Chemistry and creativity Organic Chemistry With a Biological Emphasis Volume I
Volume I: Chapters 1-9
Tim Soderberg
University of Minnesota, Morris
Organic Chemistry With a Biological Emphasis Volume I
Volume I: Chapters 1-9
Introduction
Chapter 1: Introduction to organic structure and bonding I
Introduction
Section 1: Atomic orbitals and electron configuration
A: The atom
B: Atomic orbitals
C: Electron configuration
Section 2: Chemical Bonds
A: Ionic bonds
B: Covalent bonds and Lewis structures
C: Formal charges
Section 3: Drawing organic structures
A: Common bonding patterns in organic structures
B: Using the ‘line structure’ convention
C: Constitutional isomers
D: The Index of Hydrogen Deficiency
Section 4: Functional groups and organic nomenclature
A: Common functional groups in organic compounds
B: Naming organic compounds
C: Abbreviated organic structures
Section 5: Valence bond theory
A: Formation of sigma bonds: the H2 molecule
B: Hybrid orbitals: sp3 hybridization and tetrahedral bonding
C: Formation of pi bonds: sp2 and sp hybridization
D: The valence bonding picture in carbocations, carbanions, and carbon free radicals
Chapter 2: Introduction to organic structure and bonding II
Introduction
Section 1: Molecular orbital theory
A: Another look at the H2 molecule: bonding and antibonding sigma molecular orbitals
B: MO theory and pi bonds: conjugation
C: Aromaticity
Section 2: Resonance
A: The meaning of resonance contributors: benzene and its derivatives
B: Resonance contributors of the carboxylate group
C: Rules for drawing resonance structures
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D: Major vs minor resonance contributors – four more rules to follow
E: More examples of resonance: peptide bonds, enolates, and carbocations
Section 3: Non-covalent interactions
A: Dipoles
B: Ion-ion, dipole-dipole and ion-dipole interactions
C: van der Waals forces
D: Hydrogen bonds
Section 4: The relationship between noncovalent interactions physical properties
A: Solubility
B: Illustrations of solubility concepts – metabolic intermediates, lipid bilayer membranes,
soaps and detergent
C: Boiling points and melting points
D: The melting behavior of lipid structures
Chapter 3: Conformations and Stereochemistry
Introduction
Section 1: Conformations of straight-chain organic molecules
A: Conformations of ethane
B: Conformations of butane
Section 2: Conformations of cyclic organic molecules
A: Introduction to sugars and other cyclic molecules
B: Ring size
C: Conformations of glucose and other six-membered ring structures
D: Conformations of pentose and other five-membered ring structures
E: 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
A: Compounds with multiple stereocenters
B: Meso compounds
C: Stereoisomerism of alkenes
Section 8: Fischer and Haworth projections
Section 9: Stereochemistry and organic reactivity
Section 10: Prochirality
A: Prochiral substituents on tetrahedral carbons
B: Carbonyl and imine carbons as prochiral centers
Chapter 4: Structure determination part I: Infrared spectroscopy, UV-visible spectroscopy,
and mass spectrometry
Introduction
Section 1: Introduction to molecular spectroscopy
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A: The electromagnetic spectrum
B: Molecular spectroscopy – the basic idea
Section 2: Infrared spectroscopy
Section 3: Ultraviolet and visible spectroscopy
A: Electronic transitions
B: Looking at UV-vis spectra
C: Applications of UV spectroscopy in organic and biological chemistry
Section 4: Mass Spectrometry
A: The basics of mass spectrometry
B: Looking at mass spectra
C: Gas Chromatography – Mass Spectrometry
D: Mass spectrometry of proteins – applications in proteomics
Chapter 5: Structure determination part II- Nuclear magnetic resonance spectroscopy
Introduction
Section 1: The origin of the NMR signal
A: NMR-active nuclei
B: Nuclear precession, spin states, and the resonance condition
Section 2: Chemical equivalence
Section 3: The NMR experiment
A: The basics of an NMR experiment
B: The chemical shift
C: Signal integration
Section 4: The basis for differences in chemical shift
A: Diamagnetic shielding and deshielding
B: Diamagnetic anisotropy
C: Hydrogen-bonded protons
Section 5: Spin-spin coupling
A: The source of spin-spin coupling
B: Coupling constants
C: Complex coupling
Section 6: 13C-NMR spectroscopy
A: The basics of 13C-NMR spectroscopy
B: 13C-NMR in isotopic labeling studies
Section 7 : Determining unknown structures
Section 8: NMR of phosphorylated molecules
Chapter 6: Introduction to organic reactivity and catalysis
Introduction
