Organocatalysis Flashcards
What is organocatalysis?
Catalysis by a substoichiometric amount of a low molecular weight organic molecule, unchanged at the end and devoid of metal atoms.
What are the advantages of organocatalysis?
Organocatalysts stable to air and moisture, available from biological material, relatively inexpensive and simple to prepare, simple to use, robust, non-toxic or less toxic, metal-free, often more easily separated from product and removed from waste stream
What are the different classifications of organocatalysis and what are some examples?
Covalent and non-covalent organocatalysts. Covalent work by forming a covalent bond (enamines, iminium ions, Breslow intermediates, radicals) and non-covalent interact via non-covalent interactions like hydrogen bonding and electrostatic interactions (e.g. thioureas, phosphates).
What types of non-covalent interactions should be considered?
Charge-charge, charge-dipole, dipole-dipole, charge=induced dipole, dipole-induced dipole, dispersion, hydrogen bonding, steric effects. What is the range of these types of interactions?
How are Lewis and Bronsted acids and bases involved in organocatalysis?
Lewis base: organocat. attaches to substrate via nucleophilic addition or substitution
Lewis acid: Organocat. interacts with nucleophilic reaction partner via Lewis acid/base interactions (adduct formation)
Bronsted base: Organocat. activates a reagent via deprotonation
Bronsted acid: Organocat. activates one reagent by protonation or hydrogen bonding
What stereoselection models can be used with aminolysis and carbonyl reactions?
Houk and Zimmerman-Traxler transition state models
Zimmerman-Traxler - 6-membered ring transition states with 1,3-diaxial interactions repulsive.
What is a general catalytic cycle for the reactions covered in this course via proline-type catalysis?
Formation of enamine, followed by nucleophilic reaction at carbonyl via Zimmerman-Traxler transition state. Removal of iminium ion by hydrolysis to form product.
What factors affect the catalytic activity of proline derivatives?
Ring size (best done by 5 membered ring), acidity of the amine proton (affects nucleophilicity of N), steric effects by protection or alteration of COOH on proline (interception of key H-bonding interaction?)
What is the mechanism for enamine and iminium ion formation and what is specifically good about proline?
Attack of amine at carbonyl to give loss of water and form a double bond at the nitrogen to give iminium ion. Proton transfer to give enamine (similar to enol formation). For proline, intramolecular as COOH deprotonates to form the enamine.
What do bifunctional H-bond catalysts do?
Bifunctional catalysts both provide the reagent to form the enamine [active catalytic species] and Bronsted acid co-catalyst to aid proton transfer. This enables simultaneous activation of the nucleophile and the electrophile. Example is tertiary amine with thiourea attached (tertiary amine undergoes enamine/enol formation (or forms hydrogen bonding with substrate) with thiourea acting as hydrogen bonding to bring reactants together in right orientations).
How do the LUMO lowering and HOMO raising activation modes work?
Enamine activation of the nucleophile to raise the HOMO, i.e. making nucleophile more nucleophilic. Iminium ion formation at electrophile to lower the LUMO, further stereoselectivity induced by bulky groups.
What is the Curtin-Hammett principle?
Product composition dependent on both proportions of intermediates A and B but also the difference in G between the respective transition states.
PA <– A <=> B –> PB (case for the C-H principle to apply). with A <=> B faster than subsequent reactions.
How is enantioselectivity affected by reaction barriers and temperature?
G will change depending on temperature and enantioselectivity depends on diastereomeric transition states such that difference between will change depending on temperature influencing selectivity. Assume kinetic control.
What can cause deviations in linearity for Eyring/Arrhenius plots in these cases?
Competing multiple reaction pathways of similar energy and changes in mechanism can result in deviations from linearity.
What are the main things to consider for a successfully catalysed reaction?
Activation energy < 25 kcal/mol and difference in energy between starting material and product < -3 kcal/mol. Require eqm arrows, influenced by low activation energies of steps.
