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IX. Nucleophilic Substitution

Basic mechanistic divide: S_N1 and S_N2
S_N1 reactions
1. Carbocation intermediate
  1. Stability trends for carbocations
  2. sp2 hybridization and loss of stereogenicity
2. Typical examples
  1. Acid-catalyzed displacement of alcohols
  2. Solvolysis of haloalkanes
  3. Lewis-acid induced ionization of haloalkanes
3. Solvent effects
S_N2 reactions
1. Concerted reaction
2. Pentacoordinate transition state
3. Walden inversion of stereochemistry
4. Leaving group trends
5. Sensitivity to sterics
6. Acceleration by allylic, benzylic substitution
7. Solvent effects
8. Acid-base reactions as S_N2 on hydrogen
9. S_N2 on other nuclei (halogens, sulfur, phosphorus)
S_N2’ mechanism
1. ambident reactivity of allylic systems
2. S_N2 vs. S_N2’ in allylic systems
3. Importance of steric effects

X. Addition to p systems

Exchange of p bond for 2 s bonds
Three different mechanisms: electrophilic, nucleophilic & concerted
Electrophilic addition
1. To alkenes
  1. HX
  2. X2
  3. X2/H2O
  4. Hg2+
2. To alkynes
  1. HX
  2. X2
  3. Hg2+/H2SO4
3. To carbonyls
  1. H+, H2O
  2. H+, ROH
4. To nitriles
  1. H+, H2O
  2. H+, ROH
Nucleophilic addition
1. To carbonyls
  1. OH-
  2. Hydride reagents
  3. HCN
  4. Organometallics
    1. Grignard reagents
      - formation
      - structure
      - basicity
      - nucleophilicity
    2. Alkyllithium reagents
    3. Other metals: Zn, Cr, Al
2. To nitriles
  1. OH-
  2. Hydride reagents
  3. Organolithium reagents
3. To a, b-unsaturated carbonyls
  1. Formation of enolate
  2. Need for equilibrium conditions
  3. Competition between 1,2- and 1,4- addition
Concerted mechanisms
1. Hydroboration
  1. Cyclic transition state
  2. syn stereochemistry of addition
  3. Regiochemical preferences
  4. Of alkynes: formation of aldehydes from terminal alkynes
2. Osmylation
  1. Cyclic transition state
  2. Syn stereochemistry
3. Catalytic hydrogenation
  1. Need for noble metal catalysts
  2. Reaction at surface of metal
  3. Predominance of syn addition
4. Ozonolysis
  1. Structure of ozone
  2. [3+2] cycloaddition mechanism
  3. Rearrangement of ozonide to mol-ozonide
5. Cyclopropanation of alkenes
  1. The nature of carbenes
    1. Divalent carbon
    2. Neutrality
    3. Lack of octet
    4. Highly reactive
  2. [1+2] cycloaddition mechanism
  3. Use of carbenoids in cyclopropenation
6. Epoxidation
  1. Need for electrophilic oxygen
  2. Structure of peroxyacids
  3. Reactive form of peroxyacids
  4. Concerted O transfer mechanism
7. The Diels-Alder reaction
  1. [4+2] cycloaddition
  2. Boat-like transition state
  3. Regiochemical preferences
  4. Stereospecificity
  5. Alder’s endo rule

XI. Elimination reactions

Reverse of addition
Mechanistic possibilities: E1, E2, E1CB
Competition between substitution and elimination
1. SN1 vs. E1
2. SN2 vs. E2/E1CB
  1. Role of sterics
  2. Role of leaving group
  3. Role of solvent
Regiochemistry of elimination
1. Zaitsev’s Rule
2. Hoffmann’s Rule
Stereochemistry of E2-like eliminations
Formation of alkynes by elimination
Formation of carbonyls by elimination
1. Reversibility
2. Unfavorable equilibrium

XII. Addition-Elimination Sequences

Electrophilic Aromatic Substitution
1. Mechanism
2. Variety of electrophiles
3. Substituent effects
  1. Directing effects
  2. Hammond’s postulate
  3. Activation/Deactivation
Nucleophilic Aromatic Substitution
1. Addition-Elimination
  1. Mechanism
  2. Need for EWGs
2. Elimination-Addition: Benzyne intermediates
  1. Formation of benzynes
  2. Multiplicity of products
  3. Instability of benzynes
Nucleophilic Acyl Substitution
1. Anionic mechanisms: direct nucleophilic attack
  1. Formation of tetrahedral intermediate
  2. Reformation of carbonyl
  3. Need for reactive nucleophiles
2. Electrophilic mechanisms: acid-catalysis
  1. Weak nucleophiles
  2. Regeneration of acid catalyst
Formation of C-N double bonds
1. Range of nucleophiles
2. Formation of tetrahedral intermediate
3. Possiblity of acid catalysis
Dehydrative aldol condensations