Section 1: A first look at reaction mechanisms
A: An acid-base (proton transfer) reaction
B: A one-step nucleophilic substitution reaction (SN2)
C: A two-step nucleophilic substitution reaction (SN1)
Section 2: Describing the thermodynamics and kinetics of chemical reactions – energy diagrams
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Section 3: Enzymatic catalysis – the basic ideas
Section 4: Protein structure
A: Amino acids and peptide bonds
B: Visualizing protein structure: X-ray crystallography
C: The four levels of protein structure
D: The molecular forces that hold proteins together
Section 5: How enzymes work
A: The active site
B: Transition state stabilization
C: Site-directed mutagenesis
D: Enzyme inhibition
E: Catalysts in the laboratory
Chapter 7: Organic compounds as acids and bases
Introduction
Section 1: The ‘basic’ idea of an acid-base reaction
A: The Brønsted-Lowry definition of acidity
B: The Lewis definition of acidity
Section 2: Comparing the acidity and basicity of organic functional groups– the acidity constant
A: Defining Ka and pKa
B: Using pKa values to predict reaction equilibria
C: pKa and pH: the Henderson-Hasselbalch equation
Section 3: Structural effects on acidity and basicity
A: Periodic trends
B: The resonance effect
C: The inductive effect
Section 4: More on resonance effects on acidity and basicity
A: The acidity of phenols
B: 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
Chapter 8: Nucleophilic substitution reactions part I
Introduction
Section 1: Introduction to the nucleophilic substitution reaction
Section 2: Two mechanistic models for a nucleophilic substitution reaction
A: Associative nucleophilic substitution: the SN2 reaction
B: Dissociative nucleophilic substitution: the SN1 reaction
C: Nucleophilic substitutions occur at sp3-hybridized carbons
Section 3: More about nucleophiles
A: What makes a nucleophile?
B: Protonation states and nucleophilicity
C: Periodic trends and solvent effects in nucleophilicity
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Tim Soderberg
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D: Resonance effects on nucleophilicity
E: Steric effects on nucleophilicity
Section 4: Electrophiles and carbocation stability
A: Steric effects on electrophilicity
B: Stability of carbocation intermediates
Section 5: Leaving groups
A: What makes a good leaving group?
B: Leaving groups in biochemical reactions
C: Synthetic parallel – conversion of alcohols to alkyl halides, tosylates and mesylates
D: SN1 or SN2? Predicting the mechanism
Section 6: Epoxides as electrophiles in nucleophilic substitution reactions
A: Epoxide structure
B: Epoxide ring-opening reactions – SN1 vs SN2, regioselectivity, and stereoselectivity
Chapter 9: Nucleophilic substitution reactions part II
Introduction
Section 1: Methyl group transfers: examples of SN2 reactions
A: SAM methyltransferase
B: Synthetic parallel – the Williamson ether synthesis
Section 2: Digestion of carbohydrate by glycosidases – an SN1 reaction
Section 3: Protein prenyltransferase – a hybrid SN1/SN2 substitution
A: The biological relevance of the protein prenyltransferase reaction
B: Determining the mechanism of protein prenyltransferase with fluorinated substrate
analogs
C: The zinc-thiolate interaction in protein prenyltransferase – ‘tuning’ the nucleophile
Section 4: Biochemical nucleophilic substitutions with epoxide electrophiles
A: Hydrolysis of stearic acid epoxide: investigating the mechanism with kinetic isotope
effect experiments
B: Fosfomycin – an epoxide antibiotic
Section 5: Nucleophilic substitution over conjugated pi systems – the SN’ mechanism
Tables
Table 1: Some characteristic absorption frequencies in IR spectroscopy
Table 2: Typical values for 1H-NMR chemical shifts Table 3: Typical values for 13C-NMR chemical shifts Table 4: Typical coupling constants in NMR
Table 5: The 20 common amino acids Table 6: Structures of common coenzymes Table 7: Representative acid constants
Table 8: Some common laboratory solvents, acids, and bases
Table 9: Examples of common functional groups in organic chemistry
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Volume II: Chapters 10-17
Chapter 10: Phosphoryl transfer reactions
Introduction: Abundance of phosphoryl groups in metabolic intermediates
Section 1: Overview of phosphates and phosphoryl transfer reactions
A: Nomenclature and abbreviations
B: Acid constants and protonation states
C: Bonding in phosphines and phosphates
D: Phosphoryl transfer reactions – the general picture
E: Phosphoryl transfer reactions – associative, addition-elimination, or dissociative?
