The Mechanistic Studies of the Wacker xidation Tyler W. Wilson SE Group Meeting 11.27.2007
Introduction xidation of ethene by (II) chloride solutions (Phillips, 1894) -First used as a test for alkenes ( black was the indicator) C 2 4 + (II) 2 + 2 C 2 4 + (0) + 2 Later Smidt and co-workers employed cupric chloride to regenerate the (0) catalyst (Smidt, 1962) C 2 4 + (II) 2 + 2 C 2 4 + (0) + 2 (0) + 2Cu 2 (II) 2 + 2Cu What made Smidt s process applicable to large scale production was the final recycling of Cu back to Cu(II) 2 by air 2 Cu + 1/2 2 + 2 2Cu 2 + 2
Introduction Adding up the three reactions gives the Wacker xidation Reaction : 2-4 + C 2 4 + 2 (0) + C 3 C +2 + 2 - (1) (0) + 2 Cu 2 + 2-2- 4 + 2 Cu(I) (2) 2 Cu(I) + 2 + 1/2 2 2 Cu(II) 2 + 2 (3) Net: C 2 4 + 1/2 2 C 3 C (4) Wacker xidation Reaction Why is it called the Wacker xidation? -Smidt and co-workers discovered the reaction at Consortium Fur Elecktrochemie Industrie G.M.B., Munich, Germany (a subsidiary of Wacker Chemie) Industrial Importance: - Plants with production capacity of 15,000 tons of acetaldehyde per year have been developed
Introduction Rate Equation: Rate = -d[olefin] dt Chloride Inhibition: = k [ 4-2 ] [olefin] [ + ] [ - ] 2 -First order in and alkene -Chloride squared inhibition term -Proton inhibition term 2- K 4 + C 2 1 4 3 (C 2 4 ) 1- + 1-1/[ - ] term 3 (C 2 4 ) 1- K 2 + 2 2 (C 2 4 )( 2 ) + 1-1/[ - ] term Proton Inhibition: 2 C C 2 2 2 K 2 outer sphere (trans) Slow K a C 3 C 2 C C 2 Slow 2 2 inner sphere (cis) Fast
Early Evidence for Inner-Sphere Mechanism: KIEs bserved Kinetic Isotope Effects C 2 4 + 2-4 + 2 C 3 C + (0) + 2 + 2 - k C 2 4 + 2-4 + 2 C 3 C + (0) + 2 + 2 - bserved KIE = k / k = 1.07 k Competitive isotope effect: + 4 2- + 2 + 2 2( 2 ) C C Competitive isotope effect = k / k = 1.9 C 2 C C 2 C No deuterium incorporation is observed when reaction is run in 2 GRUP EXERCISE
Early Evidence for Inner-Sphere Mechanism: KIEs Inner-sphere was initially proposed based on observed kinetics in combination with kinetic isotope effect (circa 1964) Proton Inhibition 2 C C 2 2 K a 2 K Proton Inhibition 2 RS C 3 C 2 C C 2 RS 2 2 inner sphere (cis) Fast uter-sphere was disfavored because RS is after hydroxypalladation reasonable to assume a KIE would be observed Stereochemical probe of the reaction is needed
Evidence For uter-spere Addition: Stille Study Trapping hydropalladated intermediate with C 2 Na 2 C 3 2 C C Problem: Sterically, syn addition would be disfavored with a chelating diolefin 2 2 2 NaAc C 3 CN 2 C retentive insertion CL 3 Problems: -Solvent is C 3 CN not water -Previous studies have shown that dimeric (II) complexes were prone to anti addition -Strong C binds strongly and could prevent coordination of 2 Trans stereochemistry confirmed by 1 -NMR coupling constant
Evidence for uter-spere: Backvall Study Product distribution depends on chloride and Cu 2 concentrations: 2 C C 2 + 2-4 2 2 C C 2 2 [ - ] < 1M [Cu 2 ] < 1M 2 C 3 C Stereochemistry is lost [ - ] > 3 M [Cu 2 ] > 2.5 M C 3 C Major Assumptions: -Chlorohydrin and ethanal are formed from the same intermediate: ( 2 ( 2 )(C 2 4 )) - Steric course of the reaction is not altered by running at higher chloride and cupric chloride concentrations 2 Stereochemistry is retained (potentially)
