Organic Chemistry with Biological Applications PDF

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Summary

Structures of Common Coenzymes The reactive parts of the molecules are darkened, while nonreactive parts are ghosted. Adenosine triphosphate—ATP (phosphorylation) NH2 N N O O O –O P O P O P OCH2 N N O O– O– O– OH OH Coenzyme A (acyl transfer) NH2 N N O O CH3 O O HSCH2CH2NHCCH2CH2NHCCHCCH2OPOPOCH2 N...

Description

Structures of Common Coenzymes The reactive parts of the molecules are darkened, while nonreactive parts are ghosted.

Adenosine triphosphate—ATP (phosphorylation) NH2 N O –O

P O–

O

P

N

O

O

P

O

N

OCH2

N

O

O–

O–

OH

OH Coenzyme A (acyl transfer)

NH2 N O

O

CH3

N

O O N

HSCH2CH2NHCCH2CH2NHCCHCCH2OPOPOCH2 HO CH3

N

O

O– O– 2–O PO 3

OH

Nicotinamide adenine dinucleotide—NAD+ (oxidation/reduction) (NADP+) NH2 CONH2

N

N

O O +

N

CH2OPOPOCH2

N OH HO O

N

O

O– O–

OH

OH (OPO32–)

Flavin adenine dinucleotide—FAD (oxidation/reduction) NH2 N HO OH HO

CHCHCHCH2OPOPOCH2 O– O–

CH2 H3C

N

H3C

N

N

N O

O OH N

O

N

O O

H

OH

N

Tetrahydrofolate (transfer of C1 units) H H2N

H

N

N

H N

N

N

CO2–

H

O

H

O

NHCHCH2CH2C

O– 1–5

O S-Adenosylmethionine (methyl transfer) NH2 N

N

CH3

O –OCCHCH CH 2 2 +NH

S +

CH2

N

N

O

3

OH

OH

Lipoic acid (acyl transfer)

S

Pyridoxal phosphate (amino acid metabolism) CH2OPO32–

S

CHO

CH2CH2CH2CH2CO2– + H

N OH CH3

Biotin (carboxylation)

Thiamin diphosphate (decarboxylation) H S

O

NH2 + N

H

N

O O –OPOPOCH CH 2 2 O– O–

N

N

H CH3

N

H H H

CH3 S

CH2CH2CH2CH2CO2–

s, even ts in our course en ud st e th Dear Colleague: of t in pure know that mos nces rather than ganic chemistry ie or sc h fe ac li te e th ho in w ily doctors All of us terested primar ochemists, and in bi , e ts ar is s, og or ol aj bi m y re we tu the chemistr hing so many fu questioning why e ac te ar e us ar e of w e or se m the details of ves, more and chemistry. Becau h time discussing rsions of oursel uc ve r m ge so un d yo en sp an ogy? Why e rather th nnection to biol e do. Why do w co w le ay tt w li e ve th ha h t ac ng organisms? continue to te ch chemists bu chemistry of livi interest to resear c of ni e ga ar or at e th th s ng on reacti me discussi t it is d spend more ti aditional way, bu tr e th in y tr don’t we instea is organic chem who want to id for teaching ose instructors sa th r be fo to e h iv at uc rn m l te al gical There is stil istry with Biolo has been no real m e er he C th ic w an no l rg ti O and also true that un spect that more at is why I wrote th su I , nd ce A en y. tl in en om er t diff s to gain in pr teach somewha biology continue al ic em ch s A cordingly. Applications. their teaching ac ng ciple in gi an ch be l my guiding prin ut B y. tr is more faculty wil em ch on organic clusively on focus almost ex is still a textbook to is th en : be ke s ta is ha t m ou saved by e Make no istry. The space and what to leav em e ch ud cl al ic in og to t ol bi ha deciding w every reaction counterpart in use, for almost at have a direct od th go s voted to on t ti pu ac re en e thos of the book is de s has be on % ti 25 ac y re el l at ca im gi lo io addition, ple and approx leaving out nonb nsformations. In biological exam ra a ot bi by r ed ei th ow ll of fo y andard istr discussed is s shorter than st the organic chem ge d pa an 0 es 20 ul ly ec ar ol ne urse. entirely to biom l Applications is l two-semester co ca ca gi pi lo ty io a B h in it ok w try the entire bo Organic Chemis faculty to cover r fo le ib text; I believe ss po it from any other t en texts, making er ff di is s l Application y with Biologica tr is m he C ic an Org ts. r today’s studen that it is ideal fo Sincerely, John McMurry

All royalties from Organic Chemistry with Biological Applications will be donated to the Cystic Fibrosis (CF) Foundation. This book and donation are dedicated to the author’s eldest son and to the thousands of others who daily fight this disease. To learn more about CF and the programs and services provided by the CF Foundation, please visit http://www.cff.org.