Section 2: Phosphorylation reactions – kinase enzymes
A: ATP – the principle phosphoryl group donor
B: Monophosphorylation of alcohols
C: Diphosphorylation of alcohols
D: Phosphorylation of carboxylates
E: Generation of nucleotide phosphates
F: Regeneration of ATP from ADP
Section 3: Hydrolysis of phosphates
Section 4: Phosphate diesters
A: Phosphate diesters as the backbone for DNA and RNA
B: The chemistry of genetic engineering
Chapter 11: Nucleophilic carbonyl addition reactions
Introduction
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
Organic Chemistry With a Biological Emphasis
Chapter 12: Acyl substitution reactions
Introduction
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
12.2D: 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
Chapter 13: Reactions with stabilized carbanion intermediates, part I – isomerization, aldol
and Claisen condensation, and decarboxylation
Introduction
Section 1: Tautomers
A: Keto-enol tautomerization
B: Imine/enamine tautomerization
Section 2: Isomerization reactions
A: Carbonyl isomerization
B: Stereoisomerization at chiral carbons
C: Alkene isomerization in the degradation of unsaturated fatty acids
Section 3: Aldol reactions
A: The general mechanism for an aldol reaction
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B: Typical aldolase reactions: three variations on a theme
C: Going backwards: the retroaldol reaction
D: Going both ways: transaldolase
Section 4: Claisen reactions
A: Claisen condensations
B: Retro-Claisen cleavages
C: Enolates as nucleophiles in SN2 displacements
Section 5: Carboxylation and decarboxylation reactions
A: The metabolic context of carboxylation and decarboxylation
B: The carboxylation mechanism of Rubisco
C: Decarboxylation
D: Biotin is a CO2-carrying coenzyme
Section 6: Synthetic parallel – carbon nucleophiles in the lab
A: Lab reactions with enolate /enamine intermediates
B: The Wittig reaction
C: Terminal alkynes as carbon nucleophiles
D: Grignard, Gilman, and organolithium reagents
Chapter 14: Reactions with stabilized carbanion intermediates, part II: Michael additions,
eliminations, and electron sink cofactors
Introduction
Section 1: Michael additions and β-eliminations
A: Overview of Michael addition and β-elimination mechanisms
B: Stereochemistry of Michael additions and β-eliminations
C: NMR experiments to determine the stereochemistry of a Michael addition
D: More examples of elimination and addition reactions
Section 2: Variations on the Michael reaction
A: Cis/trans alkene isomerization
B: Nucleophilic aromatic substitution
C: Synthetic parallel – Michael addition reactions in the laboratory
Section 3: Elimination by the E1 and E2 mechanisms
A: E1 and E2 reactions in the laboratory
B: Enzymatic E1 and E2 reactions
Section 4: Pyridoxal phosphate – an electron sink cofactor
A: PLP and the Schiff-base linkage to lysine
B: PLP-dependent amino acid racemases
C: PLP-dependent decarboxylation
D: PLP-dependent retroaldol reactions
E: PLP-dependent transaminase reactions (aspartate aminotransferase)
F: PLP-dependent β-elimination and β-substitution reactions
G: PLP-dependent γ-elimination and γ-substitution reactions
H: Altering the course of a PLP reaction through site-directed mutagenesis
Section 5: Thiamine diphosphate-dependent reactions
A: The benzoin condensation reaction
B: The transketolase reaction
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C: Pyruvate decarboxylase
D: Synthetic parallel – carbonyl nucleophiles via dithiane anions
Section 6: The transition state geometry of reactions involving pi bonds
A: Transition state geometry of E2 reactions
B: Transition state geometry of PLP-dependent reactions
Chapter 15: π electrons as nucleophiles: electrophilic additions, addition/eliminations, and
rearrangements
Introduction
