Katalis KD III

Catalyst

CatalystAcid-base catalytic reactionCatalystsCatalysts increase the rate of a reaction by decreasing the activation energy of the reaction.Catalysts change the mechanism by which the process occurs.

2CatalystsOne way a catalyst can speed up a reaction is by holding the reactants together and helping bonds to break.

3Enzymes

Enzymes are catalysts in biological systems.The substrate fits into the active site of the enzyme much like a key fits into a lock.4Influence of pH on reaction rateThe hydrolysis of esters is catalysed by both acid and base:pHlog kobs7.0

Another example: imine formation:pHlog kobs4.5pH optimum ~ 4.5

Slope of plot of log kobs vs. pH is often close to 1:linearly dependent on [H+] or [OH-]Two mechanisms for acid catalysisSpecific acid catalysis:- A proton is transferred to the substrate in a rapid preequilibrium; 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):

Specific 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] !!Specific base catalysisExample: the retro-aldol reaction of I:

xxxxxxkobs[OH-]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.General 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-Ph-OH/m-NO2-Ph-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-OH]}[III]

[buffer]n{k(H3O+)[H3O+] + k(H2O)[H2O]}[III]k(buffer)NUCLEOPHILICITYWHAT MAKES A GOOD NUCLEOPHILE?WHAT IS A NUCLEOPHILE ? A BASE ?NucleophilicityBasicityNUCLEOPHILES AND BASESAll nucleophiles are bases ... and all bases are nucleophiles.THE FUNDAMENTAL DISTINCTIONA good base is not necessarily a good nucleophile, and vice versa.HOWEVER :kinetic (or rate) parameterthermodynamic (or equilibrium) parameter.NUCLEOPHILE VERSUS BASENu2 is a betternucleophileNu1 is a better base( FASTER RATE )( STRONGER BOND )Nucleophilicity = KineticBasicity = ThermodynamicRate = k2[RX][Nu]B:- + H+B-HNu1Nu2strong baseshifts equilib.good nucleophileincreases k2(I.e., the rate)Nucleophilicity isdetermined hereactivation energyand rate (kinetics)Basicity isdetermined herestrength of bondsand position ofequilibriumDIFFERENT PLACES ON THE ENERGY PROFILE DETERMINE NUCLEOPHILICITY AND BASICITYfaster is betterlower energy is betterNUCLEOPHILESBASESIS THE NUCLEOPHILE IMPORTANTIN BOTH SN1 AND SN2 REACTIONS ?Nucleophiles are unimportant in an SN1 reaction;they are not involved in the rate-determining step.SN1 rate = K1 [RX]The nature of a nucleophile is only important toan SN2 reaction.SN2 rate = K2 [RX][Nu] NUCLEOPHILESIMPORTANCE IN SN1 AND SN2 REACTIONS WHAT IS A GOOD NUCLEOPHILE ?SN2 REACTIONSCRBr:RRY::....WHAT IS THE IDEAL NUCLEOPHILE ?no way ! badSTERIC PROBLEMSSmalleris better !LARGESMALLSN2 REACTIONSFor an SN2 reaction the nucleophile must find the back lobe of the sp3 hybrid orbital that the leaving group is bonded to.:....X:-good:C N:..:F:..:Cl:....SMALLSPHERESROD OR SPEARSHAPEDEXPECTED IDEAL NUCLEOPHILES:N N N:-----+etc.These types should be able to findthe target !azidecyanideGenerally this idea is correct.FClBrI1.36 A 1.81 A 1.95 A 2.16 A----smallestionand we would expect the smallest one (fluoride) to be the best nucleophile,.. however, that is not usually the case.OUR NAVE EXPECTATIONWe would expect the halides to be good nucleophiles:ionic radii:F-5 x 102Cl-2.3 x 104Br-6 x 105I-2 x 107slowestfastestkCH3-I + NaXCH3-X + NaIRate = k [CH3I] [X-]RELATIVE RATES OF REACTION FOR THE HALIDESMeOH* MeOH solvates like water but dissolves everything better.EXPERIMENTAL RESULTSSN2SOLVATIONSolvation reverses our ideas of size.F- 120 Kcal / mole-gas phaseF-HOHwater solutionHOHHEAT OF SOLVATIONHOHHOHF- (g)F- (aq)HEAT OF SOLVATIONSOLVATEDIONENERGY IS RELEASED WHEN AN ION IS PLACED IN WATERThe interaction between the ion and the solventis a type of weak bond.Energy is released when it occurs. Solvation lowers the potential energy of the nucleophile making it less reactive.FClBrI1.36 A 1.81 A 1.95 A 2.16 AHALIDE IONSHeats ofsolvationin H2O- 120- 90Kcal / mole- 65X(H2O)n-----increasing solvation- 75SMALL IONS SOLVATE MORE THAN LARGE IONSsmallestionlarger nsmaller nIONICRADIUS

