoester (intramolecular: Dieckmann condensation) (23-1) O RCH2 ϩ RCH2 Preparation: ROH oxidation; RMgX CO2; RCN hydrolysis (8-6, 19-6) Functional group: Highly polar, H-bonding (19-2); Lewis basic n d2OPCOOOHd1 m acidic (pKa 4) (19-4); Nu adds to CPO, OH may leave (addition–elimination) (19-7) COEt O RCH2 ϪEtOH (Et ϭ ethyl) O O R O Cl Ͼ R C fast at rt C CH3 C O H C COEt ϪOEt; RX ϪOEt; R؅X O CH3 H ϪCO2 O CH3 C CHR Malonic Ester Synthesis of Carboxylic Acids: Same (23-2) C NHR؅ requires Δ O O H C COEt ϪOEt; RX ϪOEt; R؅X O EtOC H ϪCO2 Amide formation: Halide, ester excess R9NH2 n RCONHR9 (20-2 to 4) Hydride reduction to aldehyde: Halide LiAl(OtBu)3; ester, amide DIBAL (20-2 to 6) Hydride reduction to prim alcohol: Halide, ester LiAlH4 (20-2 to 4) R؅2CuLi Hϩ, H2O O R C R؅ Grignard addition: Tert alcohols from esters (20-4) O R C OR؅ R؆MgX Hϩ, H2O O HO C ϪR؅OH C R؆ CHR 21 Amines Nomenclature: Alkanamine, follow rules for alcohols, use N- for additional groups on nitrogen; common, alkyl amine (21-1) NH2 CH3NH2 Methanamine (Methyl amine) CH3CH2CHCH3 CH3CH2CH2N(CH3)2 2-Butanamine (sec-Butyl amine) N,N-Dimethyl-1-propanamine (Dimethyl propyl amine) Functional group: Nonplanar (pyramidal), sp3 N, inverts easily; Lewis basic, nucleophilic N; NOH m weakly d1 (pKa 35) (21-2, 4) Basicity: Amine H1 n ammonium ion (pKa 10) (21-4) Preparation: RX N32 n RN3 (azide), then LiAlH4 n RNH2 (primary amine) (21-5) OH R COEt R؅ Hydride reduction to amine: RCONHR9 LiAlH4 n RCH2NHR9 (20-6) Cuprate addition: Ketones from halides (20-2) O R C R؅ ϪOH, H2O Hϩ, H2O, Δ Esterification: Halide, ester (transesterification) excess R0OH n RCO2R0 (20-2 to 4) Cl COEt R؅ Hydrolysis: All excess H2O n RCO2H (acid) (20-2 to 6) C O R C R؅ ϪOH, H2O Hϩ, H2O, Δ EtOC R C O OR؅ Ͼ R slow at rt O COEt R Reactivity order: Toward Nu addition/elimination of leaving group (bold); halides (and anhydrides)—no catalyst needed; esters, amidesOH1 or 2OH catalyst required (20-1) O H C C Acetoacetic Ester Synthesis of Methyl Ketones: Alkylate, hydrolyze, decarboxylate (23-2) Reduction: LiAlH4 n RCH2OH (19-11) Derivatives: RCO2H (acid) SOCl2 n RCOCl (halide); RCO2H R9OH, H+ n RCO2R9 (ester); RCO2H R9NH2, D n RCONHR9 (amide) (19-8 to 10) COEt O ϪOEt Hϩ, H2O R؆ One less carbon: RCONH2 (amide) Cl2, NaOH n RNH2 (Hofmann) (20-7, 21-7) CH2OH O OH OH OH H OH OH CH2OH HO HO Haworth CH2OH O OH conformational OH anomeric carbon ␤-D-glucopyranose (cyclic) HO OH Fischer (open-chain) COOϪ H3Nϩ H same as R O COOϪ ; R H Nomenclature: Heterocycloalkane; common names for many (25-1) H N O H N Oxacyclopropane Azacyclopropane Oxacyclopentane Azacyclopentane (Oxirane, epoxide) (Aziridine) (Tetrahydrofuran, THF) (Pyrrolidine) Heteroaromatics: Common names (25-1) O H N Furan Pyrrole Polypeptides: Contain amino acids linked by amide bonds; amide N trigonal planar, sp2 (26-4) H O N C ´C R H H R؅ ´% N C H C O Peptide linkage Bold atoms coplanar 25 Heterocycles O H3Nϩ % Conventional representations: For D-(1)-glucose (24-1, 2) CHO A-Amino acids: Most have l (S) stereocenter, exist as zwitterions, common names (26-1) Acid/base properties: At low pH, H1 converts COO2 to CO2H; at high pH, 2OH converts NH31 to NH2 (26-1) 24 Carbohydrates H HO H H 26 Amino Acids, Peptides, Proteins, and Nucleic Acids š One more carbon: RX 2CN n RCN (nitrile), then LiAlH4 n RCH2NH2 (20-8) G Reductive amination: CP O ϩ NH3, NaBH3CN n D G G CHNH2 (prim amine); CP O ϩ RNH2, NaBH3CN n D D G G CHNHR (sec amine); CP O ϩ RRЈNH, NaBH3CN n D D G CHNRRЈ (tert amine) (21-6) D S N Thiophene Pyridine Proteins: Polypeptides with polar amino acid side chains