Biochemistry: An Organic Chemistry Approach

Preface……………………………………………………………………………………………………………………………..xi

Author…………………………………………………………………………………………………………………………… xiii

Common Abbreviations……………………………………………………………………………………………………..xv

Chapter 1 Fundamental Principles of Organic Chemistry……………………………………………………1

1.1 Bonding and Orbitals……………………………………………………………………………..1

1.2 Ionic versus Covalent Chemical Bonds……………………………………………………..2

1.3 Breaking Covalent Bonds………………………………………………………………………..3

1.4 Polarized Covalent σ-Bonds…………………………………………………………………….4

1.5 Reactive Intermediates……………………………………………………………………………5

1.6 Alkanes and Isomers………………………………………………………………………………7

1.7 The IUPAC Rules of Nomenclature………………………………………………………….8

1.8 Rings Made of Carbon: Cyclic Compounds…………………………………………….. 11

1.9 Hydrocarbon Functional Groups……………………………………………………………. 11

1.10 Heteroatom Functional Groups……………………………………………………………… 13

1.10.1 C—X Type Functional Groups………………………………………………….. 13

1.10.2 C=X Type Functional Groups……………………………………………………. 17

1.11 Hydrogen-Bonding and Solubility………………………………………………………….. 21

1.12 Rotamers and Conformation………………………………………………………………….24

1.13 Conformations with Functional Groups…………………………………………………..30

1.14 Conformation of Cyclic Molecules………………………………………………………… 31

1.15 Stereogenic Carbons and Stereoisomers…………………………………………………. 37

1.16 Absolute Configuration [(R) and (S) Nomenclature]…………………………………. 39

1.17 Specific Rotation………………………………………………………………………………….44

1.18 Diastereomers………………………………………………………………………………………46

1.19 Alkene Stereoisomers: (E) and (Z)-Isomers…………………………………………….. 51

Homework…………………………………………………………………………………………………….54

Chapter 2 The Importance of Water in Biochemical Systems…………………………………………….. 55

2.1 Hydrogen Bonding……………………………………………………………………………….. 55

2.2 Solubility……………………………………………………………………………………………. 58

2.3 Water Molecules in Biological Systems………………………………………………….. 59

2.4 Acid-Base Equilibria in Water………………………………………………………………. 61

2.5 Buffers………………………………………………………………………………………………..65

2.6 Structural Features That Influence Acid Strength……………………………………..66

2.7 Acid and Base Character of Alcohols, Thiols, Amines and Carbonyls……….. 67

2.7.1 Acids………………………………………………………………………………………. 67

2.7.2 Bases……………………………………………………………………………………….69

2.8 Elimination Reactions of Alkyl Halides (E2 and E1 Reactions)………………… 71

2.9 Acid-Base Equilibria in Amino Acids……………………………………………………. 74

2.10 Directionality………………………………………………………………………………………. 78

Homework…………………………………………………………………………………………………….80

Chapter 3 Nucleophiles and Electrophiles………………………………………………………………………..83

3.1 Nucleophiles and Bimolecular Substitution (the SN2 Reaction)…………………..83

3.2 Nucleophilic Substitution with Alcohols, Ethers, Amines, or Phosphines……85

3.3 Carbocations and the SN1 Reaction…………………………………………………………88

3.4 Ethers and Thioethers as Nucleophiles……………………………………………………90

3.5 Chemical Reactions of Carbonyl Groups…………………………………………………93

3.6 Biochemical Reactions of Ketones and Aldehydes……………………………………96

3.7 Carboxylic Acid Derivatives and Acyl Substitution…………………………………..97

3.8 Biological Hydrolysis………………………………………………………………………….. 102

Homework………………………………………………………………………………………………….. 106

Chapter 4 Radicals……………………………………………………………………………………………………… 109

4.1 Structure of Radicals………………………………………………………………………….. 109

4.2 Formation of Radicals in Organic Chemistry………………………………………… 110

4.3 Reactions of Radicals…………………………………………………………………………. 111

4.4 Formation of Radicals in Biological Systems………………………………………… 112

4.5 Radicals in Biological Systems……………………………………………………………. 114

4.6 Radical Reactions in Biochemical Systems…………………………………………… 116

4.7 Radicals and Cancer…………………………………………………………………………… 118

Homework………………………………………………………………………………………………….. 119

Chapter 5 Dienes and Conjugated Carbonyl Compounds in Biochemistry…………………………. 121

