Catalysis by Acids, Bases and Metal IonsMechanism:1) The diffusion-controlled formation of a hydrogen bondbetween the base B and the acid HA2) The transfer of a proton, leading to the formation of a newhydrogen bonded complex3) The diffusion-controlled dissociation of the productThe rate of proton transfer1 proton transfer to N, O, S is fast; proton transfer to carbon (C) is slow proton transfer from H3O+ to N or O is diffusion-controlled: k-1 1011 l.mol-1.s-1Formation of the hydrogen bond between the proton donor and the proton acceptor is the rate determining step: this step is slower than the actual proton transfer!Typical for cases where a proton is both bound to and transferred to oxygen or nitrogen atoms, where the negative charge is localized on one atom.2Nevertheless, diffusion of H+ in water is much faster than diffusion of other ions:3Proton Transfer from/to Carbon Acids/Basesk1 = 4x10 8 l.mol 1.s1, slow process due to:- lack of hydrogen bond formation before proton transfer- low acidity of the hydrogen atoms.k-1 = 16 l.mol 1.s1, also much slower than diffusion rate, because:- upon protonation a considerable redistribution of charge has to take place, including the concomitant change of solvation.12: carbon acid, k1 and k-1 relatively small23: oxygen acid, k1 and k-1 relatively large (H-bond formation)Another example:45Most carbon acids are stabilized by resonance. Hence significantstructural reorganization must accompany deprotonationThe greater the structural reorganization during deprotonation, the lower the kinetic acidityInfluence of pH on Reaction RateThe hydrolysis of esters is catalysed by both acid and base:pHlog kobs7.06Another example: the mutarotation of glucosepHlog kobs7.07Another example: imine formationpHlog kobs4.5pH optimum 4.5Slope of plot of log kobs vs. pH is often close to 1:linearly dependent on H+ or OH-8Two mechanisms for acid catalysisSpecific acid catalysis:- A proton is transferred to the substrate in a rapid pre-equilibrium; subsequently, the protonated substrate reacts further to the product(s) in the rate determining step:General acid catalysis:- Proton transfer occurs in a slow, rate-determining step; subsequently, the protonated substrate rapidly reacts to give the product(s):9Specific acid/base catalysisUsually found for electronegative elements (O, N), where proton transfer is fast:The second step is rate-determining and can be mono- or bimolecular:Reaction rate:sincewe can now write:So the rate is only dependent on the pH, not on HA !10Example of specific acid catalysis: hydrolysis of acetals (A1 mech.)xxxxxxkobsH+kobs is directly proportional to H+;addition of more acid (buffer) at constantpH has no effect on kobs.Proton transfer is not rate limiting,so the mechanism probably reads:kobsClCH2COOH/ClCH2COO- (2:1)xxxxxx11Example of a reaction that is specific acid catalysed accordingto the A2 mechanism:the hydrolysis of ethyl acetate:12Specific Base CatalysisExample: the retro-aldol reaction of I:xxxxxxkobsOH-kobs is directly proportional to OH. Addition of more base(in buffer) at constant pH has no effect on kobs;OH- is the only base that occurs in the rate equation.13Therefore, the reaction mechanism most probably reads:Reaction equation:there is the acid-base equilibrium in water:rewriting:soIt is clear that only OH- occurs in the rate equation!14General Acid/Base CatalysisProton transfer is the rate-determining step.Example: the hydrolysis of ortho esters:The reaction is studied in a series of buffers (m-NO2-C6H4-OH/m-NO2-C6H4-O): reaction rate increases with increasing buffer concentration, even if the pH remains constantn = k(H2O)H2O + k(H3O+)H3O+ + k(m-NO2-Ph-OH)m-NO2-Ph-OHIIIbuffernk(H3O+)H3O+ + k(H2O)H2OIIIk(buffer)15General acid/base catalysis:the reaction rate is dependent on all acids/bases present in solutionGeneral acid catalysis:kobs = S kiHAiGeneral base catalysis:kobs = S kiBiExample of general base catalysis:The reaction rate is dependent on the buffer concentration, at constant pH. There is also a contribution of OH- and H2O.ClCH2COO-/ClCH2COOHkobs16So, the reaction mechanism is most probably:= k(H2O)H2OIV + k(ClCH2COO)ClCH2COOIV + k(OH)OHIV17SummarizingSpecific acid/base catalysis:n = kSH3O+ orn = kSOHGeneral acid/base catalysis:n = kxH3O+ + kyH2O + kzHA + .S = SHAiS, or with bases:n = SBiS.When kxH3O+ or kxOH are large, the contributions of other acids/bases become negligible and the kinetics resemble specific acid/base catalysis. For this reason, general acid/base catalysis usually only occurs around neutral pH.18How effective is a general acid catalyst:the Brnsted relationThe effectiveness of a general acid catalyst depends on its acid strength (= the Brnsted relation):log kHA = a log KHA + a constantkHA = rate constant of the catalytic stepKHA = dissociation constant