Copyright 2008 Thomson Learning, Inc All Rights Reserved May not be copied, scanned, or duplicated, in whole or in part 79 Gold 196.9665 Au 47.88 40 44.9559 39 40.078 57 Radium 227.0278 Francium (223) Actinides Lanthanides (261) Rutherfordium Actinium (227) 106 Pm 61 Hassium (265) Hs 108 190.2 Osmium Os 76 Ruthenium 101.07 Ru 44 Iron 55.847 Fe 26 (8) 231.0359 Protactinium Thorium 232.0381 Uranium 238.00289 U 92 91 Pa 90 144.24 140.9076 (237) Neptunium Np 93 (145) Praseodymium Neodymium Promethium Th Cerium 140.115 60 Nd 59 Pr 58 Ce Bh 107 186.207 Bohrium (262) Sg 75 Re Rhenium Seaborgium (263) Dubnium (262) Db 105 Rf 104 Ac 89 88 Ra 87 Fr 183.85 180.9479 178.49 138.9055 74 W Tungsten 73 Tantalum Hf Hafnium Ta Tc 43 54.9380 Manganese Mn 25 (7) Molybdenum Technetium (98) 95.94 Mo 42 51.9961 La 72 Niobium 92.9064 Nb 41 50.9415 24 Cr Chromium Lanthanum 56 Ba Zirconium 91.224 Zr V 23 Vanadium (6) Barium 137.327 55 Cs Cesium 132.9054 Yttrium 88.9059 Strontium 87.62 Rubidium 85.4678 Y 38 Sr 37 Rb 22 Titanium Ti 39.0983 21 K Sc Scandium 20 Ca Calcium 19 (5) (4) (3) Potassium 5B 4B 3B 28 46 78 110 1B (11) 29 Cu Rg 111 Gold 196.9665 Au 79 Silver 107.8682 Ag 47 63.546 Copper 95 (244) Plutonium (243) Americium Am 94 Pu 2B (12) 30 Zn Berkelium (247) (247) Bk 97 Terbium 158.9253 Tb 65 200.59 Mercury Hg 80 Cadmium 112.411 Cd 48 Zinc 65.39 Curium Cm 96 157.25 Gadolium 151.965 Europium 64 Gd 63 Eu 150.36 Samarium Sm 62 Meitnerium Darmstadtium Roentgenium (266) (269) (272) Ds 109 Mt 195.08 192.22 Platinum Pt 77 Iridium Ir Palladium 106.42 Rhodium 102.9055 Pd 45 Rh Nickel 58.693 Ni 27 Cobalt 58.9332 Co (9) 8B (10) 8B 13 12 Mg Magnesium 24.3050 11 Na 9.0122 6.941 Sodium 22.9898 Boron 10.811 Beryllium Lithium (251) Californium Cf 98 162.50 Dysprosium Dy 66 Thallium 204.3833 Tl 81 Indium 114.82 In 49 69.723 Gallium Ga 31 Aluminum 26.9815 Al B Be 3A (13) 8B Nonmetals Semimetals Metals (2) 7B Atomic number Symbol Name Atomic mass 2A 6B An element Key Li Hydrogen 1.0079 H (1) 1A Numbers in parentheses are mass numbers of radioactive isotopes Period number Group number, U.S system IUPAC system Periodic Table of the Elements Si (252) Einsteinium Es 99 164.9303 Holmium Ho 67 Lead 207.2 Pb 82 Tin 118.710 Sn 50 72.61 Germanium Ge 32 Silicon 28.0855 (257) Fermium Fm 100 167.26 Erbium Er 68 Bismuth 208.9804 Bi 83 Antimony 121.757 Sb 51 Arsenic 74.9216 As 33 Phosphorus 30.9738 P 15 14.0067 12.011 14 Nitrogen Carbon 17 16 (258) Mendelevium Md 101 Thulium 168.9342 Tm 69 (209) Polonium Po 84 Tellurium 127.60 Te 52 78.96 Selenium Se 34 Sulfur 32.066 (259) Nobelium No 102 173.04 Ytterbium Yb 70 (210) Astatine At 85 Iodine 126.9045 I 53 79.904 Bromine Br 35 Chlorine 35.4527 Cl 18.9984 S Fluorine 15.9994 F 7A (17) Oxygen O N C 6A (16) 5A (15) 4A (14) Lawrencium (260) Lr 103 174.967 Lutetium Lu 71 (222) Radon Rn 86 Xenon 131.29 Xe 54 83.80 Krypton Kr 36 Argon 39.948 Ar 18 Neon 20.1797 Ne 10 4.0026 Helium He 8A (18) 7 Organic KNOWLEDGE TOOLS Succeed in your course with the help of this best-selling text and its powerful Organic Knowledge Tools John McMurry’s Organic Chemistry carefully and thoroughly integrates powerful multimedia learning components with the text, providing a seamless learning system that will improve your understanding of course concepts for Organic Chemistry Link to interactive tutorials based on your unique level of understanding! 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States): ISBN-10: 0-495-11628-9 ISBN-13: 978-0-495-11628-8 Asia (including India) Thomson Learning Shenton Way #01-01 UIC Building Singapore 068808 Australia/New Zealand Thomson Learning Australia 102 Dodds Street Southbank, Victoria 3006 Australia Canada Thomson Nelson 1120 Birchmount Road Toronto, Ontario M1K 5G4 Canada UK/Europe/Middle East/Africa Thomson Learning High Holborn House 50–51 Bedford Row London WC1R 4LR United Kingdom Latin America Thomson Learning Seneca, 53 Colonia Polanco 11560 Mexico D.F Mexico Spain (including Portugal) Thomson Paraninfo Calle Magallanes, 25 28015 Madrid, Spain Copyright 2008 Thomson Learning, Inc All Rights Reserved May not be copied, scanned, or duplicated, in whole or in part Contents in Brief 10 11 Structure and Bonding Polar Covalent Bonds; Acids and Bases 35 Organic Compounds: Alkanes and Their Stereochemistry 73 Organic Compounds: Cycloalkanes and Their Stereochemistry 107 An Overview of Organic Reactions 137 Alkenes: Structure and Reactivity 172 Alkenes: Reactions and Synthesis 213 Alkynes: An Introduction to Organic Synthesis 259 Stereochemistry 289 Organohalides 332 Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations 359 12 Structure Determination: Mass Spectrometry and Infrared Spectroscopy 408 13 Structure Determination: Nuclear Magnetic Resonance Spectroscopy 440 14 Conjugated Compounds and Ultraviolet Spectroscopy 482 15 Benzene and Aromaticity 516 16 Chemistry of Benzene: Electrophilic Aromatic Substitution 547 17 Alcohols and Phenols 599 18 Ethers and Epoxides; Thiols and Sulfides 652 > A Preview of Carbonyl Compounds 686 19 Aldehydes and Ketones: Nucleophilic Addition Reactions 695 20 Carboxylic Acids and Nitriles 751 21 Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution Reactions 785 22 Carbonyl Alpha-Substitution Reactions 841 23 Carbonyl Condensation Reactions 877 24 Amines and Heterocycles 916 25 Biomolecules: Carbohydrates 973 26 Biomolecules: Amino