5.1 Conjugated Dienes and Conjugated Carbonyl Compounds……………………… 121

5.2 Reactions of Conjugated Compounds……………………………………………………124

5.3 Conjugate (Michael) Addition……………………………………………………………… 127

5.4 Enzyme-Mediated Conjugate Additions……………………………………………….. 128

5.5 Sigmatropic Rearrangement Reactions…………………………………………………. 129

5.6 Enzyme-Mediated Sigmatropic Rearrangements……………………………………. 132

Homework………………………………………………………………………………………………….. 133

Chapter 6 Enolates and Enolate Anions………………………………………………………………………… 135

6.1 Aldehydes and Ketones Are Weak Acids………………………………………………. 135

6.2 Formation of Enolate Anions………………………………………………………………. 136

6.3 The Aldol Condensation……………………………………………………………………… 137

6.4 Enzyme-Mediated Aldol Condensations……………………………………………….. 138

6.5 The Claisen Condensation…………………………………………………………………… 141

6.6 Enzyme-Mediated Claisen Condensation……………………………………………… 142

6.7 Decarboxylation………………………………………………………………………………… 143

Homework………………………………………………………………………………………………….. 144

Chapter 7 Enzymes…………………………………………………………………………………………………….. 147

7.1 Enzyme Kinetics……………………………………………………………………………….. 147

7.1.1 Kinetics in Organic Chemistry………………………………………………… 147

7.1.2 Catalysts and Catalytic Reactions…………………………………………….. 149

7.1.3 Enzyme Kinetics……………………………………………………………………. 149

7.2 Enzymes and Enzyme Classes…………………………………………………………….. 153

7.3 Oxidoreductases (EC 1)………………………………………………………………………. 157

7.3.1 Chemical Oxidation of Alcohols………………………………………………. 157

7.3.2 Oxidases……………………………………………………………………………….. 159

7.3.3 Chemical Reduction of Carbonyl Compounds……………………………. 161

7.3.4 Reductases…………………………………………………………………………….. 162

7.4 Transferases (EC 2)……………………………………………………………………………. 163

7.4.1 Chemical Reactions That Incorporate Methyl, Hydroxyl,

Glycosyl or Amino Groups into New Molecules………………………… 163

7.4.2 Methyl, Hydroxyl, Thiol, and Glycosyl Transferases…………………… 166

7.5 Hydrolyases (EC 3)…………………………………………………………………………….. 168

7.5.1 Chemical Hydrolysis………………………………………………………………. 169

7.5.2 Esterases……………………………………………………………………………….. 170

7.5.3 Other Hydrolyases………………………………………………………………….. 171

7.6 Lyases (EC 4)……………………………………………………………………………………. 174

7.6.1 Bond Cleavage in Organic Chemistry……………………………………….. 174

7.6.1.1 Decarboxylation……………………………………………………….. 174

7.6.1.2 Enol Formation and the Acid-Catalyzed Aldol…………….. 175

7.6.1.3 Dehydration Reactions………………………………………………. 176

7.6.1.4 [2+2]-Photocycloaddition…………………………………………… 177

7.6.2 Lyase Reactions……………………………………………………………………… 178

7.7 Isomerases (EC 5)……………………………………………………………………………… 180

7.7.1 Chemical Isomerization Reactions……………………………………………. 181

7.7.2 Isomerase Reactions……………………………………………………………….. 184

7.8 Ligases (EC 6)…………………………………………………………………………………… 185

7.8.1 Chemical Methods for Carboxylation and Nucleotide Synthesis….. 185

7.8.1.1 Reactions with Carbon Dioxide………………………………….. 185

7.8.1.2 Synthesis of Polynucleotides and Polynucleosides………… 186

7.8.2 Enzymatic Coupling……………………………………………………………….. 187

7.9 Translocases (EC 7)……………………………………………………………………………. 189

7.9.1 Enzymatic Transport Reactions……………………………………………….. 189

7.9.2 Transport of Organic Materials………………………………………………… 189

Homework………………………………………………………………………………………………….. 190

Chapter 8 Lipids…………………………………………………………………………………………………………. 193

8.1 Carboxylic Acids and Esters……………………………………………………………….. 193

8.2 Nitrate Esters, Sulfate Esters, and Phosphate Esters……………………………….. 196

8.3 Lipid Classes…………………………………………………………………………………….. 199

8.4 Chemical Synthesis of Esters……………………………………………………………….203

8.5 Biosynthesis and Biodegradation of Esters…………………………………………….205

Homework…………………………………………………………………………………………………..209

Chapter 9 Aromatic Compounds and Heterocyclic Compounds……………………………………….. 211

9.1 Benzene and Aromaticity……………………………………………………………………. 211

9.2 Benzene Is a Carcinogen…………………………………………………………………….. 213

9.3 Functionalized Benzene Derivatives…………………………………………………….. 214

9.4 Electrophilic Aromatic Substitution: The SEAr Reaction………………………… 216

9.5 Enzymatic SEAr Reactions………………………………………………………………….. 219

9.6 Reduction of Aromatic Compounds………………………………………………………222

9.7 Biological Reduction of Aromatic Rings……………………………………………….224

9.8 Nucleophilic Aromatic Substitution. The SNAr Reaction…………………………225

9.9 Enzymatic SNAr Reactions…………………………………………………………………..226

9.10 Polynuclear Aromatic Hydrocarbons…………………………………………………….227

9.11 Heteroaromatic Compounds: Nitrogen, Oxygen, or Sulfur……………………….230

9.12 Reactions of Heteroaromatic Compounds……………………………………………… 233

9.13 Enzymatic Reactions That Generate Heterocyclic Compounds………………..234

9.14 Reduced Forms of Nitrogen, Oxygen, and Sulfur Heterocycles………………..238

9.15 Heteroaromatic Compounds with More Than One Ring…………………………. 239

Homework…………………………………………………………………………………………………..240

Chapter 10 Carbon–Metal Bonds, Chelating Agents and Coordination Complexes………………. 243