Section 1: An overview of the different types of electrophilic reactions
Section 2: Electrophilic addition
A: The general picture
B: The regiochemistry of electrophilic addition
C: Enzymatic electrophilic additions
D: Synthetic parallel – electrophilic additions in the laboratory
Section 3: Electrophilic isomerization and substitution (addition/elimination)
A: Alkene isomerization
B: Substitution by electrophilic addition/elimination
Section 4: Another kind of electrophilic addition-elimination – Shikimate to chorismate
Section 5: Electrophilic aromatic substitution
A: The general picture
B: Some representative enzymatic electrophilic aromatic substitution reactions
Section 6: Synthetic parallel – electrophilic aromatic substitution in the lab
A: Friedel-Crafts reactions
B: Ring directing effects in SEAr reactions
Section 7: Carbocation rearrangements
A: Hydride and alkyl shifts
B: Enzymatic reactions with carbocation rearrangement steps
C: 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
Chapter 16: Oxidation and reduction reactions
Introduction
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
A: Nicotinamide adenine dinucleotide – a hydride transfer coenzyme
B: Carbonyl hydrogenation and alcohol dehydrogenation – the general picture
C: Stereochemistry of carbonyl hydrogenation and alcohol dehydrogenation
D: Examples of redox reactions involving alcohols, carbonyl groups, and imines
Section 5: Hydrogenation of alkenes and dehydrogenation of alkanes
Organic Chemistry With a Biological Emphasis
A: Alkene hydrogenation in fatty acid biosynthesis
B: The flavin coenzymes
C: Alkane dehydrogenation in fatty acid degradation
D: More examples of enzymatic alkene hydrogenation
Section 6: Additional examples of enzymatic hydride transfer reactions
A: More reactions involving nicotinamide adenine dinucleotide and flavin
B: Reactions with coenzymes derived from folic acid
Section 7: NAD(P)H, FADH2 and metabolism – a second look
A: NADH and FADH2 as carriers of hydrides from fuel molecules to water
B: 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
A: Enzymatic halogenation
B: Synthetic parallel – halogenation of alkenes in the lab
Section 12: Redox reactions involving thiols and disulfides
A: Disulfide bridges in proteins
B: The role of disulfides in the pyruvate dehydrogenase reaction
Section 13: Redox reactions in the organic synthesis laboratory
A: Metal hydride reducing agents
B: Catalytic hydrogenation and the trans fat issue
C: Reduction of carbonyl carbons to methylene
D: Laboratory oxidation reactions
Chapter 17: Radical reactions
Introduction
Section 1: Structure and reactivity of radical species
A: The geometry and relative stability of carbon radicals.
B: The diradical character of triplet oxygen
Section 2: Radical chain reactions
A: The three phases of radical chain reactions
B: Radical halogenation in the lab
C: Useful polymers formed by radical chain reactions
D: Destruction of the ozone layer by CFC radicals
E: Harmful radical species in cells and natural antioxidants
Section 3: Enzymatic reactions with free radical intermediates
A: Hydroxylation of alkanes
B: Reductive dehydroxylation of alcohols
C: Radical mechanisms for flavin-dependent reactions
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Tables
Table 1: Some characteristic absorption frequencies in IR spectroscopy
Table 2: Typical values for 1H-NMR chemical shifts Table 3: Typical values for 13C-NMR chemical shifts Table 4: Typical coupling constants in NMR
Table 5: The 20 common amino acids Table 6: Structures of common coenzymes Table 7: Representative acid constants
Table 8: Some common laboratory solvents, acids, and bases
Table 9: Examples of common functional groups in organic chemistry
Appendix I: Enzymatic reactions by metabolic pathway and EC number
Appendix II : Review of laboratory synthesis reactions