Acids, Peptides, and Proteins 1016 27 Biomolecules: Lipids 1060 28 Biomolecules: Nucleic Acids 1100 29 The Organic Chemistry of Metabolic Pathways 1125 30 Orbitals and Organic Chemistry: Pericyclic Reactions 1178 31 Synthetic Polymers 1206 iii Copyright 2008 Thomson Learning, Inc All Rights Reserved May not be copied, scanned, or duplicated, in whole or in part Contents © Keith Larrett/AP Photo Structure and Bonding 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 1.10 1.11 1.12 Atomic Structure: The Nucleus Atomic Structure: Orbitals Atomic Structure: Electron Configurations Development of Chemical Bonding Theory The Nature of Chemical Bonds: Valence Bond Theory 10 sp3 Hybrid Orbitals and the Structure of Methane 12 sp3 Hybrid Orbitals and the Structure of Ethane 14 sp2 Hybrid Orbitals and the Structure of Ethylene 15 sp Hybrid Orbitals and the Structure of Acetylene 17 Hybridization of Nitrogen, Oxygen, Phosphorus, and Sulfur 19 The Nature of Chemical Bonds: Molecular Orbital Theory 21 Drawing Chemical Structures 22 Focus On Chemicals, Toxicity, and Risk 25 Summary and Key Words 26 ■ Visualizing Chemistry 28 Additional Problems 29 © Gustavo Gilabert/CORBIS SABA Polar Covalent Bonds; Acids and Bases 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 2.10 2.11 2.12 2.13 35 Polar Covalent Bonds: Electronegativity 35 Polar Covalent Bonds: Dipole Moments 38 Formal Charges 40 Resonance 43 Rules for Resonance Forms 44 Drawing Resonance Forms 46 Acids and Bases: The Brønsted–Lowry Definition 49 Acid and Base Strength 50 Predicting Acid–Base Reactions from pKa Values 52 Organic Acids and Organic Bases 54 Acids and Bases: The Lewis Definition 57 Molecular Models 61 Noncovalent Interactions 61 Focus On Alkaloids: Naturally Occurring Bases 64 Summary and Key Words 65 ■ Visualizing Chemistry 66 Additional Problems 68 iv Copyright 2008 Thomson Learning, Inc All Rights Reserved May not be copied, scanned, or duplicated, in whole or in part Contents v Organic Compounds: Alkanes and Their Stereochemistry 73 © Sascha Burkard 3.1 3.2 3.3 3.4 3.5 3.6 3.7 Functional Groups 73 Alkanes and Alkane Isomers 79 Alkyl Groups 83 Naming Alkanes 86 Properties of Alkanes 91 Conformations of Ethane 93 Conformations of Other Alkanes 95 Focus On Gasoline 99 Summary and Key Words 100 Additional Problems 102 ■ Visualizing Chemistry 101 © Robert Ressmeyer/CORBIS Organic Compounds: Cycloalkanes and Their Stereochemistry 107 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 Naming Cycloalkanes 108 Cis–Trans Isomerism in Cycloalkanes 110 Stability of Cycloalkanes: Ring Strain 113 Conformations of Cycloalkanes 115 Conformations of Cyclohexane 117 Axial and Equatorial Bonds in Cyclohexane 119 Conformations of Monosubstituted Cyclohexanes 122 Conformations of Disubstituted Cyclohexanes 124 Conformations of Polycyclic Molecules 128 Focus On Molecular Mechanics 130 Summary and Key Words 131 ■ Visualizing Chemistry 132 Additional Problems 133 An Overview of Organic Reactions © BSIP/Phototake 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9 137 Kinds of Organic Reactions 137 How Organic Reactions Occur: Mechanisms 139 Radical Reactions 140 Polar Reactions 142 An Example of a Polar Reaction: Addition of HBr to Ethylene 147 Using Curved Arrows in Polar Reaction Mechanisms 149 Describing a Reaction: Equilibria, Rates, and Energy Changes 152 Describing a Reaction: Bond Dissociation Energies 155 Describing a Reaction: Energy Diagrams and Transition States 157 Copyright 2008 Thomson Learning, Inc All Rights Reserved May not be copied, scanned, or duplicated, in whole or in part Contents 5.10 5.11 Describing a Reaction: Intermediates 160 A Comparison between Biological Reactions and Laboratory Reactions 162 Focus On Where Do Drugs Come From? 164 Summary and Key Words 165 ■ Visualizing Chemistry 166 Additional Problems 168 © 2006 San Marcos Growers Alkenes: Structure and Reactivity 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 6.9 6.10 6.11 172 Industrial Preparation and Use of Alkenes 173 Calculating Degree of Unsaturation 174 Naming Alkenes 176 Cis–Trans Isomerism in Alkenes 178 Sequence Rules: the E,Z Designation 180 Stability of Alkenes 185 Electrophilic Addition Reactions of Alkenes 188 Orientation of Electrophilic Additions: Markovnikov’s Rule 191 Carbocation Structure and Stability 195 The Hammond Postulate 197 Evidence for the Mechanism of Electrophilic Additions: Carbocation Rearrangements 200 Focus On Terpenes: Naturally Occurring Alkenes 202 Summary and Key Words 204 ■ Visualizing Chemistry 205 Additional Problems 206 Alkenes: Reactions and Synthesis 7.1 7.2 7.3 © Macduff Everton/Corbis vi 7.4 7.5 7.6 7.7 7.8 7.9 7.10 7.11 213 Preparation of Alkenes: A Preview of Elimination Reactions 214 Addition of Halogens to Alkenes 215 Addition of Hypohalous Acids to Alkenes: Halohydrin Formation 218 Addition of Water to Alkenes: Oxymercuration 220 Addition of Water to Alkenes: Hydroboration 223 Addition of Carbenes to Alkenes: Cyclopropane Synthesis 227 Reduction of Alkenes: Hydrogenation 229 Oxidation of Alkenes: Epoxidation and Hydroxylation 233 Oxidation of Alkenes: Cleavage to Carbonyl Compounds 236 Radical Additions to Alkenes: Polymers 239 Biological Additions of Radicals to Alkenes 243 Focus On Natural Rubber 245 Summary and Key Words 246 ■ Summary of Reactions 247 Visualizing Chemistry 250 ■ Additional