Evidence for uter-spere: Backvall Study Stereochemical course of trans-addition (outer-sphere): (E)-d 2 -ethene 4 2- C C 2 2 "trans" L 3 Cu 2 Li "inversion" threo Stereochemical course of cis-addition (inner-sphere): 2- C C 4 2 "cis" L 3 Cu 2 Li "inversion" erythro Similarly, (Z)-d 2 -ethene "trans" erythro (Z)-d 2 -ethene "cis" threo
Evidence for uter-spere: Backvall Study Control experiments: (1) (Z)/(E) isomerization was less than 1% (2) Confirmed cleavage of 1 palladium-carbon bond by Cu 2 -Li proceeded with inversion (3) Confirmed chlorohydrin was not being obtained from an epoxide intermediate -Independent preparation of a hydroxypalladated ethene g(n 3 ) 2 Ac 2 g 4-2 "retention" L 3 -Stereochemistry predicted for chlorohydrin via epoxide intermediate Cu 2 Li 40% yield > 96% threo L 3 Cu 2 Li erythro
Evidence for uter-spere: Backvall Study C C (gas) (E or Z) 0.033 M 2 (aq.) 2.7 M Cu 2 (aq.), 3.3 M Li (aq.) 5 kg/cm 2, 20-40 h, 20 C 6 M Na And/or Model for anti addition predicts: (E)-ethene-d 2 (Z)-ethylene oxide-d 2 (Z)-ethene-d 2 (E)-ethylene oxide-d 2 Results clearly indicate that under these reactions conditions an outer-sphere mechanism is operative
Evidence for uter-spere: Backvall Study Backvall uter-sphere Mechanism: 2-4 C 2 4 2-2 [ - ] 1 RS X!"ydride Elimination C 2 2 18 e - complex 2 C C 2 2 2 RS 2 2 16 e - 3 complex K 3 2 14 e - complex Experimental observations fast 1. Chloride inhibition 2. Proton inhibition 3. Very low KIE 4. No -incorporation from 2 C 3 2 Me 4 C 2 2
Reevaluation of Inner and uter Sphere Mechansims Kinetically, the main difference between the mechanisms is the position of the rate-determining step: -uter-sphere: Trans-hydroxypalladation is in equilibrium (proton inhibition) and RS occurs downstream of this step -Inner-sphere: Proton inhibition results from Acid/Base equilibrium prior to cishydroxypalladation and the RS is the hydroxypalladation 2 C C 2 2 2 K 2 outer sphere (anti) RS K a C 3 C 2 C C 2 RS 2 2 inner sphere (syn) Fast istinguishing the mechanisms requires an olefin that will undergo an experimentally observable change if the hydroxypalladation is in equilibrium
Evidence for Inner-Sphere: Isomerization of Allylic Alcohol Isomerization of deuterated allyl alcohol 1a 4-2 2 2 k 1 k (II) 1 k -1 k -1 4-2 1b k 2 xidation Products Experimental Predictions Inner-sphere mechanism: k 2 >> k -1 At early conversion very little isomerization will be observed uter-sphere mechanism: k 2 << k -1 At early conversion isomerization will be observed
Evidence for Inner-Sphere: Isomerization of Allylic Alcohol irecting influence of hydroxyl group Me 4 2- Me Me Me 90% 10% (Markovnikov) (Anti-Markovnikov) 4 2- Me (Markovnikov) 12% (Anti-Markovnikov) 40% Me Me Me 4 2- II 2.6% Me II Me Me 49% 39%
Evidence for Inner-Sphere: Isomerization of Allylic Alcohol Control Experiments: -No detectable isomerization observed in the absence of (II) -Kinetic study revealed that the oxidation of allyl alcohol obeyed the same rate expression as observed for ethene (eqn 1) Initial Result: Less 3% isomerization observered in recoverd starting material after oxidation had preceeed to 50% conversion 4-2 2 [ + ] =0.4 M [ - ] = 0.4 M std. kinetic rxn xidation Products conditions enry, P. M. et. al. J. Mol. Cat. 1982, 16, 81-87
