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Phase Transfer Catalysis MacMillan Lab Group Meeting Anthony Mastracchio April 10 2008 Phase Transfer Catalysis PTC Presentation Outline Introduction Mechanism and basic concepts of Phase Transfer Catalysis Mechanism The PTC Matrix The Intrinsic Reaction Step Reaction Variables The Transfer Step Phase Transfer catalyzed transformations Asymmetric Phase Transfer catalyzed transformations Relevant and Comprehensive Reviews Ooi T Maruoka K Recent Advances in Asymmetric Phase Transfer Catalysis Angew Chem Int Ed 2007 46 4222 4226 Lygo B Andrews B I Asymmetric Phase Transfer Catalysis Utilizing Chiral Quaternary Ammonium Salts Asymmetric Alkylation of Glycine Imines Acc Chem Res 2004 37 518 525 Starks C M Liotta C L Halpern M E Phase Transfer Catalysis Chapman Hall New York 1994 Ch 1 3 Phase Transfer Catalysis Mechanism and Synthesis Ed Halpern M E American Chemical Society Washington DC 1997 ACS Symposium Series 659 Ch 1 3 Encyclopedia of Catalysis Vol 5 Ed Horvath I T Wiley Interscience Hoboken NJ 2003 511 564 Asymmetric Phase Transfer Catalysis Ed Maruoka K Wiley VCH Weinheim Germany 2008 The Advent of Phase Transfer Catalysis PTC 1946 First clear cut example of the commercial use of PTC Ind Chem Chem 1946 38 207 O O O Bu Cl Et3N O CO2Na aqueous phase Bu NaCl CO2Bn organic phase The phase transfer catalyst benzyltriethylammonium chloride is formed in situ by addition of triethylamine 1969 Formulation of the first mechanistic hypothesis on PTC by M Makosza Tett Lett 1969 10 4659 CH3Cl PhCH2NEt3 Cl Cl NaOHaq Cl 72 Makosza postulated an ion exchange between the tetraalkylammonium chloride and aqueous NaOH to form the base that reacts in the organic phase Mieczyslaw Makosza 1971 The concept of PTC is described by C M Starks J Am Chem Soc 1971 93 195 1984 First example of an asymmetric PTC by Merck Process J Am Chem Soc 1984 106 446 Phase Transfer Catalysis Definition of a phase transfer catalyst A phase transfer catalyst is a catalyst which facilitates the migration of a reactant in a heterogeneous system from one phase into another phase where reaction can take place Ionic reactants are often soluble in an aqueous phase but are insoluble in an organic phase unless the phase transfer catalyst is present Phase transfer catalysis or PTC refers to the acceleration of the reaction by the phase transfer catalyst PTC for anions reactant are often quaternary ammonium salts PTC for cations are often crown ethers Advantages of PTC Elimination of organic solvents Use of simple and inexpensive reactants NaOH KOH K2CO3 etc instead of NaH KHMDS t BuOK etc High yields and purity of products Simplicity of the procedure Highly scalable Low energy cosumption and lowinvestment cost Minimization of industrial waste Phase Transfer Catalysis Consider the following reaction Me Cl 4 NaCN H 2O Me CN 3 No Reaction The 1 chlorooctane and sodium cyanide solution form two separate layers Heating of this two phase mixture under reflux and vigorous stirring for 1 2 days gives no reaction Phase Transfer Catalysis Consider the following reaction Me Cl 4 NaCN H 2O Me CN 3 No Reaction The 1 chlorooctane and sodium cyanide solution form two separate layers Heating of this two phase mixture under reflux and vigorous stirring for 1 2 days gives no reaction Me Cl 4 NaCN R4N 1 wt H2O Me CN 3 Near 100 yield in 2 3 h When an appropriate quaternary ammonium salt is added tetrahexylammonium chloride the discplacement occurs rapidly in near 100 in 2 3h Phase Transfer Catalysis Consider the following reaction Me Cl 4 NaCN H 2O Me CN 3 No Reaction The 1 chlorooctane and sodium cyanide solution form two separate layers Heating of this two phase mixture under reflux and vigorous stirring for 1 2 days gives no reaction Me Cl 4 NaCN R4N 1 wt H2O Me CN 3 Near 100 yield in 2 3 h When an appropriate quaternary ammonium salt is added tetrahexylammonium chloride the discplacement occurs rapidly in near 100 in 2 3h In this process the ammonium salt catalyst 1 Transfers the cyanide into the organic phase 2 Activates the transferred cyanide for the reaction with the alkyl halide 3 Transfers the discplaced chloride anions back to the aqueous phase to start a new catalytic cycle The Mechanisms of PTC Case study The PTC cyanide displacement reaction Me Cl 4 R Cl NaCN Q CN R4N cat CN Me H2O solvent R CN 4 Q Cl Organic Phase Interface Q CN Q Cl Interface Aqueous Phase CN Cl The reaction occurs in at least two steps Step 1 The intrinsinc reaction or organic phase displacement reaction step If this step is rate determining Extraction Mechanism Step 2 The transfer step If this step is rate determining Interfacial Mechanism Q R4N The Mechanisms of PTC The Intrinsic Step The PTC cyanide displacement reaction Me Cl 4 NaCN R4N cat H2O solvent Me CN 4 Once in solution the cyanide anion must be sufficiently reactive to allow displacement to proceed The Mechanisms of PTC The Intrinsic Step The PTC cyanide displacement reaction Me Cl 4 NaCN R4N cat H2O solvent Me CN 4 Once in solution the cyanide anion must be sufficiently reactive to allow displacement to proceed NaCN poor reactivity The poor reactivity is due to the tight ion pairs of NaCN or large interaction energy binding the two ions together The Mechanisms of PTC The Intrinsic Step The PTC cyanide displacement reaction Me Cl 4 NaCN R4N cat CN Me H2O solvent 4 Once in solution the cyanide anion must be sufficiently reactive to allow displacement to proceed NaCN poor reactivity The poor reactivity is due to the tight ion pairs of NaCN or large interaction energy binding the two ions together Na Br o 2 85 A Bu4N Br o 6 32 A The difference in ionic radii can be translated into ionic interaction energies by simple Coulombic calculations Coulombic Interaction Energy Kcal mol 11 4 5 3 By substracting the tetrabutylammonium energy from the potassium energy we can compare the calculated differences between ion pairs If these differences in ion pair energies are translated in reduction of kinetic activation energies then a 5 Kcal mol difference in activation energy is equivalent to a 4400 fold changes in reaction rate The Mechanisms of PTC The Intrinsic Step Cation Size and Coulombic Interaction Energies of Bromide Salts Cation Cation Radius Coulombic Interaction Energy with bromide anion Kcal mol Li 0 6 12 8 Na 0 9 11 4 K 1 33 9 9 Rb 1 48 9 5 Cs 1 69 9 Me4N 2 85 6 8 Et4N n Pr N 3 48 6 2 4 3 98 5 5 n Bu4N 4 37 5 3 As the cationic radius of the quaternary salt increases the activating effect becomes larger


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