in an active site that catalyze biochemical reactions (26-8) Nucleic acids: Polymers made of phosphate-linked sugars bearing the heterocyclic bases adenine (A), guanine (G), cytosine (C), and thymine (T) in DNA or uracil (U) in RNA; contain the genetic code for protein biosynthesis (26-9) 9-5 9-10 A A O C O O OC O A A A O C O S OH A G D CP C G D O C q C OH Alcohols Ethers Thiols Alkenes Alkynes 15-2 to 15-7 13-2, 13-3 15-8 to 16-6, 22-4 to 22-11, 25-5, 26-7 13-4, 13-5 7-6 to 7-9, 9-2, 9-3, 9-7, 11-6, 11-7, 12-14, 12-16, 13-4, 13-6 to 13-10, 17-12, 18-5 to 18-7, 21-8 9-10, 26-5 9-6, 9-7, 12-6, 12-7, 12-10, 12-13, 17-7, 17-8, 18-9, 22-5 8-4 to 8-6, 8-8, 9-8, 9-9, 12-4, 12-6 to 12-8, 12-11, 13-5, 17-6, 17-7, 17-9, 17-11, 18-5, 18-9, 19-11, 20-4, 23-4, 24-6 3-4 to 3-9, 9-2, 9-4, 12-3, 12-5, 12-6, 12-13, 13-7, 14-2, 19-12 8-7, 11-5, 12-2, 13-6, 17-10, 18-8, 21-10 14-7, 15-2, 15-9 to 16-6, 22-1 to 22-8, 22-10, 22-11, 25-4, 25-6, 26-7 13-2, 13-3, 13-5 to 13-10, 17-4 8-4, 11-5, 12-2 to 12-16, 13-4, 14-2 to 14-4, 14-6 to 14-10, 15-7, 15-11, 16-4, 18-8 to 18-11, 21-10 9-10, 26-5 9-8, 9-9, 23-4, 25-2 8-3, 8-6, 9-1 to 9-4, 9-6, 9-7, 9-9, 11-7, 12-6, 15-11, 17-4, 17-7, 17-11, 18-9, 20-2 to 20-4, 22-2, 24-2, 24-5, 24-8 6-2, 6-4 to 7-9, 8-5, 8-7, 11-6, 13-9, 14-3, 15-11, 17-12, 19-6, 21-5 3-3 to 3-11, 8-6, 19-5 Reactions Red nucleophilic or basic atom; blue electrophilic or acidic atom; green potential leaving group Aromatics 8-2, 8-3 A O C O O OH A Haloalkanes 11-2 to 11-5, 11-8 to 11-11 14-5, 14-11 6-1 A O C OX A 2-7 to 2-9, 3-1, 3-11, 4-2 to 4-6 A A O C OC OH A A Alkanes Preparations X 19-8 20-1 EC H EH N A 21-2 to 21-4, 26-1 20-8 O C qN Nitriles Amines 20-1, 20-6 O B C E H EH N A Amides 16-5, 17-9, 18-9, 20-6 to 20-8, 21-5 to 21-7, 21-9, 22-4, 25-2, 25-6, 26-2, 26-5 17-11, 18-9, 20-8, 21-10, 22-10, 24-9 19-10, 20-2, 20-4, 26-6 7-4, 7-8, 9-4, 17-13, 19-9, 20-2, 22-5 15-13, 20-2 19-8 20-1 20-1, 20-4, 20-5 9-4, 19-4, 19-7 to 19-12, 21-10, 23-2, 24-9, 26-4, 26-6, 26-7 8-5, 8-6, 17-14, 19-5, 19-6, 19-9, 20-1 to 20-3, 20-5, 20-6, 20-8, 22-2, 23-2, 24-4 to 24-6, 24-9, 26-2, 26-5, 26-6 19-2 to 19-4, 26-1 16-5, 17-9, 18-4, 18-9, 19-10, 20-2 to 20-4, 21-4, 21-5, 21-7 to 21-10, 22-4, 22-10, 22-11, 25-2, 25-3, 26-1, 26-5, 26-6 17-11, 19-6, 20-8, 21-12, 24-9, 26-2 20-6, 20-7, 26-5 20-4, 23-1 to 23-3, 26-6 15-13, 20-3 8-6, 8-8, 16-5, 17-5 to 17-14, 18-1 to 18-11, 19-5, 19-6, 21-6, 21-9, 22-8, 23-1 to 23-4, 24-4 to 24-7, 24-9, 25-3 to 25-5, 26-2 8-6, 12-12, 13-7, 13-8, 15-13, 16-5, 17-4, 17-6 to 17-9, 17-11, 18-1, 18-4, 20-2, 20-4, 20-6, 20-8, 22-2, 22-8, 23-1, 23-2, 23-4, 24-5, 24-9, 25-4 17-2, 17-3, 18-1, 23-1 Reactions Preparations Properties Esters O O B B EC H E CH O O B EC H O B EC H EH O O B H H EC H E AC A AC A O B H H EC H H AC A Functional Group O B H H EC H ECH O AC A Anhydrides Alkanoyl halides Carboxylic acids Aldehydes and ketones Compound Class A Properties A Functional Group A Compound Class Text References for Compound Classes and Functional Groups A ... protons), which equals the number of electrons The nuclear charge increases by one with each element listed The electrons occupy energy levels, or “shells,” each with a fixed capacity For example, the... effective syntheses and for predicting the processes that take place in nature But how? The answer lies in looking at reactions step by step H H C C H C C C C C O C H H H H H ´] S C C H C H C. .. through a direct subscription to the Premium component of the Web site Premium Media Resource The Organic Chemistry Book Companion Web site, which can be accessed at www.whfreeman.com /organic 7e,