WATER AS A SOLVENTpolar OH bondsWater is a polar molecule. Negative on the oxygen end, and positive on the hydrogen end.It can solvate both cations and anions.SMALL IONS SOLVATE MORE HEAVILY THAN LARGE ONESsolventshell--...smaller solvent shell

...escapes easily

more potential energyBETTERNUCLEOPHILE IF--Effective size is larger.HOHHOHHOHHOHHOHHOHHOHHOHHOHHOHHeavy solvation lowers the potential energy of the nucleophile.It is difficult for the solvated nucleophileto escape the solvent shell.This ion is less reactive.strong interactionwith the solventweak interactionwith the solventPROTIC SOLVENTSwater methanol ethanol amines

Water is an example of a protic solvent.Protic solvents are those that haveProtic solvents can form hydrogen bonds and can solvate both cations and anions.O-H, N-H or S-H bonds.In protic solvents the larger ions are solvated less (smaller solvent shell) and they are, therefore, effectively smaller in size and have more potentialenergy.Since the solvent shell is smaller in a larger ion it can more easily escape from the surrounding solvent molecules during reaction. There is morepotential energy.LARGER IONS ARE BETTER NUCLEOPHILES IN PROTIC SOLVENTSTHREE FACTORS ARE INVOLVED :123The larger ions are thought (by some) to be more polarizable.see the next slide ..POLARIZABILITYPolarizability assumes larger ions are able to easilydistort the electons in their valence shell, and that smaller ions cannot.CBrThe distortion of large ions is easier because the orbital clouds are more diffuse.The nucleophile flows into the reactive site.VERYHYPOTHETICALIf everything else is equal, the stronger base is the better nucleophile.BASICITYThis principle shows up in a period, where atoms do not vary appreciably in size, andsolvate to similar extents.OH- is a better nucleophile than F-NUCLEOPHILICITY TRENDS IN PROTIC SOLVENTS OBSERVED NUCLEOPHILICITY TRENDS H2O OR OTHER PROTIC SOLVENTSCH3- NH2- OH- F-PH2- SH- Cl-Br-I-increasing nucleophilicity (ROWS)increasingnucleophilicity(COLUMNS)GROUPIV V VI VIIbasicitymore solvation, larger effective size,lower potential energybasicityMeOHRELATIVE RATES OF SOME NUCLEOPHILESCH3-I + Nu:CH3-Nu + I-Rate = k [CH3I] [X-]F-5 x 102CH3COO-2 x 104Cl-2.3 x 102

C6H5O-5.6 x 105N3-6 x 105Br-6 x 105CH3O-2 x 106CN-5 x 106I-2 x 107C6H5S-8 x 109CH3OH1.0