Problems 251 Copyright 2008 Thomson Learning, Inc All Rights Reserved May not be copied, scanned, or duplicated, in whole or in part 158 CHAPTER An Overview of Organic Reactions H Br Br H H H C H C H H – H + C C H H H H H C C H H Br Carbocation As the reaction proceeds, ethylene and HBr must approach each other, the ethylene ␲ bond and the H ᎐ Br bond must break, a new C ᎐ H bond must form in the first step, and a new C ᎐ Br bond must form in the second step To depict graphically the energy changes that occur during a reaction, chemists use reaction energy diagrams, such as that shown in Figure 5.4 The vertical axis of the diagram represents the total energy of all reactants, and the horizontal axis, called the reaction coordinate, represents the progress of the reaction from beginning to end Let’s see how the addition of HBr to ethylene can be described in an energy diagram Figure 5.4 An energy diagram Transition state Carbocation product Energy for the first step in the reaction of ethylene with HBr The energy difference between reactants and transition state, ⌬G‡, defines the reaction rate The energy difference between reactants and carbocation product, ⌬G°, defines the position of the equilibrium Activation energy ⌬G‡ CH3CH2+ + Br– ⌬GЊ Reactants H2C CH2 + HBr Reaction progress Br– H H C C H H H Active Figure 5.5 A hypothetical transition-state structure for the first step of the reaction of ethylene with HBr The CϭC ␲ bond and H ᎐ Br bond are just beginning to break, and the C ᎐ H bond is just beginning to form Sign in at www.thomsonedu.com to see a simulation based on this figure and to take a short quiz At the beginning of the reaction, ethylene and HBr have the total amount of energy indicated by the reactant level on the left side of the diagram in Figure 5.4 As the two reactants collide and reaction commences, their electron clouds repel each other, causing the energy level to rise If the collision has occurred with enough force and proper orientation, the reactants continue to approach each other despite the rising repulsion until the new C ᎐ H bond starts to form At some point, a structure of maximum energy is reached, a structure called the transition state The transition state represents the highest-energy structure involved in this step of the reaction It is unstable and can’t be isolated, but we can nevertheless imagine it to be an activated complex of the two reactants in which both the CϭC ␲ bond and H ᎐ Br bond are partially broken and the new C ᎐ H bond is partially formed (Figure 5.5) The energy difference between reactants and transition state is called the activation energy, ⌬G‡, and determines how rapidly the reaction occurs at a given temperature (The double-dagger superscript, ‡, always refers to the transition state.) A large activation energy results in a slow reaction because few collisions occur with enough energy for the reactants to reach the transition state Copyright 2008 Thomson Learning, Inc All Rights Reserved May not be copied, scanned, or duplicated, in whole or in part 5.9 Describing a Reaction: Energy Diagrams and Transition States 159 A small activation energy results in a rapid reaction because almost all collisions occur with enough energy for the reactants to reach the transition state As an analogy, you might think of reactants that need enough energy to climb the activation barrier to the transition state as similar to hikers who need enough energy to climb to the top of a mountain pass If the pass is a high one, the hikers need a lot of energy and surmount the barrier with difficulty If the pass is low, however, the hikers need less energy and reach the top easily As a rough generalization, many organic reactions have activation energies in the range 40 to 150 kJ/mol (10–35 kcal/mol) The reaction of ethylene with HBr, for example, has an activation energy of approximately 140 kJ/mol (34 kcal/mol) Reactions with activation energies less than 80 kJ/mol take place at or below room temperature, whereas reactions with higher activation energies normally require a higher temperature to give the reactants enough energy to climb the activation barrier Once the transition state is reached, the reaction can either continue on to give the carbocation product or revert back to reactant When reversion to reactant occurs, the transition-state structure comes apart and an amount of free energy corresponding to Ϫ⌬G‡ is released When the reaction continues on to give the carbocation, the new C ᎐ H bond forms fully and an amount of energy corresponding to the difference between transition state and carbocation product is released The net change in energy for the step, ⌬G°, is represented in the diagram as the difference in level between reactant and product Since the carbocation is higher in energy than the starting alkene, the step is endergonic, has a positive value of ⌬G°, and absorbs energy Not all energy diagrams are like that shown for the reaction of ethylene and HBr Each reaction has its own energy profile Some reactions are fast (small ⌬G‡) and some are slow (large ⌬G‡); some have a negative ⌬G°, and some have a positive ⌬G° Figure 5.6 illustrates some different possibilities (b) ⌬G‡ Energy Energy (a) ⌬GЊ ⌬G‡ ⌬GЊ Reaction progress Reaction progress (d) ⌬GЊ ⌬G‡ Energy (c) Energy Active Figure 5.6 Some hypothetical energy diagrams: (a) a fast exergonic