Evidence for Inner-Sphere: Isomerization of Allylic Alcohol 1a 4-2 [ Li] = 0.2-3.3 M [ 4 ] = 0.2-2.0 M [ 4 2- ] = 0.01-0.10 M Quinone, 2 isomerization Me oxidation Kinetic ata for Isomerization xidation rate is 2x isomerization rate Isomerization rate is 5x xidation rate Rate = -d[olefin] dt = k ox [ 4-2 ] [olefin] [ + ] [ - ] 2 (1) Rate expresion for oxidation Rate = -d[olefin] dt = k i [ 4-2 ] [olefin] [ - ] (2) Rate expresion for isomerization
Evidence for Inner-Sphere: Isomerization of Allylic Alcohol Question: Why is isomerization the predominate process at high [ - ]? C 2 1-2 2 C C 2 2-1- 2 C 2 + + Unfavorable at high [ - ] 2 C 1- C 2 - Compare to proposed wacker intermediates that lead to oxidation 2 C K 1- C 2 2 2 2 C 3 C 2 C 1-1- Slow C 2 2 2 Labile coordination site C 3 C
Evidence for Inner-Sphere: Kinetic Probe esign a kinetic probe in which RS is hydroxypalladation F 3 C Assumption: -Exchange is completely symmetric then k 1 = k -1 and k -1 = k -1, then the rate of isomerization only depends on the rate of formation of 3, not on its equilibrium conc. Prediction: 16 C 4 3 C 3 CF 3 2a -2 k -1 k 1 2 18 16 (II) 18 3 C CF C 3 3 CF 3 3 2 16 4-2 -Kinetics will follow rate equation (1) if syn hydroxypalladation is operative (b/c proton equilibrium is prior to RS) -Kinetics will follow rate equation (3) if trans hydroxypalladation is operative k 1 ' k -1 ' 18 = k i [ -2 4 ] [olefin] Rate [ - ] 2 [ + (1) = k i [ -2 4 ] [olefin] Rate ] [ - ] 2 (3) F 3 C C 3 2b CF 3 C
Evidence for Inner-Sphere: Kinetic Probe Results: Kinetic ata -Kinetic data shows clear inverse dependence on [ + ] -The value of k i was calculated from eqn 1 and remains fairly constant over range of, and concentrations = k i [ -2 4 ] [olefin] Rate [ - ] 2 [ + (1) ] = k i [ -2 4 ] [olefin] Rate [ - ] 2 (3) Kinetic data is consistent with syn hydoxypalladation, what about stereochemistry of isomerization
Evidence for Inner Sphere: Kinetic Probe Prediction on stereochemical outcome of the isomerization -Syn should lead to inversion and Anti should give retention Isomerization Results: Stereochemistry of isomerzation is also consistent with a syn hydroxypalladation ownside this alkene is not a good model of an actual Wacker substrate
Evidence for Inner Sphere: Transfer of Chirality Chirality Transfer to study modes of addition Study stereochemistry of products at both high and low chloride concentrations Anti-addition at low chloride will give the opposite absolute stereochemistry R 2 R C C II X S C R X R R 1 (S)-5, 5' or 5'' or C R 1 (S)-(E)-1a R 2 X
Controls: Evidence for Inner Sphere: Transfer of Chirality 1. Test a nucleophile whose mode of addition is known to be syn regardless of chloride concentration Me C C C (R)-Z-3a (53% ee) Results: Me Li 2 4, NEt 3 Cu 2, Phg Me Me Me Ph (R)-2 Low Chloride 84% yield 30% ee Similarily, (S)-Z-3a (74% ee) Me Ph Me (S)-Z-3a'' igh Chloride 70% yield 68% ee Results suggest a syn hydroxypalladation at low chloride concentrations and an anti hydroxypalladation at high chloride concentrations
Computational Study of the Wacker xidation Combined catalytic cycles of the Wacker xidation Wacker Conditions: LL conditions (Industria): Low [ - ] (< 1M) and low [Cu 2 ] (< 1M) yield only aldehyde via internal syn addition (rate eqn 1) conditions: high [ - ] (> 3 M) and high [Cu 2 ] (> 2.5M) yield both aldehyde and chlorohydrin via external anti addition (rate eqn 2) L conditions: yield no oxidation products L conditions: yield syn and anti products, and obey a combined rate law Employed computational models (hybrid density functional theory and implicit solvation methods) to investigate relevant steps in cycle Goddard, W. A. et. al. J. Am. Chem. Soc. 2007, 129, 12342-12343