of the acid HAa = Brnsted coefficient (normally 0 a 1)indicates the sensitivity of the catalytic step forchanges in acid strength of HA (pKa)19Example:Plot log kHA against log KHA, slope = aa indicates to what extent a proton is transferred from the acid to the substrate in the transition state:a = 1: Every change in acid strength fully affects catalysis. The proton is(almost) completely transferred to the substrate in the transition state.a = 0: The reaction is insensitive to changes in acid strength. All acids catalysethe reaction equally strongly (log kHA = constant). The proton is hardlytransferred in the transition state of the reaction.a = 0.5: The proton is transferred halfway between the acid anion A and thesubstrate in the transition state: AH+S, symmetrical TS.20There is also a Brnsted relation for general base catalysis:log kB = -b log KHB+ + a constantThe coefficient b has the same meaning as a for generalacid catalysis21The relation between general and specific catalysisWhy is there sometimes general and sometimes specific acid/base catalysis? pH: H+ and OH are very low in neutral solution, whereas HA or B can be high beneficial for general catalysis rate of proton transfer: H transfer to and from C atoms is slower than transfer to N, O, etc. beneficial for general catalysis stability of reaction intermediates plays an important role. Example: compare the hydrolysis of ortho esters and acetals22Ereaction co-ordinate1a,2aEa1Ea2products1b,2b2c1c1c is more stabilised than 2c protonation becomes the rate limiting step general acid catalysis!23General Acid/Base Catalysis by EnzymesEnzymes often use general acid or base catalysis:u They work at neutral pH, so low H+ and OH u High effective concentration of general acid/baseu Correct orientation of the acidic/basic group around thesubstrateu Optimum catalysis at pH around pKaAmino acid residues often have a pKa that is close to neutral pH and are therefore able to act as a general acid or base catalyst:24 Prototropic Groups of EnzymesAmino acid Acidic group Basic grouppKaN-terminusa-NH3+a-NH2 7.8C-terminusa-COOHa-COO3.8aspartic acidb-COOHb-COO4.4glutamic acidg-COOHg-COO4.6histidine imidazolium ionimidazole7.0cysteineSHS8.7tyrosineC6H4OHC6H4O9.6lysinee-NH3+e-NH210.4serineb-OHb-O13threonineb-OHb-O13arginineNH(C=NH2+)NH2 NH(C=NH)NH212.5peptide bond RCONHRRCONR 14.8The pKa is strongly influenced by its environment: e.g., in enzymes the pKa of lysine can drop to 725Metal Ion CatalysisRoles of metals in catalysis: As “super acid”: comparable to H+ but stronger As template: metal ions are able to coordinate to more than 2 ligands and can thereby bring molecules together As redox catalyst: many metal ions can accept or donate electrons by changing their redox stateSuper acid catalysisFeatures:Introduces positive charge into the substrate, making it more susceptible toward nucleophilic attack.Exchange of metal ions is fast (105-109 s-1), but slower than exchange of H+ (1011 s-1)26Metal Ion Catalysis in C-C Bond CleavageDecarboxylation of oxalosuccinate by isocitrate dehydrogenase:Mn2+ is very well able to accept the developing negative charge (“electron sink”); M3+ like Al3+ are also good, M+ like Na+, K+ (and H+!) are much less effective.Other acceptable substrates:- both COO- and C=O are needed for correct binding of Mn2+- cleaving COO group on b-position27Metal ion catalysis in additions to C=O(N) bondsCu2+ ions are very effective catalysts for the hydrolysis of a-amino acid esters:They are less effective in the hydrolysis of amides, because of a tighter bond between the metal and the substrate (= ground state stabilisation):Ereaction co-ordinateamideesteruncatalysedcatalysed28Metal ion catalysis in the hydrolysis of phosphate esters and anhydridesHydrolysis of phosphate esters (e.g. acetyl phosphate) or anhydrides (e.g. ATP) is always catalysed by metal ions, usually Mg2+:The role of the metal ion is twofold: neutralization of the negative charge in the substrate, to enable the the approach of the nucleophile; stabilisation of the leaving group (neutralization of charge)29Summary Super Acid CatalysisPolarisation of bonds, especially C=OAccepting negative charge (“electron sink”)Neutralization of negative charge in the substrate, to facilitate the approach of the nucleophileStabilization of the leaving group (reduction of charge)30Metal ions as template: the Sharpless epoxidationMechanism proposed by E.J. Corey:3132Sc3+-Catalyzed Aldol-Type Additions of N-Benzoylcyclopropanecarboxamides via Iodide-Mediated Ring-Opening: Stereoselective Synthesis of -Lactams33Postulated catalytic cycleSummary:Advantages of Metal Ions Compared to H+uHigher charge (M2+, M3+)uAlso works at neutral pHuCoordination with several groups is possible (template effect)uMany metal ions have redox properties34