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Organic Chemistry with Biological Applications 2e

John McMurry Cornell University

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Organic Chemistry with Biological Applications 2e John McMurry Publisher: Mary Finch Senior Acquisitions Editor: Lisa Lockwood Senior Development Editor: Sandra Kiselica Assistant Editor: Elizabeth Woods

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Brief Contents 1

Structure and Bonding

2

Polar Covalent Bonds; Acids and Bases

3

Organic Compounds: Alkanes and Their Stereochemistry

4

Organic Compounds: Cycloalkanes and Their Stereochemistry

5

Stereochemistry at Tetrahedral Centers

6

An Overview of Organic Reactions

7

Alkenes and Alkynes

8

Reactions of Alkenes and Alkynes

9

Aromatic Compounds

10

1 33 70 105

134

175

212 251

309

Structure Determination: Mass Spectrometry, Infrared Spectroscopy, and Ultraviolet Spectroscopy

11

Structure Determination: Nuclear Magnetic Resonance Spectroscopy

12

Organohalides: Nucleophilic Substitutions and Eliminations

13

Alcohols, Phenols, and Thiols; Ethers and Sulfides Preview of Carbonyl Chemistry

367

404

444

501

555

14

Aldehydes and Ketones: Nucleophilic Addition Reactions

15

Carboxylic Acids and Nitriles

16

Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution Reactions

17

Carbonyl Alpha-Substitution and Condensation Reactions

18

Amines and Heterocycles

19

Biomolecules: Amino Acids, Peptides, and Proteins

20

Amino Acid Metabolism

21

Biomolecules: Carbohydrates

22

Carbohydrate Metabolism

23

Biomolecules: Lipids and Their Metabolism

24

Biomolecules: Nucleic Acids and Their Metabolism

25

Secondary Metabolites: An Introduction to Natural Products Chemistry

564

610 643

695

749 791

832 862

901 936 987 1015

Key to Sequence of Topics (chapter numbers are color coded as follows): • Traditional foundations of organic chemistry • Organic reactions and their biological counterparts • The organic chemistry of biological molecules and pathways

v

Detailed Contents

1

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

1

Atomic Structure: The Nucleus 3 Atomic Structure: Orbitals 4 Atomic Structure: Electron Configurations 6 Development of Chemical Bonding Theory 7 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 13 sp2 Hybrid Orbitals and the Structure of Ethylene 14 sp Hybrid Orbitals and the Structure of Acetylene 17 Hybridization of Nitrogen, Oxygen, Phosphorus, and Sulfur 18 The Nature of Chemical Bonds: Molecular Orbital Theory 20 Drawing Chemical Structures 21 Summary 24 Lagniappe—Chemicals, Toxicity, and Risk 25 Working Problems 26 Exercises 26

2

Polar Covalent Bonds; Acids and Bases 2.1 2.2 2.3 2.4 2.5 2.6 2.7

vi

Polar Covalent Bonds: Electronegativity 33 Polar Covalent Bonds: Dipole Moments 36 Formal Charges 38 Resonance 41 Rules for Resonance Forms 43 Drawing Resonance Forms 45 Acids and Bases: The Brønsted–Lowry Definition 48

33

detailed contents

2.8 2.9 2.10 2.11 2.12

Acid and Base Strength 49 Predicting Acid–Base Reactions from pKa Values 51 Organic Acids and Organic Bases 53 Acids and Bases: The Lewis Definition 56 Noncovalent Interactions between Molecules 60 Summary 62 Lagniappe—Alkaloids: Naturally Occurring Bases 63 Exercises 64

Organic Compounds: Alkanes and Their Stereochemistry 70 3.1 3.2 3.3 3.4 3.5 3.6 3.7

3

Functional Groups 70 Alkanes and Alkane Isomers 77 Alkyl Groups 81 Naming Alkanes 84 Properties of Alkanes 89 Conformations of Ethane 90 Conformations of Other Alkanes 92 Summary 97 Lagniappe—Gasoline 98 Exercises 99