Computational Study of the Wacker xidation Key Results (Syn pathway): 1. For the syn manifold, the calculated barrier for the deprotonation from 3 (5.8 kcal/mol) to 4 (15.3 kcal/mol) is plausible under the standard conditions (p 0-2) 2. The calculated barrier for 4 to 5 is ΔG** = 33.4 kcal/mol and is far to high to be feasible for the Wacker process (ΔG** expt = 22.4 kcal/mol) verall for syn: 1 2 TS-ALE1 3 TS-INT 10 TS-IS (RS) 6 product
Computational Study of the Wacker xidation Key Results (anti-pathway): -verall for anti: 1 2 TS-EXT (RS) 9- TS-ALE2 10 TS-IS 6 product -Since anti obeys rate equation 2 there is no proton inhibition so TS-EXT being the RS is consistent with rate law
Computational Study of Wacker xidation Results: Role of Cu 2 Stabilizing Interactions: Cu 2 stabilizes both TS-IS (by -6.0 kcal/mol) and TS-EXT (by -1.9 kcal/mol) estabilizing Interactions: Cu 2 destabilizes TS-ALE1 (by + 2.7 kcal/mol) -Predicts at anti pathway is strongly favored
Conclusions Mechanism of the Wacker oxidation is dependent on the reaction conditions and is best described by two competing processes Inner-Spere ydroxypalladation -ccurs at low [ - ] and low [Cu 2 ] -Rate is best described by eqn 1 -RS is still debated uter-sphere ydroxypalladation -ccurs at high [ - ] and high [Cu 2 ] -Rate is best described by eqn 2 -RS is still debated Kinetic and stereochemical models have been well studied and future work may need to relay more heavily on computational models
References Excellent Reviews: (1) P. M. enry, Palladium Catalyzed xidation of ydrocarbons;. Reidel, ordrecht: olland, 1980, p. 41. (2) P. M. enry, In andbook of rganopalladium Chemistry for rganic Synthesis; Negishi, E., Ed.; Wiley & Sons: New York, 2001; p. 209 Initial Kinetic Studies: (1) Smidt, J. et. al. Angew. Chem. Int. Ed. 1962, 1, 80-88 (2) enry, P. M. J. Am. Chem. Soc. 1964, 86, 3246-3250. Backvall Study: (1) Backvall, J. E. et. al. J. Am. Chem. Soc. 1979, 101, 2411-2416 Computational Studies: (2) Goddard, W. A. et. al. J. Am. Chem. Soc. 2007, 129, 12342-12343 (3) Siegbahn, E. M. J. Phys. Chem. 1996, 100, 14672-14680
Additional Comments/Questions Patrick enry Give me liberty or give me death Updated Version Give me syn or give me death http://en.wikipedia.org/wiki/patrick_enry
Group Exercise Group Exercise Given that (1) is an intermediate the reaction, write a mechanism that accounts for the formation acetaldehyde observed in the KIE studies 2? C 3 C C 2 4 + 2-4 + 2 C 3 C + (0) + 2 + 2 - k C 2 4 + 2-4 + 2 C 3 C + (0) + 2 + 2 - k bserved KIE = k / k = 1.07 + 4 2- + 2 + 2 2( 2 ) C C Competitive isotope effect = k / k = 1.9 C 2 C C 2 C Reaction run in 2 shows no incorporation
Solution for Group Exercise Recent computational work questions ability to undergo β- ydride elimination from - (see Goddard, W. A. JACS, 2006, 128, 3132 and reference therein) 2 2-2 C 2 3 C 2 C 3
Backup: Ruling out π-allyl Pathway Rate of exchange is equal to rate of isomerization Rate of isomerization is equal to 1/2 rate of exchange
Backup: Schematic for Industrial Wacker Process