NH33.2 x 105(CH3)2S3.5 x 105C6H5NH25 x 105C6H5SH5 x 105

these are the goodnucleophiles, butwatch out, some are strong bases(solvolysis is faster)SN2CHARGEDNEUTRALAPROTIC SOLVENTSAPROTIC SOLVENTS

dimethylsulfoxidedimethylformamidehexamethylphosphoramideacetoneacetonitrileif scrupulouslyfree of water+--+ APROTIC SOLVENTS DO NOT HAVEOH, NH, OR SH BONDSDMSODMFHMPAThey do not form hydrogen bonds.APROTIC SOLVENTS SOLVATE CATIONS, BUT NOT ANIONS (NUCLEOPHILES)The nucleophile isfree (unsolvated),and therefore is smalland not hindered by a solvent shell. --++

crowded

SOHHDIMETHYLSUFOXIDEdensity - electrostatic potential plotspace-filling

X-DIMETHYLFORMAMIDEnucleophile is free (unsolvated)OBSERVED NUCLEOPHILICITY APROTIC SOLVENTSCH3- NH2- OH- F-PH2- SH- Cl-Br-I-increasing nucleophilicity (ROWS)increasingnucleophilicity(COLUMNS)GROUPIV V VI VIIThe direction of the red arrow (COLUMNS) represents a different order than in protic solvents.basicitydecreasing ionic size WHY NOT ALWAYS USE APROTIC SOLVENTS FOR SN2 ?Mostly, it is a matter of expense.Water, ethanol, methanol and acetone are much cheaper, especially water.WaterfreeMethanol$14.70 / LEthanol$15.35 / LAcetone$16.60 / LDMSO$47.50 / LDMF$33.75 / LHMPA$163.40 / LCheapest grades available, Aldrich Chemical Co., 2000.SOLVENTSWHAT ARE GOOD SOLVENTS FOR SN1 AND SN2 ?SN1 reactions prefer polar-protic solvents that can solvate the anion and cation formed in the rate-determining step.R-XR+ + X-rate-determiningstepsolvation of both ionsspeeds the ionizationSN1 SOLVENTS = POLARCarbocationionsSN2 reactions prefer non-polar solvents, orpolar-aprotic solvents that do not solvate the nucleophile.CRBr::....RRX:smaller is better !SMALL,UNSOLVATEDSN2 SOLVENTS = NONPOLAR OR POLAR-APROTICoverallpolarityNONPOLARPOLARPOLARPROTICSOLVENTSPOLARAPROTICSOLVENTSSN2SN1NONPOLARSOLVENTS

SOLVENT MIXTURESSOLVENT MIXTURES ARE VERY COMMONAlkyl halides dont dissolve in water,but dissolve in most organic solvents.Nucleophile salts dont dissolve in most organic solvents, but dissolve in water.RXNaX

soluble in EtOHsoluble in H2Omiscible solventsBoth dissolve in a mixed solvent.EXCEPTIONSNaXDissolve in polar-aprotic organic solvents:DMF, DMSO, HMPA.NaI and NaCN dissolve in acetone, but NaCl and NaBr do notCARBOCATIONS REACT WITH ALL NUCLEOPHILES EQUALLYSN1SN2BETTER NUCLEOPHILES REACT FASTER GIVING MORE PRODUCTTHE BOTTOM LINEThe nucleophile is not involved in the rate-determining step.The nucleophile is involved in the rate-determining step.Hard-Soft Acid-Base TheoryDefinitionsArrhenius acids form hydronium ions in water, and bases form hydroxide ions. This definition assumes that water is the solvent.Brnsted and Lowry expanded upon the Arrhenius definitions, and defined acids as proton donors and bases as proton acceptors. They also introduced the concept of conjugate acid-base pairs.Lewis Acids & BasesThe Lewis definition further expands the definitions. A base is an electron-pair donor, and an acid is an electron-pair acceptor. The two combine to form an adduct.A + :B A-B

Lewis Acids & BasesThis definition includes the standard Brnsted-Lowry acid-base reactions:H+(aq) + :NH3(aq) NH4+(aq)

It also includes the reactions of metal ions or atoms with ligands to form coordination compounds:Ag+(aq) + 2 :NH3(aq) Ag(NH3)2+(aq)

Lewis Acids & BasesIn addition, electron-deficient compounds such as trivalent boron is categorized as a Lewis acid.B(CH3)3 + :NH3 (CH3)3BNH3The HOMO on the Lewis base interacts with the electron pair in the LUMO of the Lewis acid. The MOs of the adduct are lower in energy.

Lewis Acids & BasesThe LUMO and HOMO are called frontier orbitals. If there is a net lowering of energy, the adduct is stable.

