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.

Contents

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 ¿-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...