reaction (small ⌬G‡, negative ⌬G°); (b) a slow exergonic reaction (large ⌬G‡, negative ⌬G°); (c) a fast endergonic reaction (small ⌬G‡, small positive ⌬G°); (d) a slow endergonic reaction (large ⌬G‡, positive ⌬G°) Sign in at www.thomsonedu.com to see a simulation based on this figure and to take a short quiz ⌬G‡ ⌬GЊ Reaction progress Copyright 2008 Thomson Learning, Inc All Rights Reserved May not be copied, scanned, or duplicated, in whole or in part Reaction progress 160 CHAPTER An Overview of Organic Reactions Problem 5.12 5.10 Which reaction is faster, one with ⌬G‡ ϭ ϩ45 kJ/mol or one with ⌬G‡ ϭ ϩ70 kJ/mol? Describing a Reaction: Intermediates How can we describe the carbocation formed in the first step of the reaction of ethylene with HBr? The carbocation is clearly different from the reactants, yet it isn’t a transition state and it isn’t a final product H Br Br H H H C C H H H – H + C C H H H H H C C H H Br Reaction intermediate We call the carbocation, which exists only transiently during the course of the multistep reaction, a reaction intermediate As soon as the intermediate is formed in the first step by reaction of ethylene with H؉, it reacts further with Br؊ in a second step to give the final product, bromoethane This second step has its own activation energy (⌬G‡), its own transition state, and its own energy change (⌬G°) We can picture the second transition state as an activated complex between the electrophilic carbocation intermediate and the nucleophilic bromide anion, in which Br؊ donates a pair of electrons to the positively charged carbon atom as the new C᎐Br bond starts to form A complete energy diagram for the overall reaction of ethylene with HBr is shown in Figure 5.7 In essence, we draw a diagram for each of the individual steps and then join them so that the carbocation product of step is the reactant for step As indicated in Figure 5.7, the reaction intermediate lies at an energy Figure 5.7 An energy diagram for the overall reaction of ethylene with HBr Two separate steps are involved, each with its own transition state The energy minimum between the two steps represents the carbocation reaction intermediate First transition state Carbocation intermediate Second transition state Energy ⌬G2‡ ⌬G1‡ H2C CH2 + HBr ⌬GЊ CH3CH2Br Reaction progress Copyright 2008 Thomson Learning, Inc All Rights Reserved May not be copied, scanned, or duplicated, in whole or in part 5.10 Describing a Reaction: Intermediates 161 minimum between steps Since the energy level of the intermediate is higher than the level of either the reactant that formed it or the product it yields, the intermediate can’t normally be isolated It is, however, more stable than the two transition states that neighbor it Each step in a multistep process can always be considered separately Each step has its own ⌬G‡ and its own ⌬G° The overall ⌬G° of the reaction, however, is the energy difference between initial reactants and final products The biological reactions that take place in living organisms have the same energy requirements as reactions that take place in the laboratory and can be described in similar ways They are, however, constrained by the fact that they must have low enough activation energies to occur at moderate temperatures, and they must release energy in relatively small amounts to avoid overheating the organism These constraints are generally met through the use of large, structurally complex, enzyme catalysts that change the mechanism of a reaction to an alternative pathway that proceeds through a series of small steps rather than one or two large steps Thus, a typical energy diagram for a biological reaction might look like that in Figure 5.8 Figure 5.8 An energy diagram Uncatalyzed Energy for a typical, enzyme-catalyzed biological reaction (blue curve) versus an uncatalyzed laboratory reaction (red curve) The biological reaction involves many steps, each of which has a relatively small activation energy and small energy change The end result is the same, however Enzyme catalyzed Reaction progress Drawing Energy Diagrams for Reactions WORKED EXAMPLE 5.3 Sketch an energy diagram for a one-step reaction that is fast and highly exergonic Strategy A fast reaction has a small ⌬G‡, and a highly exergonic reaction has a large negative ⌬G° Solution Energy ⌬G‡ ⌬GЊ Reaction progress Copyright 2008 Thomson Learning, Inc All Rights Reserved May not be copied, scanned, or duplicated, in whole or in part 162 CHAPTER An Overview of Organic Reactions Problem 5.13 5.11 Sketch an energy diagram for a two-step reaction with an endergonic first step and an exergonic second step Label the parts of the diagram corresponding to reactant, product, and intermediate A Comparison between Biological Reactions and Laboratory Reactions In comparing laboratory reactions with biological reactions, several differences are apparent For one thing, laboratory reactions are usually carried out in an organic solvent such as diethyl ether or dichloromethane to dissolve the reactants and bring them into contact, whereas biological reactions occur in the aqueous medium inside cells For another thing, laboratory reactions often take place over a wide range of temperatures without catalysts, while biological reactions take place at the temperature of the organism and are catalyzed by enzymes We’ll look at enzymes in more detail