Organic Compounds: Cycloalkanes and Their Stereochemistry 105 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9

Naming Cycloalkanes 106 Cis–Trans Isomerism in Cycloalkanes 109 Stability of Cycloalkanes: Ring Strain 112 Conformations of Cycloalkanes 113 Conformations of Cyclohexane 115 Axial and Equatorial Bonds in Cyclohexane 117 Conformations of Monosubstituted Cyclohexanes 120 Conformations of Disubstituted Cyclohexanes 123 Conformations of Polycyclic Molecules 126 Summary 127 Lagniappe—Molecular Mechanics 128 Exercises 129

4

vii

viii

detailed contents

5

Stereochemistry at Tetrahedral Centers 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9 5.10 5.11 5.12

134

Enantiomers and the Tetrahedral Carbon 135 The Reason for Handedness in Molecules: Chirality 136 Optical Activity 140 Pasteur’s Discovery of Enantiomers 142 Sequence Rules for Specifying Configuration 143 Diastereomers 149 Meso Compounds 151 Racemic Mixtures and the Resolution of Enantiomers 154 A Review of Isomerism 156 Chirality at Nitrogen, Phosphorus, and Sulfur 158 Prochirality 159 Chirality in Nature and Chiral Environments 162 Summary 164 Lagniappe—Chiral Drugs 165 Exercises 166

6

An Overview of Organic Reactions 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 6.9 6.10 6.11

175

Kinds of Organic Reactions 176 How Organic Reactions Occur: Mechanisms 177 Radical Reactions 178 Polar Reactions 181 An Example of a Polar Reaction: Addition of H2O to Ethylene 186 Using Curved Arrows in Polar Reaction Mechanisms 189 Describing a Reaction: Equilibria, Rates, and Energy Changes 192 Describing a Reaction: Bond Dissociation Energies 195 Describing a Reaction: Energy Diagrams and Transition States 197 Describing a Reaction: Intermediates 200 A Comparison between Biological Reactions and Laboratory Reactions 202 Summary 204 Lagniappe—Where Do Drugs Come From? 205 Exercises 206

7

Alkenes and Alkynes 7.1 7.2 7.3 7.4 7.5

212

Calculating a Degree of Unsaturation 213 Naming Alkenes and Alkynes 216 Cis–Trans Isomerism in Alkenes 219 Alkene Stereochemistry and the E,Z Designation 221 Stability of Alkenes 223

detailed contents

7.6 7.7 7.8 7.9 7.10

Electrophilic Addition Reactions of Alkenes 227 Writing Organic Reactions 229 Orientation of Electrophilic Addition: Markovnikov’s Rule 230 Carbocation Structure and Stability 233 The Hammond Postulate 235 Evidence for the Mechanism of Electrophilic Additions: Carbocation Rearrangements 238 Summary 241 Lagniappe—Terpenes: Naturally Occurring Alkenes 242 Exercises 243

Reactions of Alkenes and Alkynes 8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8 8.9 8.10 8.11 8.12 8.13 8.14 8.15

251

8

Preparing Alkenes: A Preview of Elimination Reactions 252 Halogenation of Alkenes 254 Halohydrins from Alkenes 256 Hydration of Alkenes 257 Reduction of Alkenes: Hydrogenation 261 Oxidation of Alkenes: Epoxidation 265 Oxidation of Alkenes: Hydroxylation 267 Oxidation of Alkenes: Cleavage to Carbonyl Compounds 270 Addition of Carbenes to Alkenes: Cyclopropane Synthesis 272 Radical Additions to Alkenes: Alkene Polymers 274 Biological Additions of Radicals to Alkenes 278 Conjugated Dienes 279 Reactions of Conjugated Dienes 283 The Diels–Alder Cycloaddition Reaction 285 Reactions of Alkynes 290 Summary 293 Learning Reactions 294 Summary of Reactions 295 Lagniappe—Natural Rubber 298 Exercises 299

Aromatic Compounds 9.1 9.2 9.3 9.4 9.5 9.6

309

Naming Aromatic Compounds 310 Structure and Stability of Benzene 313 Aromaticity and the Hückel 4n ⫹ 2 Rule 315 Aromatic Ions and Aromatic Heterocycles 317 Polycyclic Aromatic Compounds 322 Reactions of Aromatic Compounds: Electrophilic Substitution 324