10.1 Organometallics………………………………………………………………………………… 243

10.2 Organometallics in Organic Chemistry………………………………………………… 243

10.3 Biologically Relevant Metals………………………………………………………………..246

10.4 Chelating Agents………………………………………………………………………………..248

Homework………………………………………………………………………………………………….. 251

Chapter 11 Amino Acids………………………………………………………………………………………………. 253

11.1 Characteristics of Amino Acids…………………………………………………………… 253

11.2 Structure of α-Amino Acids………………………………………………………………… 255

Homework………………………………………………………………………………………………….. 259

Chapter 12 Peptides and Proteins…………………………………………………………………………………… 261

12.1 Reactions and Synthesis of α-Amino Acids…………………………………………… 261

12.2 Amino Acid Biosynthesis……………………………………………………………………. 267

12.3 Peptides Are Poly(amides) of Amino Acid Residues……………………………….268

12.4 Chemical Synthesis of Peptides……………………………………………………………. 274

12.5 Peptide Biosynthesis……………………………………………………………………………277

12.6 Proteins and Enzymes Are Poly(peptides)……………………………………………..280

12.7 Peptide Degradation and End Group Identification…………………………………280

12.8 Peptidases………………………………………………………………………………………….284

Homework…………………………………………………………………………………………………..285

Chapter 13 Carbohydrates……………………………………………………………………………………………..287

13.1 (Poly)hydroxy Carbonyl Compounds…………………………………………………….287

13.2 Monosaccharides………………………………………………………………………………..288

13.3 Mutarotation………………………………………………………………………………………293

13.4 The Anomeric Effect…………………………………………………………………………..294

13.5 Ketose Monosaccharides……………………………………………………………………..295

Homework…………………………………………………………………………………………………..297

Chapter 14 Glycosides…………………………………………………………………………………………………..299

14.1 Monosaccharides………………………………………………………………………………..299

14.2 Disaccharides, Trisaccharides, Oligosaccharides, and Polysaccharides……..300

14.3 Reactions of Carbohydrates…………………………………………………………………. 301

14.4 Biologically Important Glycosides………………………………………………………..305

14.5 Biosynthesis of Carbohydrates and Glycosides……………………………………….308

14.6 Biodegradation of Carbohydrates and Glycosides………………………………….. 313

Homework………………………………………………………………………………………………….. 316

Chapter 15 Nucleic Acids, Nucleosides and Nucleotides…………………………………………………… 317

15.1 Nucleosides and Nucleotides……………………………………………………………….. 317

15.2 Polynucleotides………………………………………………………………………………….. 320

15.3 Chemical Synthesis of Nucleotides………………………………………………………. 325

15.4 Biosynthesis of Nucleotides…………………………………………………………………. 328

15.5 Ribozymes………………………………………………………………………………………… 330

15.6 Hydrolysis of RNA and DNA………………………………………………………………. 332

15.7 RNA-Mediated Programmable DNA Cleavage……………………………………… 333

15.8 Restriction Enzymes…………………………………………………………………………… 334

Homework………………………………………………………………………………………………….. 336

Chapter 16 Answers to Homework Problems…………………………………………………………………… 337

Chapter 1……………………………………………………………………………………………………. 337

Chapter 2……………………………………………………………………………………………………. 338

Chapter 3……………………………………………………………………………………………………. 339

Chapter 4……………………………………………………………………………………………………. 341

Chapter 5……………………………………………………………………………………………………. 343

Chapter 6…………………………………………………………………………………………………….344

Chapter 7……………………………………………………………………………………………………. 345

Chapter 8…………………………………………………………………………………………………….349

Chapter 9……………………………………………………………………………………………………. 350

Chapter 10………………………………………………………………………………………………….. 352

Chapter 11………………………………………………………………………………………………….. 353

Chapter 12………………………………………………………………………………………………….. 354

Chapter 13………………………………………………………………………………………………….. 356

Chapter 14………………………………………………………………………………………………….. 358

Chapter 15………………………………………………………………………………………………….. 361

Index…………………………………………………………………………………………………………………………….. 363

Professor Michael B. Smith was born in Detroit, Michigan, and moved to

