Phase-TransferCatalysisMacMillan Lab. Group MeetingAnthony MastracchioApril 10 2008Phase-Transfer Catalysis (PTC)! Introduction" MechanismStarks, 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.Ooi, T., Maruoka, K., "Recent Advances in Asymmetric Phase-Transfer Catalysis." Angew. Chem. Int. Ed. 2007, 46, 4222-4226Lygo, 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.Asymmetric Phase-Transfer Catalysis (Ed., Maruoka, K.), Wiley-VCH, Weinheim, Germany, 2008.Relevant and Comprehensive Reviews:! Mechanism and basic concepts of Phase-Transfer Catalysis" The Intrinsic Reaction Step" The Transfer Step" The PTC Matrix" Reaction Variables! Phase-Transfer catalyzed transformations! Asymmetric Phase-Transfer catalyzed transformationsPresentation OutlineThe Advent of Phase-Transfer Catalysis (PTC)! 1946 - First clear-cut example of the commercial use of PTC (Ind. Chem. Chem., 1946, 38, 207.)CO2NaOOBuClorganicphaseaqueousphaseEt3NCO2BnOOBuNaCl" 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.)Mieczyslaw MakoszaCH3Cl(PhCH2NEt3)+ Cl–NaOHaqClCl72 %" Makosza postulated an ion exchange between the tetraalkylammonium chloride andaqueous NaOH to form the base that reacts in the organic phase! 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" Phase transfer catalysis or PTC refers to the acceleration of the reaction by the 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" 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 wastePhase-Transfer Catalysis! Consider the following reaction:MeCl4MeCN3NaCN+H2ONo 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.MeCl4MeCN3NaCN+R4N+(1 wt%)Near 100% yield in 2-3 hH2O! 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:MeCl4MeCN3NaCN+H2ONo 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.MeCl4MeCN3NaCN+R4N+(1 wt%)Near 100% yield in 2-3 hH2O! 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 cyclePhase-Transfer Catalysis! Consider the following reaction:MeCl4MeCN3NaCN+H2ONo 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.The Mechanisms of PTC! Case study: The PTC cyanide displacement reaction! The reaction occurs in at least two stepsQ+CN–Q+Cl–Interface InterfaceAqueous PhaseOrganic PhaseCN–Cl–RClQ+CN–+RCNQ+Cl–+MeCl4MeCN4NaCN+R4N+(cat)H2O, solventQ+=R4N+" Step 1: The intrinsinc reaction or organic-phase displacement reaction step" Step 2: The transfer step–If this step is rate determiningExtraction Mechanism–If this step is rate determiningInterfacial MechanismThe Mechanisms of PTC! The PTC cyanide displacement reaction.MeCl4MeCN4NaCN+R4N+(cat)H2O, solventThe Intrinsic Step! Once in solution the cyanide anion must be sufficiently reactive to allow displacement to proceed.The Mechanisms of PTC! The PTC cyanide displacement reaction.MeCl4MeCN4NaCN+R4N+(cat)H2O, solventThe Intrinsic Step! Once in solution the cyanide anion must be sufficiently reactive to allow displacement to proceed.NaCNpoor reactivityThe 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 PTC cyanide displacement reaction.MeCl4MeCN4NaCN+R4N+(cat)H2O, solventThe Intrinsic Step! Once in solution the cyanide anion must be sufficiently reactive to allow displacement to proceed.NaCNpoor reactivityThe poor reactivity is due to the tight ion pairs of NaCN, or large interaction energy binding the two ions together."Na+Br–2.85 AoBu4N+Br–6.32 AoThe difference in ionic radii can be translated into ionic interaction energies by simple Coulombic calculations.Coulombic Interaction Energy (Kcal/mol):5.311.4By 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 PTCThe Intrinsic StepCationCation Radius, ÅLi+Na+K+Rb+Cs+Me4N+Et4N+n-Pr4N+n-Bu4N+0.60.91.331.481.692.853.483.984.37Coulombic Interaction Energy with bromide anion