9

ix

x

detailed contents

9.7 9.8 9.9 9.10 9.11

Alkylation and Acylation of Aromatic Rings: The Friedel–Crafts Reaction 331 Substituent Effects in Electrophilic Substitutions 336 Nucleophilic Aromatic Substitution 344 Oxidation and Reduction of Aromatic Compounds 347 An Introduction to Organic Synthesis: Polysubstituted Benzenes 349 Summary 355 Summary of Reactions 356 Lagniappe—Aspirin, NSAIDs, and COX-2 Inhibitors 357 Exercises 359

10

Structure Determination: Mass Spectrometry, Infrared Spectroscopy, and Ultraviolet Spectroscopy 367 10.1 10.2 10.3 10.4 10.5 10.6 10.7 10.8 10.9 10.10 10.11

Mass Spectrometry of Small Molecules: Magnetic-Sector Instruments 368 Interpreting Mass Spectra 369 Mass Spectrometry of Some Common Functional Groups 373 Mass Spectrometry in Biological Chemistry: Time-of-Flight (TOF) Instruments 376 Spectroscopy and the Electromagnetic Spectrum 377 Infrared Spectroscopy 380 Interpreting Infrared Spectra 381 Infrared Spectra of Some Common Functional Groups 384 Ultraviolet Spectroscopy 389 Interpreting Ultraviolet Spectra: The Effect of Conjugation 391 Conjugation, Color, and the Chemistry of Vision 392 Summary 394 Lagniappe—Chromatography: Purifying Organic Compounds 395 Exercises 396

11

Structure Determination: Nuclear Magnetic Resonance Spectroscopy 404 11.1 11.2 11.3 11.4 11.5 11.6 11.7

Nuclear Magnetic Resonance Spectroscopy 405 The Nature of NMR Absorptions 406 Chemical Shifts 409 13C NMR Spectroscopy: Signal Averaging and FT–NMR 411 Characteristics of 13C NMR Spectroscopy 412 DEPT 13C NMR Spectroscopy 415 Uses of 13C NMR Spectroscopy 417

detailed contents

11.8 11.9 11.10 11.11 11.12 11.13

1H NMR Spectroscopy and Proton Equivalence

418

Chemical Shifts in 1H NMR Spectroscopy 421 Integration of 1H NMR Absorptions: Proton Counting 423 Spin–Spin Splitting in 1H NMR Spectra 423 More Complex Spin–Spin Splitting Patterns 428 Uses of 1H NMR Spectroscopy 430 Summary 431 Lagniappe—Magnetic Resonance Imaging (MRI) 432 Exercises 433

Organohalides: Nucleophilic Substitutions and Eliminations 444 12.1 12.2 12.3 12.4 12.5 12.6 12.7 12.8 12.9 12.10 12.11 12.12 12.13 12.14 12.15

12

Names and Structures of Alkyl Halides 445 Preparing Alkyl Halides from Alkenes: Allylic Bromination 447 Preparing Alkyl Halides from Alcohols 451 Reactions of Alkyl Halides: Grignard Reagents 453 Discovery of the Nucleophilic Substitution Reaction 454 The SN2 Reaction 457 Characteristics of the SN2 Reaction 460 The SN1 Reaction 467 Characteristics of the SN1 Reaction 471 Biological Substitution Reactions 476 Elimination Reactions: Zaitsev’s Rule 478 The E2 Reaction 481 The E1 and E1cB Reactions 484 Biological Elimination Reactions 486 A Summary of Reactivity: SN1, SN2, E1, E1cB, and E2 486 Summary 488 Summary of Reactions 489 Lagniappe—Green Chemistry 491 Exercises 492

Alcohols, Phenols, and Thiols; Ethers and Sulfides 501 13.1 13.2 13.3 13.4 13.5 13.6

Naming Alcohols, Phenols, and Thiols 503 Properties of Alcohols, Phenols, and Thiols 504 Preparing Alcohols from Carbonyl Compounds 508 Reactions of Alcohols 516 Oxidation of Alcohols and Phenols 520 Protection of Alcohols 524

13

xi

xii

detailed contents

13.7 13.8 13.9 13.10 13.11 13.12

Preparation and Reactions of Thiols 526 Ethers and Sulfides 528 Preparing Ethers 529 Reactions of Ethers 531 Preparation and Reactions of Sulfides 534 Spectroscopy of Alcohols, Phenols, and Ethers 536 Summary 538 Summary of Reactions 539 Lagniappe—Ethanol: Chemical, Drug, and Poison 542 Exercises 543
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