in Section 26.10, but you may already be aware that an enzyme is a large, globular protein molecule that contains in its structure a protected pocket called its active site The active site is lined by acidic or basic groups as needed for catalysis and has precisely the right shape to bind and hold a substrate molecule in the orientation necessary for reaction Figure 5.9 shows a molecular model of hexokinase, along with an X-ray crystal structure of the glucose substrate and adenosine diphosphate (ADP) bound in the active site Hexokinase is an enzyme that catalyzes the initial step of glucose metabolism—the transfer of a phosphate group from ATP to glucose, giving glucose 6-phosphate and ADP The structures of ATP and ADP were shown at the end of Section 5.8 OPO32– OH CH2 ATP O HO HO ADP Hexokinase OH Glucose CH2 HO O HO OH OH OH Glucose 6-phosphate Note how the hexokinase-catalyzed phosphorylation reaction of glucose is written It’s common when writing biological equations to show only the structure of the primary reactant and product, while abbreviating the structures of various biological “reagents” and by-products such as ATP and ADP A curved arrow intersecting the straight reaction arrow indicates that ATP is also a reactant and ADP also a product Yet another difference is that laboratory reactions are often done using relatively small, simple reagents such as Br2, HCl, NaBH4, CrO3, and so forth, while biological reactions usually involve relatively complex “reagents” called coenzymes In the hexokinase-catalyzed phosphorylation of glucose just shown, Copyright 2008 Thomson Learning, Inc All Rights Reserved May not be copied, scanned, or duplicated, in whole or in part 5.11 A Comparison between Biological Reactions and Laboratory Reactions 163 Figure 5.9 Models of hexokinase in space-filling and wireframe formats, showing the cleft that contains the active site where substrate binding and reaction catalysis occur At the bottom is an X-ray crystal structure of the enzyme active site, showing the positions of both glucose and ADP as well as a lysine amino acid that acts as a base to deprotonate glucose Active site Lysine Adenosine diphosphate (ADP) Glucose for instance, ATP is the coenzyme Of all the atoms in the entire coenzyme, only the one phosphate group shown in red is transferred to the glucose substrate NH2 N O O –O P O– O P O– N O O P O CH2 O– O OH N N OH Adenosine triphosphate, ATP (a coenzyme) Don’t be intimidated by the size of the molecule; most of the structure is there to provide an overall shape for binding to the enzyme and to provide appropriate solubility behavior When looking at biological molecules, focus on the small part of the molecule where the chemical change takes place One final difference between laboratory and biological reactions is in their specificity A catalyst might be used in the laboratory to catalyze the reaction of thousands of different substances, but an enzyme, because it can bind only a specific substrate molecule having a specific shape, will catalyze only a specific reaction It’s this exquisite specificity that makes biological chemistry so remarkable and that makes life possible Table 5.4 summarizes some of the differences between laboratory and biological reactions Copyright 2008 Thomson Learning, Inc All Rights Reserved May not be copied, scanned, or duplicated, in whole or in part 164 CHAPTER An Overview of Organic Reactions Table 5.4 A Comparison of Typical Laboratory and Biological Reactions Laboratory reaction Biological reaction Solvent Organic liquid, such as ether Aqueous environment in cells Temperature Wide range; Ϫ80 to 150 °C` Temperature of organism Catalyst Either none or very simple Large, complex enzymes needed Reagent size Usually small and simple Large, complex coenzymes Specificity Little specificity for substrate Very high specificity for substrate Focus On Where Do Drugs Come From? © BSIP/Phototake It has been estimated that major pharmaceutical companies in the United States spend some $33 billion per year on drug research and development, while government agencies and private foundations spend another $28 billion What does this money buy? For the period 1981–2004, the money resulted in a total of 912 new molecular entities (NMEs)—new biologically active chemical substances approved for sale as drugs by the U.S Food and Drug Administration (FDA) That’s an average of only 38 new drugs each year spread over all diseases and conditions, and the number has been steadily falling In 2004, only 23 NMEs were approved Where the new drugs come from? According to a study carried out at the U.S National Cancer Institute, only 33% of new drugs are entirely synthetic and completely unrelated to any naturally occurring substance The remaining 67% take their lead, to a greater or lesser extent, from nature Vaccines and genetically engineered proteins of biological origin account for 15% of NMEs, but most new drugs come from natural products, a catchall term generally taken to mean small molecules found in bacteria, plants, and other living organisms Unmodified natural products isolated directly from the producing organism account for 28% of NMEs, while natural products that have been chemically modified in the laboratory account for the remaining 24% Approved for sale in March, 1998, Viagra has been used by more than 16 million men It