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IX. Nucleophilic Substitution

  1. Basic mechanistic divide: SN1 and SN2
  2. SN1 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
  3. SN2 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 SN2 on hydrogen
    9. SN2 on other nuclei (halogens, sulfur, phosphorus)
  4. SN2’ mechanism
    1. ambident reactivity of allylic systems
    2. SN2 vs. SN2’ in allylic systems
    3. Importance of steric effects

X. Addition to p systems

  1. Exchange of p bond for 2 s bonds
  2. Three different mechanisms: electrophilic, nucleophilic & concerted
  3. 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
  4. 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
  5. 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

  1. Reverse of addition
  2. Mechanistic possibilities: E1, E2, E1CB
  3. 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
  4. Regiochemistry of elimination
    1. Zaitsev’s Rule
    2. Hoffmann’s Rule
  5. Stereochemistry of E2-like eliminations
  6. Formation of alkynes by elimination
  7. Formation of carbonyls by elimination
    1. Reversibility
    2. Unfavorable equilibrium

XII. Addition-Elimination Sequences

  1. Electrophilic Aromatic Substitution
    1. Mechanism
    2. Variety of electrophiles
    3.  Substituent effects
      1. Directing effects
      2. Hammond’s postulate
      3. Activation/Deactivation
  2. 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
  3. 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
  4. Formation of C-N double bonds
    1. Range of nucleophiles
    2. Formation of tetrahedral intermediate
    3. Possiblity of acid catalysis
  5. Dehydrative aldol condensations

XIII. Complex reaction mechanisms

  1. The Robinson annulation: Michael+aldol
    1. Initial Michael addition
    2. Intermediate proton transfers
    3. Intramolecular aldol condensation
    4. Final dehydration
  2. 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
  3. Acetal formation: addition + SN1
    1. Initial hemiacetal formation
    2. Need for acid catalysis
    3. Proton transfer reactions
    4. Loss of water via SN1 displacement
  4. Diazotization of amines
    1. Mechanism
    2. Instability of alkyldiazonium ions
    3. Stability of aryl diazonium ions

XIV. Reactions of free radicals and radical ions

  1. Generation of free radicals: radical initiation reactions
    1. Homolytic cleavage of weak s bonds
    2. Hydrogen atom abstration by radical initiators
  2. 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
  3. 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
  4. 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

  1. 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
  2. Fundamental reaction mechanisms
    1. Ligation/deligation
    2. Oxidative insertion
    3. Reductive elimination
    4. Migratory insertion
    5. b-hydride elimination
  3. Sandmeyer reaction
    1. Mechanism
    2. Scope
  4. Heck reaction
    1. Mechanism
    2. Amiguity of b-hydride elimination
    3. Role of base
  5. Pd-catalyzed cross-coupling
    1. Mechanism
    2. Coupling partners: Sn, B, Zn, Cu, Si
    3. Application to synthesis of biaryls, etc.
  6. 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

  1. 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
  2. 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
  3. 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
  4. 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