Full Table of Contents

Section 1: Atomic orbitals and electron configuration

1. The atom
2. Atomic orbitals

Section 2: Chemical Bonds

1. Ionic bonds
2. Covalent bonds and Lewis structures
3. Formal charges

Section 3: Drawing organic structures

1. Common bonding patterns in organic structures
2. Using the 'line structure' convention
3. Constitutional isomers
4. The Index of Hydrogen Deficiency

Section 4: Functional groups and organic nomenclature

1. Common functional groups in organic compounds
2. Naming organic compounds
3. Abbreviated organic structures

Section 5: Valence bond theory

1. Formation of sigma bonds: the H₂ molecule
2. Hybrid orbitals: sp³ hybridization and tetrahedral bonding
3. Formation of pi bonds: sp² and sp hybridization
4. The valence bonding picture in carbocations, carbanions, and carbon free radicals

Section 1: Molecular orbital theory

1. Another look at the H₂ molecule: bonding and antibonding sigma molecular orbitals
2. MO theory and pi bonds: conjugation
3. Aromaticity

Section 2: Resonance

1. The meaning of resonance contributors: benzene and its derivatives
2. Resonance contributors of the carboxylate group
3. Rules for drawing resonance structures
4. Major vs minor resonance contributors - four more rules to follow
5. More examples of resonance: peptide bonds, enolates, and carbocations

Section 3: Non-covalent interactions

1. Dipoles
2. Ion-ion, dipole-dipole and ion-dipole interactions
3. van der Waals forces
4. Hydrogen bonds

Section 4: The relationship between noncovalent interactions physical properties

1. Solubility
2. Illustrations of solubility concepts - metabolic intermediates, lipid bilayer membranes, soaps and detergent
3. Boiling points and melting points
4. The melting behavior of lipid structures

Section 1: Conformations of straight-chain organic molecules

1. Conformations of ethane
2. Conformations of butane

Section 2: Conformations of cyclic organic molecules

1. Introduction to sugars and other cyclic molecules
2. Ring size
3. Conformations of glucose and other six-membered ring structures
4. Conformations of pentose and other five-membered ring structures
5. The importance of conformation in organic reactivity

Section 3: Stereoisomerism – chirality, stereocenters, enantiomers

Section 4: Defining stereochemical configuration - the Cahn-Ingold-Prelog system

Section 5: Interactions between chiral molecules and proteins

Section 6: Optical activity

Section 7: Diastereomers

1. Compounds with multiple stereocenters
2. Meso compounds
3. Stereoisomerism of alkenes

Section 8: Fischer and Haworth projections

Section 9: Stereochemistry and organic reactivity

Section 10: Prochirality

1. Prochiral substituents on tetrahedral carbons
2. Carbonyl and imine carbons as prochiral centers

Section 1: Introduction to molecular spectroscopy

1. The electromagnetic spectrum
2. Molecular spectroscopy – the basic idea

Section 2: Infrared spectroscopy

Section 3: Ultraviolet and visible spectroscopy

1. Electronic transitions
2. Looking at UV-vis spectra
3. Applications of UV spectroscopy in organic and biological chemistry

Section 4: Mass Spectrometry

1. The basics of mass spectrometry
2. Looking at mass spectra
3. Gas Chromatography - Mass Spectrometry
4. Mass spectrometry of proteins - applications in proteomics

Section 1: The origin of the NMR signal

1. NMR-active nuclei
2. Nuclear precession, spin states, and the resonance condition

Section 2: Chemical equivalence

Section 3: The NMR experiment

1. The basics of an NMR experiment
2. The chemical shift
3. Signal integration

Section 4: The basis for differences in chemical shift

1. Diamagnetic shielding and deshielding
2. Diamagnetic anisotropy
3. Hydrogen-bonded protons

Section 5: Spin-spin coupling

1. The source of spin-spin coupling
2. Coupling constants
3. Complex coupling

Section 6: ¹³C-NMR spectroscopy

1. The basics of ¹³C-NMR spectroscopy
2. ¹³C-NMR in isotopic labeling studies

Section 7 : Determining unknown structures

Section 8: NMR of phosphorylated molecules

Section 1: A first look at reaction mechanisms

1. acid-base (proton transfer) reaction
2. one-step nucleophilic substitution reaction (S_N2)
3. Two-step nucleophilic substitution reaction (S_N1)