is currently undergoing study as a treatment for preeclampsia, a complication of pregnancy that is responsible for as many as 70,000 deaths each year Where new drugs like this come from? Origin of New Drugs 1981–2002 Natural products (28%) Natural product related (24%) Synthetic (33%) Biological (15%) (continued) Copyright 2008 Thomson Learning, Inc All Rights Reserved May not be copied, scanned, or duplicated, in whole or in part Summary and Key Words 165 Many years of work go into screening many thousands of substances to identify a single compound that might ultimately gain approval as an NME But after that single compound has been identified, the work has just begun because it takes an average of to 10 years for a drug to make it through the approval process First, the safety of the drug in animals must be demonstrated and an economical method of manufacture must be devised With these preliminaries out of the way, an Investigational New Drug (IND) application is submitted to the FDA for permission to begin testing in humans Human testing takes to years and is divided into three phases Phase I clinical trials are carried out on a small group of healthy volunteers to establish safety and look for side effects Several months to a year are needed, and only about 70% of drugs pass at this point Phase II clinical trials next test the drug for to years in several hundred patients with the target disease, looking both for safety and for efficacy, and only about 33% of the original group pass Finally, phase III trials are undertaken on a large sample of patients to document definitively the drug’s safety, dosage, and efficacy If the drug is one of the 25% of the original group that have made it this far, all the data are then gathered into a New Drug Application (NDA) and sent to the FDA for review and approval, which can take another years Ten years and at least $500 million has now been spent, and only 20% of the drugs that began testing have succeeded Finally, though, the drug will begin to appear in medicine cabinets The following timeline shows the process IND application Drug discovery Year Animal tests, manufacture Phase I trials Phase II clinical trials Phase III clinical trials NDA Ongoing oversight 10 SUMMARY AND KEY WORDS activation energy (⌬G‡), 158 addition reaction, 137 bond dissociation energy (D), 155 carbocation, 148 electrophile, 145 elimination reaction, 138 endergonic, 153 endothermic, 154 enthalpy change (⌬H), 154 entropy change (⌬S), 154 exergonic, 153 There are four common kinds of reactions: addition reactions take place when two reactants add together to give a single product; elimination reactions take place when one reactant splits apart to give two products; substitution reactions take place when two reactants exchange parts to give two new products; and rearrangement reactions take place when one reactant undergoes a reorganization of bonds and atoms to give an isomeric product A full description of how a reaction occurs is called its mechanism There are two general kinds of mechanisms by which reactions take place: radical mechanisms and polar mechanisms Polar reactions, the more common type, occur because of an attractive interaction between a nucleophilic (electronrich) site in one molecule and an electrophilic (electron-poor) site in another molecule A bond is formed in a polar reaction when the nucleophile donates an electron pair to the electrophile This movement of electrons is indicated by a curved arrow showing the direction of electron travel from the nucleophile to Copyright 2008 Thomson Learning, Inc All Rights Reserved May not be copied, scanned, or duplicated, in whole or in part 166 CHAPTER An Overview of Organic Reactions exothermic, 154 Gibbs free-energy change (⌬G), 153 heat of reaction, 154 the electrophile Radical reactions involve species that have an odd number of electrons A bond is formed when each reactant donates one electron Polar nucleophile, 145 B – A+ + Nucleophile A B Electrophile polar reaction, 139 radical, 139 Radical B + A A B radical reaction, 139 reaction intermediate, 160 reaction mechanism, 139 rearrangement reaction, 138 substitution reaction, 138 transition state, 158 EXERCISES The energy changes that take place during reactions can be described by considering both rates (how fast the reactions occur) and equilibria (how much the reactions occur) The position of a chemical equilibrium is determined by the value of the free-energy change (⌬G) for the reaction, where ⌬G ϭ ⌬H Ϫ T⌬S The enthalpy term (⌬H) corresponds to the net change in strength of chemical bonds broken and formed during reaction; the entropy term (⌬S) corresponds to the change in the amount of randomness during the reaction Reactions that have negative values of ⌬G release energy, are said to be exergonic, and have favorable equilibria Reactions that have positive values of ⌬G absorb energy, are said to be endergonic, and have unfavorable equilibria A reaction can be described pictorially using an energy diagram that follows the reaction course from reactant through transition state to product The transition state is an activated complex occurring at the highest-energy point of a reaction The amount of energy needed by reactants to reach this high point is the activation energy, ⌬G‡ The higher the activation energy, the slower the reaction Many reactions take place in more than one step and involve the formation of a reaction intermediate An intermediate is a species that lies at an energy minimum between steps on the reaction curve and is formed briefly during the course of a reaction Organic KNOWLEDGE TOOLS Sign in at www.thomsonedu.com to assess your knowledge of this chapter’s topics by taking a pre-test The pre-test will link you to interactive organic chemistry resources based on your score in each concept area Online homework for this chapter may be assigned in Organic OWL ■ indicates problems assignable in Organic OWL ▲ denotes problems linked to Key Ideas of this chapter and testable in ThomsonNOW VISUALIZING CHEMISTRY (Problems 5.1–5.13 appear within the chapter.) 