XIII. Complex reaction mechanisms

The Robinson annulation: Michael+aldol
1. Initial Michael addition
2. Intermediate proton transfers
3. Intramolecular aldol condensation
4. Final dehydration
The Wolff-Kishner reduction of carbonyls
1. Formation of hydrazone
2. Base-catalyzed proton transfers
3. Elimination of N2
4. Formation of carbanion
5. Need for vigorous conditions
Acetal formation: addition + SN1
1. Initial hemiacetal formation
2. Need for acid catalysis
3. Proton transfer reactions
4. Loss of water via SN1 displacement
Diazotization of amines
1. Mechanism
2. Instability of alkyldiazonium ions
3. Stability of aryl diazonium ions

XIV. Reactions of free radicals and radical ions

Generation of free radicals: radical initiation reactions
1. Homolytic cleavage of weak s bonds
2. Hydrogen atom abstration by radical initiators
Reactions of free radicals
1. Radical halogenation reactions
  1. Radical halogenation of alkanes
  2. Mechanism of radical halogenation
  3. Allylic and benzylic bromination
  4. Termination reactions
2. Free radical addition to p systems
  1. H2O2/HBr addition to alkenes
  2. Free radical polymerization
  3. Radical cyclization
3. Clemmensen reduction of carbonyls
  1. Debate about mechanism
  2. SET mechanism
Radical anions
1. Definition
2. Production by single electron transfer
3. The Grignard reaction
  1. Elemental metals as sources of electrons
  2. Reduction of weak C-Br or C-I bonds
  3. Mechanism
4. Dissolving metal reduction of alkynes
  1. Ammonia as solvent
  2. Mechanism
  3. Ammonia as proton source
5. Birch reduction
  1. Use of dissolving metal conditions
  2. Alcohol as proton source
  3. 1,4-diene
  4. Substituent effects
6. Dissolving metal reduction of enones
Radical cations
1. Production by removal of an electron
2. Radical cations in mass spectrometry
  1. Production by electron detachment
  2. Commonly produced radical cations
  3. Characteristic reactions
    1. a-cleavage
    2. b-cleavage of carbonyl r.c.
    3. McLafferty rearrangement

XV. Transition metal-catalyzed reactions

Electronic configuration of transition metals
1. 18 electron rule
2. Ligands
  1. s donors
  2. Coordinative (dative) bonding ligands
  3. p donors
3. Oxidation states of transition metals
Fundamental reaction mechanisms
1. Ligation/deligation
2. Oxidative insertion
3. Reductive elimination
4. Migratory insertion
5. b-hydride elimination
Sandmeyer reaction
1. Mechanism
2. Scope
Heck reaction
1. Mechanism
2. Amiguity of b-hydride elimination
3. Role of base
Pd-catalyzed cross-coupling
1. Mechanism
2. Coupling partners: Sn, B, Zn, Cu, Si
3. Application to synthesis of biaryls, etc.
Olefin metathesis
1. Mechanism
2. RCM
  1. Production of ethylene
  2. Thermodynamically driven
3. ROMP
  1. Relief of ring strain
  2. Propagation
4. Cross metathesis
5. Catalyst choice

XVI. Biopolymers and polyfunctional molecules

Amino acids, peptides and proteins
1. Amino acids
  1. Sidechains, names and abbreviations
  2. Chirality
  3. pKa values and pI
2. Peptides
  1. Structure
  2. The peptide bond
  3. Primary sequence
  4. Sequencing
  5. Synthesis
    1. SPPS
    2. Coupling reagents
    3. Protecting groups
  6. Secondary structure
    1. alpha helix
    2. beta sheet
    3. beta turn
3. Proteins
  1. Size distinction
  2. Tertiary structure
  3. Proteolytic enzymes
Carbohydrates
1. Monosaccharides
  1. General structure
  2. Aldose vs. ketonse
  3. Carbon count
  4. Stereochemistry, D- vs. L-
  5. Cyclic hemiacetal structure
    1. Mechanism
    2. Anomeric center
    3. a vs. b anomer
  6. Glycoside formation
    1. Mechanism
    2. Disaccharide formation
2. Oligosaccharides
  1. Terminology
  2. Maltose and sucrose
  3. Structure
3. Polysaccharides
Nucleic Acids
1. Generic structure of nucleotides
  1. Ribose/2-deoxyribose
  2. Bases
  3. a-anomers
2. Phosphorylation: nucleosides
3. Oligonucleotides
  1. Primary sequence
  2. DNA double helix (B-DNA)
  3. Z-DNA
  4. RNA structural motifs
    1. Stablity of single strands
    2. Stem-loops and double helices
Lipids
1. Generic structure
2. Fatty acids
  1. Saturated
  2. Unsaturated
3. Polar head groups
  1. Phosphatidylcholine
  2. Phosphatidylserine
4. Physical properties
  1. Melting point
  2. Solubility
  3. Oligomerization
5. Lamellar structures and lipid bilayers
6. Micelles and lipsosomes