Madison Heights, Virginia, in 1957. He graduated from Amherst County

High School in 1964. He worked at Old Dominion Box Factory for a year

after graduation and then started college at Ferrum Jr. College in 1965. He

graduated in 1967 with an A.A. and began studies at Virginia Tech later that

year, graduating with a B.S. in Chemistry in 1969. He worked as a chemist at

the Newport News Shipbuilding & Dry Dock Co, Newport News, Virginia,

from 1969 until 1972. In 1972 he began studies in graduate school at Purdue

University in West Lafayette, Indiana, working with Prof. Joseph Wolinsky.

He graduated in 1977 with a Ph.D. in Organic Chemistry. He took a postdoctoral

position at Arizona State University in Tempe, Arizona, working on the isolation of anti-cancer

agents from marine animals with Professor Bob Pettit. After one year, he took another postdoctoral

position at MIT in Cambridge, Massachusetts, working on the synthesis of the anti-cancer drug

bleomycin with Professor Sidney Hecht.

Professor Smith began his independent career as an assistant professor in the Chemistry department

at the University of Connecticut, Storrs, Connecticut, in 1979. He received tenure in 1986, and

spent six months on sabbatical in Belgium, with Professor Leon Ghosez at the Universite Catholique

de Louvain in Louvain la Neuve, Belgium. He was promoted to full professor in 1994 and spent his

entire career at UCONN. Prof. Smith’s research involved the synthesis of biologically interesting

molecules. His most recent work involved the preparation of functionalized indocyanine dyes for

the detection of hypoxic cancerous tumors (breast cancer). Another project involved the synthesis of

inflammatory lipids derived from the dental pathogen, Porphyromonas gingivalis.

He has published 26 books, including Organic Chemistry: An Acid-Base Approach, 2nd edition

(Taylor & Francis), the 5th–8th editions of March’s Advanced Organic Chemistry (Wiley), and

Organic Synthesis, 4th edition (Elsevier), winner of a 2018 Texty Award. Prof. Smith published 96

peer-reviewed research papers and retired from UCONN in January of 2017.

Describing an interesting way to teach biochemistry, especially in conjunction with organic chemistry, this textbook should find application at many schools. The first of 15 chapters is a review of the fundamentals of an organic chemistry course, but a full course may be necessary for beginners to benefit from further study. Subsequent discussion of organic reactions and mechanisms will be more meaningful for students already familiar with organic chemistry basics. Chapter 2 describes acid-base chemistry, elimination reactions, and the importance of water in chemistry. Chapter 3 discusses nucleophilic substitution; chapter 4 explains free radical reactions. Subsequent chapters discuss, respectively, dienes, conjugated systems, sigmatropic rearrangements, enols and enolate reactions, enzymes, enzyme kinetics, carboxylic acid and derivatives, lipids, aromatic chemistry, heteroaromatic chemistry, organometallic compounds, biologically relevant metals, chelating reagents, amino acids, peptides, proteins, carbohydrates and derivatives, glycosides, nucleosides, nucleotides, DNA, and RNA. Each chapter concludes with homework questions; finally, chapter 16 includes the answers to the questions. Common abbreviations are listed at the beginning of the book, and several compounds and functional groups also have line formulas or partial structures shown. The book can be used by teachers and students of chemistry, and will be useful for all chemists as a review.

–R. E. Buntrock, independent scholar

Summing Up: Recommended. Lower- and upper-division undergraduates. Graduate students, faculty, and professionals.