5.14 ■ The following alkyl halide can be prepared by addition of HBr to two different alkenes Draw the structures of both (reddish brown ϭ Br) ■ Assignable in OWL ▲ Key Idea Problems Copyright 2008 Thomson Learning, Inc All Rights Reserved May not be copied, scanned, or duplicated, in whole or in part Exercises 167 5.15 ■ The following structure represents the carbocation intermediate formed in the addition reaction of HBr to two different alkenes Draw the structures of both 5.16 Electrostatic potential maps of (a) formaldehyde (CH2O) and (b) methanethiol (CH3SH) are shown Is the formaldehyde carbon atom likely to be electrophilic or nucleophilic? What about the methanethiol sulfur atom? Explain (a) (b) Formaldehyde Methanethiol Energy 5.17 ■ Look at the following energy diagram: Reaction progress (a) Is ⌬G° for the reaction positive or negative? Label it on the diagram (b) How many steps are involved in the reaction? (c) How many transition states are there? Label them on the diagram Energy 5.18 Look at the following energy diagram for an enzyme-catalyzed reaction: (a) How many steps are involved? (b) Which step is most exergonic? (c) Which step is the slowest? ■ Assignable in OWL ▲ Key Idea Problems Copyright 2008 Thomson Learning, Inc All Rights Reserved May not be copied, scanned, or duplicated, in whole or in part 168 CHAPTER An Overview of Organic Reactions ADDITIONAL PROBLEMS 5.19 ■ Identify the functional groups in the following molecules, and show the polarity of each: (a) CH3CH2C (b) N (c) OCH3 O O CH3CCH2COCH3 (d) (e) O (f) O C NH2 O O H 5.20 ■ Identify the following reactions as additions, eliminations, substitutions, or rearrangements: + (a) CH3CH2Br (b) OH CH3CH2CN ( + NaBr) NaCN Acid ( + H2O) catalyst O (c) Heat + O NO2 (d) + O2N NO2 Light ( + HNO2) 5.21 What is the difference between a transition state and an intermediate? 5.22 Draw an energy diagram for a one-step reaction with Keq Ͻ Label the parts of the diagram corresponding to reactants, products, transition state, ⌬G°, and ⌬G‡ Is ⌬G° positive or negative? 5.23 Draw an energy diagram for a two-step reaction with Keq Ͼ Label the overall ⌬G°, transition states, and intermediate Is ⌬G° positive or negative? 5.24 Draw an energy diagram for a two-step exergonic reaction whose second step is faster than its first step 5.25 Draw an energy diagram for a reaction with Keq ϭ What is the value of ⌬G° in this reaction? 5.26 ■ The addition of water to ethylene to yield ethanol has the following thermodynamic parameters: H2C CH2 + H2O CH3CH2OH ⌬H ° = – 44 kJ/mol ⌬S ° = – 0.12 kJ/(K · mol) K eq = 24 (a) Is the reaction exothermic or endothermic? (b) Is the reaction favorable (spontaneous) or unfavorable (nonspontaneous) at room temperature (298 K)? ■ Assignable in OWL ▲ Key Idea Problems Copyright 2008 Thomson Learning, Inc All Rights Reserved May not be copied, scanned, or duplicated, in whole or in part Exercises 169 5.27 When a mixture of methane and chlorine is irradiated, reaction commences immediately When irradiation is stopped, the reaction gradually slows down but does not stop immediately Explain 5.28 Radical chlorination of pentane is a poor way to prepare 1-chloropentane, but radical chlorination of neopentane, (CH3)4C, is a good way to prepare neopentyl chloride, (CH3)3CCH2Cl Explain 5.29 ■ Despite the limitations of radical chlorination of alkanes, the reaction is still useful for synthesizing certain halogenated compounds For which of the following compounds does radical chlorination give a single monochloro product? (a) CH3CH3 (d) CH3 (b) CH3CH2CH3 (c) (e) CH3C (f) CCH3 CH3CCH2CH3 CH3 H3C CH3 H3C CH3 CH3 CH3 5.30 ■ ▲ Add curved arrows to the following reactions to indicate the flow of electrons in each: (a) D H + D Cl + + H + H + O Cl H H Cl H H (b) O D H OH Cl CH3 CH3 CH3 5.31 ■ ▲ Follow the flow of electrons indicated by the curved arrows in each of the following reactions, and predict the products that result: – (a) H O H O H3C C H3C O (b) H O – ? ■ Assignable in OWL C H OCH3 CH3 H ▲ Key Idea Problems Copyright 2008 Thomson Learning, Inc All Rights Reserved May not be copied, scanned, or duplicated, in whole or in part ? C H 170 CHAPTER An Overview of Organic Reactions 5.32 ■ When isopropylidenecyclohexane is treated with strong acid at room temperature, isomerization occurs by the mechanism shown below to yield 1-isopropylcyclohexene: H H H CH3 H H H H+ + (Acid catalyst) CH3 H H CH3 CH3 H H CH3 H H + H+ CH3 H 1-Isopropylcyclohexene Isopropylidenecyclohexane At equilibrium, the product mixture contains about 30% isopropylidenecyclohexane and about 70% 1-isopropylcyclohexene (a) What is an