BF3 + NH3The LUMO of the acid, the HOMO of the base and the adduct are shown below:

Lewis Acids & BasesThere is the possibility of competing reaction pathways depending upon which reactants are present, and the relative energies of possible products. As a result, a compound such as water may serve as an acid, a base, an oxidizing agent (with Group IA and IIA metals) or a reducing agent (with F2).Lewis Acids & BasesA Lewis base has an electron pair in its highest occupied molecular orbital (HOMO) of suitable symmetry to interact with the LUMO of the Lewis acid. The closer the two orbitals are in energy, the stronger the bond in the adduct.Hard and Soft Acids and BasesThe polarizability of an acid or base plays a role in its reactivity. Hard acids and bases are small, compact, and non-polarizable.Soft acids and bases are larger, with a more diffuse distribution of electrons.Hard and Soft Acids and BasesIn addition to their intrinsic strength,

Hard acids react preferentially with hard bases, and soft acids react preferentially with soft bases.Hard and Soft Acids & BasesThere have been many attempts to categorize various metal ions and anions to predict reactivity, solubility, etc.R.G. Pearson (1963) categorized acids and bases as either hard or soft (using Kf values).

Hard acids bond in the order: F->Cl->Br->I-Soft acids bond in the order: I- >Br- >Cl- > F-Hard and Soft Acids & BasesHard acids tend to bind to hard bases.Soft acids tend to bind to soft bases.Charge Density Hard AcidsHard acids typically have a high charge density. They are often metal ions with a (higher) positive charge and small ionic size. Their d orbitals are often unavailable to engage in bonding.Charge Density Soft AcidsSoft acids typically have lower charge density (lower ionic charge and greater ionic size). Their d orbitals are available for bonding. Soft acids are often 2nd and 3rd row transition metals with a +1 or +2 charge, and filled or nearly filled d orbitals.Acid or Base StrengthIt is important to realize that hard/soft considerations have nothing to do with acid or base strength. An acid or a base may be hard or soft and also be either weak or strong.In a competition reaction between two bases for the same acid, you must consider both the relative strength of the bases, and the hard/soft nature of each base and the acid.65D. Energetics of Nucleophile-Electrophile Interactions

qn and qe are charges on nucleophile and electrophile, respectively.

cn and ce are orbital coefficients of nucleophile HOMO and electrophile LUMO, respectively.

is the resonance integral.

EHOMO = energy of nucleophile HOMO

ELUMO = energy of electrophile LUMO

Electrostatic term: important for interactions of hard acids with hard bases

Orbital interaction term: important for interactions of soft acids with soft bases66Bases (nucleophiles)TypeSpeciesExamplesHardsmall halide anionsF-, Cl-oxygen nucleophilesH2O, ROH, HO-, RO-, ROR, MeCO2-, SO42-, PO43-amine nucleophilesRNH2, H2NNH2Intermediatelarger halide anionsBr-nitrogen nucleophilesC6H5NH2, C5H5N, N3-oxygen nucleophilesNO2-, SO32-Softsulfur nucleophilesRSR, RSH, RS-phosphorus nucleophilesR3P, (RO)3P, R3Ascarbon nucleophilesCN-, CO, R-, C2H4, ArothersH-, I-67Acids (electrophiles)TypeSpeciesExamplesHardhigh charge/radius cationsH+, Li+, Mg2+, Ca2+, Al3+, Cr3+, Ti4+, I5+group II speciesBe(CH3)2group III speciesAl(CH3)3, BF3, B(OR)3H-bond donorsROH, HOH, RNH2, RNH3+Intermediatemoderate charge/radius cationsFe2+, Cu2+, Zn2+, Pb2+, Sn2+, Co2+, Ni2+carbocations(CH3)3C+, ArH+Softlow charge/radius cations Cu+, Ag+, Au+, Hg+, Hg2+, I+, Br+, RO+carbon electrophilesRL, ArL (L = nucleofuge)diatomic halogensI2, Br2, ICNradicalsO, Cl, Br, I, RO