Section 2: Describing the thermodynamics and kinetics of chemical reactions - energy diagrams

Section 3: Enzymatic catalysis - the basic ideas

Section 4: Protein structure

1. Amino acids and peptide bonds
2. Visualizing protein structure: X-ray crystallography
3. The four levels of protein structure
4. The molecular forces that hold proteins together

Section 5: How enzymes work

1. The active site
2. Transition state stabilization
3. Site-directed mutagenesis
4. Enzyme inhibition
5. Catalysts in the laboratory

Section 1: The ‘basic’ idea of an acid-base reaction

1. The Brønsted-Lowry definition of acidity
2. The Lewis definition of acidity

Section 2: Comparing the acidity and basicity of organic functional groups– the acidity constant

1. Defining K_a and pK_a
2. Using pKa values to predict reaction equilibria
3. pKa and pH: the Henderson-Hasselbalch equation

Section 3: Structural effects on acidity and basicity

1. Periodic trends
2. The resonance effect
3. The inductive effect

Section 4: More on resonance effects on acidity and basicity

1. The acidity of phenols
2. The basicity of nitrogen-containing groups: aniline, imines, pyridine, and pyrrole

Section 5: Carbon acids and enolate ions

Section 6: Polyprotic acids

Section 7: The effects of solvent and enzyme microenvironment on acidity

Section 1: Introduction to the nucleophilic substitution reaction

Section 2: Two mechanistic models for a nucleophilic substitution reaction

1. Associative nucleophilic substitution: the S_N2 reaction
2. Dissociative nucleophilic substitution: the S_N1 reaction
3. Nucleophilic substitutions occur at sp³-hybridized carbons

Section 3: More about nucleophiles

1. What makes a nucleophile?
2. Protonation states and nucleophilicity
3. Periodic trends in nucleophilicity
4. Resonance effects on nucleophilicity
5. Steric effects on nucleophilicity

Section 4: Electrophiles and carbocation stability

1. Steric effects on electrophilicity
2. Stability of carbocation intermediates

Section 5: Leaving groups

1. What makes a good leaving group?
2. Leaving groups in biochemical reactions
3. Synthetic parallel - conversion of alcohols to alkyl halides, tosylates and mesylates
4. S_N1 or S_N2? Predicting the mechanism.

Section 6: Epoxides as electrophiles in nucleophilic substitution reactions

1. Epoxide structure
2. Epoxide ring-opening reactions - S_N1 vs S_N2, regioselectivity, and stereoselectivity

Section 1: Methyl group transfers: examples of S_N2 reactions

1. SAM methyltransferase
2. Synthetic parallel – the Williamson ether synthesis

Section 2: Digestion of carbohydrate by glycosidases - an S_N1 reaction

Section 3: Protein prenyltransferase - a hybrid S_N1/S_N2 substitution

1. The biological relevance of the protein prenyltransferase reaction
2. Determining the mechanism of protein prenyltransferase with fluorinated substrate analogs
3. The zinc-thiolate interaction in protein prenyltransferase - 'tuning' the nucleophile

Section 4: Biochemical nucleophilic substitutions with epoxide electrophiles

1. Hydrolysis of stearic acid epoxide: investigating the mechanism with kinetic isotope effect experiments
2. Fosfomycin - an epoxide antibiotic

Section 1: Overview of phosphates and phosphoryl transfer reactions

1. Nomenclature and abbreviations
2. Acid constants and protonation states
3. Bonding in phosphines and phosphates
4. Phosphoryl transfer reactions - the general picture
5. Phosphoryl transfer reactions - associative, addition-elimination, or dissociative?

Section 2: Phosphorylation reactions - kinase enzymes

1. ATP - the principle phosphoryl group donor
2. Monophosphorylation of alcohols
3. Diphosphorylation of alcohols
4. Phosphorylation of carboxylates
5. Generation of nucleotide phosphates
6. Regeneration of ATP from ADP

Section 3: Hydrolysis of phosphates

Section 4: Phosphate diesters

1. Phosphate diesters as the backbone for DNA and RNA
2. The chemistry of genetic engineering

Section 1: Nucleophilic additions to aldehydes and ketones: the general picture

Section 2: Stereochemistry of the nucleophilic addition reaction

Section 3: Hemiacetals, hemiketals, and hydrates

A. The general picture
B. Simple sugars are hemiacetals and hemiketals

Section 4: Acetals and ketals

A. Glycosidic bonds revisited
B. Synthetic parallel: cyclic acetals/ketals as 'protecting groups' for ketones and aldehydes

Section 5: N-glycosidic bonds

Section 6: Imine (Schiff base) formation

A. Imines-the general picture
B. Pyridoxal phosphate coenzyme links to enzymes by a Schiff base
C. Schiff base formation in aldolase reactions

Section 7: A look ahead: addition of carbon and hydride nucleophiles to carbonyls

Section 1: Introduction to carboxylic acid derivatives and the nucleophilic acyl substitution reaction

A: Carboxylic acid derivatives and acyl groups
B: The nucleophilic acyl substitution reaction
C: The relative reactivity of carboxylic acid derivatives

Section 2: Acyl phosphates as activated carboxylic acids

A: Glutamine synthetase
B: Asparagine synthetase
C: Glycinamide ribonucleotide synthetase
D: Synthetic parallel - activated carboxylic acids in the lab

Section 3: Thioesters

A: Introduction to thioesters and Coenzyme A
B: Activation of fatty acids by coenzyme A - a thioesterification reaction
C: Transfer of fatty acyl groups to glycerol: a thioester to ester substitution
D: More transthioesterification reactions
E: Hydrolysis of thioesters

Section 4: Esters

A: Nonenzymatic esterification: synthesis of ‘banana oil’
B: Nonenzymatic ester hydrolysis and the soap-making process
C: Enzymatic ester hydrolysis: acetylcholinesterase and sarin nerve gas
D: More enzymatic ester hydrolysis: lipase, the resolution of enantiomers, and dehalogenation
E: Transesterification: the chemistry of aspirin and biodeisel

Section 5: Nucleophilic acyl substitution reactions involving peptide bonds

A: Formation of peptide bonds on the ribosome
B: Hydrolysis of peptide bonds: HIV protease
C: The chemical mechanism of penicillin

Section 6: Activated amide groups

Section 7: A look ahead: acyl substitution reactions with a carbon or hydride nucleophile

Section 1: Tautomers

1. Keto-enol tautomerization
2. Imine/enamine tautomerization

Section 2: Isomerization reactions

1. Carbonyl isomerization
2. Stereoisomerization at chiral carbons

Section 3: Aldol reactions

1. The general mechanism for an aldol reaction
2. Typical aldolase reactions: three variations on a theme
3. Going backwards: the retroaldol reaction
4. Going both ways: transaldolase

Section 4: Claisen reactions

1. Claisen condensations
2. Retro-Claisen cleavages
3. Enolates as nucleophiles in S_N2 displacements

Section 5: Carboxylation and decarboxylation reactions

1. The metabolic context of carboxylation and decarboxylation
2. The carboxylation mechanism of Rubisco
3. Decarboxylation

Section 6: Synthetic parallel - carbon nucleophiles in the lab

1. Lab reactions with enolate /enamine intermediates
2. The Wittig reaction
3. Terminal alkynes as carbon nucleophiles
4. Grignard, Gilman, and organolithium reagents

Section 14.1: Michael additions and beta-eliminations

1. Overview of Michael addition and beta-elimination mechanisms
2. Stereochemistry of Michael additions and beta-eliminations
3. NMR experiments to determine the stereochemistry of a Michael addition
4. More examples of elimination and addition reactions

Section 14.2: Variations on the Michael reaction

1. Cis/trans alkene isomerization
2. Nucleophilic aromatic substitution
3. Synthetic parallel - Michael addition reactions in the laboratory

Section 14.3: Elimination by the E1 and E2 mechanisms

1. E1 and E2 reactions in the laboratory
2. Enzymatic E1 and E2 reactions

Section 14.4: Pyridoxal phosphate - an electron sink cofactor

1. PLP and the Schiff-base linkage to lysine
2. PLP-dependent amino acid racemases
3. PLP-dependent decarboxylation
4. PLP-dependent retroaldol reactions
5. PLP-dependent transaminase reactions (aspartate aminotransferase)
6. PLP-dependent β-elimination and β-substitution reactions
7. PLP-dependent γ-elimination and γ-substitution reactions
8. Altering the course of a PLP reaction through site-directed mutagenesis

Section 14.5: Thiamine diphosphate-dependent reactions

1. The benzoin condensation reaction
2. The transketolase reaction
3. Pyruvate decarboxylase
4. Synthetic parallel - carbonyl nucleophiles via dithiane anions

Section 14.6: The transition state geometry of reactions involving pi bonds

1. Transition state geometry of E2 reactions
2. Transition state geometry of PLP-dependent reactions

Section 14.7: Problems

Section 1: An overview of the different types of electrophilic reactions

Section 2: Electrophilic addition

1. The general picture
2. The regiochemistry of electrophilic addition
3. Enzymatic electrophilic additions
4. Synthetic parallel - electrophilic additions in the laboratory

Section 3: Electrophilic isomerization and substitution (addition/elimination)

1. Alkene isomerization
2. Substitution by electrophilic addition/elimination

Section 4: Another kind of electrophilic addition-elimination - Shikimate to chorismate

Section 5: Electrophilic aromatic substitution

1. The general picture
2. Some representative enzymatic electrophilic aromatic substitution reactions

Section 6: Synthetic parallel - electrophilic aromatic substitution in the lab

1. Friedel-Crafts reactions
2. Ring directing effects in SEAr reactions

Section 7: Carbocation rearrangements

1. Hydride and alkyl shifts
2. Enzymatic reactions with carbocation rearrangement steps
3. The acyloin, pinacol, and Hoffman rearrangements (isoleucine biosynthesis).

Section 8: Cation-pi interactions and the stabilization of carbocation intermediates

Section 9: Outside the box - 1,3-elimination and rearrangement in squalene synthase

Section 10: The Diels-Alder reaction and other pericyclic reactions

Section 1: Oxidation and reduction of organic compounds - an overview

Section 2: The importance of redox reactions in metabolism

Section 3: Outside the box - methanogenesis

Section 4: Hydrogenation/dehydrogenation reactions of carbonyls, imines, and alcohols

1. Nicotinamide adenine dinucleotide - a hydride transfer coenzyme
2. Carbonyl hydrogenation and alcohol dehydrogenation - the general picture
3. Stereochemistry of carbonyl hydrogenation and alcohol dehydrogenation
4. Examples of redox reactions involving alcohols, carbonyl groups, and imines

Section 5: Hydrogenation of alkenes and dehydrogenation of alkanes

1. Alkene hydrogenation in fatty acid biosynthesis
2. The flavin coenzymes
3. Alkane dehydrogenation in fatty acid degradation
4. More examples of enzymatic alkene hydrogenation

Section 6: Additional examples of enzymatic hydride transfer reactions

Section 7: NAD(P)H, FADH₂ and metabolism - a second look

1. NADH and FADH₂ as carriers of hydrides from fuel molecules to water
2. The source of NADPH for reductive biosynthesis

Section 8: Observing the progress of hydrogenation and dehydrogenation reactions by UV assay

Section 9: Hydrogenation/dehydrogenation reactions and renewable energy technology

Section 10: Oxygenase reactions- flavin-dependent monoxygenases

Section 11: Halogenation of organic compounds

1. Enzymatic halogenation
2. Synthetic parallel - halogenation of alkenes in the lab

Section 12: Redox reactions involving thiols and disulfides

1. Disulfide bridges in proteins
2. The role of disulfides in the pyruvate dehydrogenase reaction

Section 13: Redox reactions in the organic synthesis laboratory

1. Metal hydride reducing agents
2. Catalytic hydrogenation and the trans fat issue
3. Reduction of carbonyl carbons to methylene
4. Laboratory oxidation reactions

Section 1: Structure and reactivity of radical species

1. The geometry and relative stability of carbon radicals.
2. The diradical character of triplet oxygen

Section 2: Radical chain reactions

1. The three phases of radical chain reactions
2. Radical halogenation in the lab
3. Useful polymers formed by radical chain reactions
4. Destruction of the ozone layer by CFC radicals
5. Harmful radical species in cells and natural antioxidants

Section 3: Enzymatic reactions with free radical intermediates

1. Hydroxylation of alkanes
2. Reductive dehydroxylation of alcohols
3. Radical mechanisms for flavin-dependent reactions