approximate value of Keq for the reaction? (b) Since the reaction occurs slowly at room temperature, what is its approximate ⌬G‡? (c) Draw an energy diagram for the reaction 5.33 ▲ Add curved arrows to the mechanism shown in Problem 5.32 to indicate the electron movement in each step 5.34 ■ 2-Chloro-2-methylpropane reacts with water in three steps to yield 2-methyl2-propanol The first step is slower than the second, which in turn is much slower than the third The reaction takes place slowly at room temperature, and the equilibrium constant is near H3C CH3 CH3 C C+ Cl CH3 H3C CH3 H2O CH3 H3C C H O+ CH3 H2O H CH3 H3C C O H + H3O+ + Cl– CH3 2-Methyl-2-propanol 2-Chloro-2methylpropane (a) Give approximate values for ⌬G‡ and ⌬G° that are consistent with the above information (b) Draw an energy diagram for the reaction, labeling all points of interest and making sure that the relative energy levels on the diagram are consistent with the information given 5.35 ▲ Add curved arrows to the mechanism shown in Problem 5.34 to indicate the electron movement in each step 5.36 ■ The reaction of hydroxide ion with chloromethane to yield methanol and chloride ion is an example of a general reaction type called a nucleophilic substitution reaction: HO؊ ϩ CH3Cl -0 CH3OH ϩ Cl؊ The value of ⌬H° for the reaction is Ϫ75 kJ/mol, and the value of ⌬S° is ϩ54 J/(K · mol) What is the value of ⌬G° (in kJ/mol) at 298 K? Is the reaction exothermic or endothermic? Is it exergonic or endergonic? ■ Assignable in OWL ▲ Key Idea Problems Copyright 2008 Thomson Learning, Inc All Rights Reserved May not be copied, scanned, or duplicated, in whole or in part Exercises 171 5.37 ■ ▲ Ammonia reacts with acetyl chloride (CH3COCl) to give acetamide (CH3CONH2) Identify the bonds broken and formed in each step of the reaction, and draw curved arrows to represent the flow of electrons in each step O O NH3 C H3C – C Cl H3C O C NH3+ Cl H 3C NH3+ Acetyl chloride O NH3 C H3C NH2 NH4+ Cl– + Acetamide 5.38 The naturally occurring molecule ␣-terpineol is biosynthesized by a route that includes the following step: CH3 CH3 Isomeric H3C H2O carbocation + H2C H3C H3C CH3 OH ␣-Terpineol Carbocation (a) Propose a likely structure for the isomeric carbocation intermediate (b) Show the mechanism of each step in the biosynthetic pathway, using curved arrows to indicate electron flow 5.39 Predict the product(s) of each of the following biological reactions by interpreting the flow of electrons as indicated by the curved arrows: (a) (b) H3C + RЈ N O R S C HO (c) 2–O POCH O ? ? ؊ O CH3 O ؊ OPP Base H3C N H OPO32– H 3C H CO2– +N ? OH CH3 5.40 ■ Reaction of 2-methylpropene with HBr might, in principle, lead to a mixture of two alkyl bromide addition products Name them, and draw their structures 5.41 ■ Draw the structures of the two carbocation intermediates that might form during the reaction of 2-methylpropene with HBr (Problem 5.40) We’ll see in the next chapter that the stability of carbocations depends on the number of alkyl substituents attached to the positively charged carbon—the more alkyl substituents there are, the more stable the cation Which of the two carbocation intermediates you drew is more stable? ■ Assignable in OWL ▲ Key Idea Problems Copyright 2008 Thomson Learning, Inc All Rights Reserved May not be copied, scanned, or duplicated, in whole or in part Organic KNOWLEDGE TOOLS Throughout this chapter, sign in at www.thomsonedu.com for online self-study and interactive tutorials based on your level of understanding Online homework for this chapter may be assigned in Organic OWL Alkenes: Structure and Reactivity An alkene, sometimes called an olefin, is a hydrocarbon that contains a carbon–carbon double bond Alkenes occur abundantly in nature Ethylene, for instance, is a plant hormone that induces ripening in fruit, and ␣-pinene is the major component of turpentine Life itself would be impossible without such alkenes as ␤-carotene, a compound that contains 11 double bonds An orange pigment responsible for the color of carrots, ␤-carotene is a valuable dietary source of vitamin A and is thought to offer some protection against certain types of cancer H3C H H C H CH3 C H Ethylene CH3 ␣-Pinene ␤-Carotene (orange pigment and vitamin A precursor) Carbon–carbon double bonds are present in most organic and biological molecules, so a good understanding of their behavior is needed In this chapter, we’ll look at some consequences of alkene stereoisomerism and then focus on the broadest and most general class of alkene reactions, the electrophilic addition reaction 172 Copyright 2008 Thomson Learning, Inc All Rights Reserved May not be copied, scanned, or duplicated, in whole or in part Sean Duggan WHY THIS CHAPTER? ... viii 11 .1 11. 2 11 .3 11 .4 11 .5 11 .6 11 .7 11 .8 11 .9 11 .10 11 .11 11 .12 The Discovery of Nucleophilic Substitution Reactions 359 The SN2 Reaction 362 Characteristics of the SN2 Reaction 365 The SN1... Spectroscopy 440 13 .1 13.2 13 .3 13 .4 13 .5 13 .6 13 .7 13 .8 13 .9 13 .10 13 .11 13 .12 13 .13 Nuclear Magnetic Resonance Spectroscopy 440 The Nature of NMR Absorptions 442 Chemical Shifts 445 13 C NMR Spectroscopy:... whole or in part Contents © Keith Larrett/AP Photo Structure and Bonding 1. 1 1. 2 1. 3 1. 4 1. 5 1. 6 1. 7 1. 8 1. 9 1. 10 1. 11 1 .12 Atomic Structure: The Nucleus Atomic Structure: Orbitals Atomic Structure: