Wilkinson s other (ruthenium) catalyst Cl 3 ; 2 h 3, reflux 3h h 3 Cl h 3 h Cl 3 Good catalyst especially for 2 1-alkenes 2, base toluene Cl h 3 h 3 h 3 Et 3 Cl h 3 Cl h 3 h 3 R h 3 h 3 Cl h 3 R RC 2 C 3 Cl h 3 h 3 R 2 Cl h 3 h 3 R ow does this mechanism differ from Wilkinson s Rh catalyst?
verview of thenium Asymmetric ydrogenation Much broader in scope than rhodium asymmetric hydrogenation Wide range of functional directing groups Works effectively for ketones and imines as well as for alkenes Synthetically useful kinetic resolutions chanism is distinct from the rhodium case BIA is quite generally useful; normally no need to scope ligands
BIA is the key to successful ruthenium hydrogenations C 3 Better for alkenes C 3 h 2 h 2 Br Br Br Br Better for heteroatomic double bonds X Some of the many (II) catalyst precursors Br
Contrasting hydrogenation routes for Rh and catalysts 2, 2, 2 C Ch 1 bar, 20 C 2 C Ch 1 bar, 20 C 2 C Ch [ 2 Cl 2 ] 2. Et 3 92 (S) 65(S) [ 2 Cl 2 ] 2. Et 3 2 Rh() 2 Cl 4 96(R) 87(S) 2 Rh() 2 Cl 4 (S)-BIA 2 h 2 h 2
In catalysis the intermediates are a monohydride and a metal alkyl BF BF 4 4 C, RT C 2 C 2 h X-ray structure (R)-BIA ote the differences between Rh and - 18e octahedral preferred to 16e square planar What s the structure of the corresponding Rh intermediates?
(BIA) catalysed hydrogenations have a wider scope than Rh-catalysed hydrogenations Geraniol 2, BIA S-Citronellol 2, catalyst 99% e.e. CC 3 CC 3 Tetrahydropapaverine C 2 C 2 2, catalyst aproxen C 2 6
Alkene isomerisation can compete with hydrogenation, and the isomerized alkene may dominate the reaction fast at low pressures Geraniol 2, BIA favoured by high pressure, efficient interfacial stirring S-Citronellol 99% e.e. C 2!-Geraniol 2, BIA favoured by low pressure, inefficient interfacial stirring R-Citronellol 85% e.e.
The reason becomes clearer when the isomeric allyl alcohol nerol is reduced - not sensitive to pressure. erol 2, BIA R-Citronellol catalyst = 0.05-0.5 mol% 99% e.e. R R R! 2 -alkene! 3 -allyl! 2 -alkene Why?? Isomerization mechanism not available to nerol C 2 and C 3 must be cis
thenium catalysed hydrogenation of unsaturated carboxylic acids is effective C 3 C 3 C 3 10-4 M C 3 2, 1 atm,, 25 0 C C 3 C 3 D D C 3 C 3 90% e.e. with D 2 in CD 3 D h 2 h 2 as ligand
The key point of the mechanism is that the two hydrogens are delivered distinctly - the first from hydrogen, the second from solvent C 3 C 3 D 2 bound reactant D D C 3 D 2 cleaves -C bond bound product C 3 D anionic intermediates What would you expect with D 2 and a Rh catalyst?
olar groups at an adjacent chiral centre can lead to diastereoselective directed hydrogenations. Start with examples from rhodium chemistry h 2 TBS 2 C C 2 Rh h 2 2, C 2 Cl 2 BF 4 TBS 2 C C 2 omoallylic alcohol h 2 95:5 selectivity 2 C C 2 h Rh h 2 2, BF 4 3 C C 2 h Allylic alcohol 12 99:1 selectivity
Basis of Kinetic Resolution in Asymmetric Synthesis C 2 Et Ti(r i ) 4 C 2 Et 5 mol% hc() 2 Racemic mixture of allylic alcohols With an asymmetric catalyst the enantiomers react at different rates If the difference is sufficient, the less reactive enantiomer will be enriched Up to 100% e.e.; but yield at high e.e. is <50%
Background to kinetic resolutions (popularised by Sharpless epoxidations 1980 ff) enantiomerically pure catalyst Bu t racemate Two products The reaction is diastereoselective (new on same face as ) and enantioselective (two hands react at different rates). (of remaining reactant) S = k(fast) k(slow) = ln(1-c)(1- e.e.) ln(1-c)(1 e.e.) S is the Selectivity Factor C is the fraction reacted
Take a closer look at the region where the remaining reactant has high e.e. At high S-values the remaining reactant has a high enantiomer excess at >50% reaction
Kinetic resolution by BIA in allyl alcohol hydrogenation; is directing group STE 1; racemate n reaction to 46% completion STE 2; slow reactant (R)-BIA- Isolate from above reaction run to 46% completion. 80% e.e. (S)-BIA- slow reacting fast reacting enantiomer enantiomer 54%, 80% e.e. 46% 95% e.e. 37% for the two steps 99% e.e. at 70% completion
Increased versatility for catalysis - many ketones are hydrogenated in high enantiomer excess DG 2 DG R R' cat (R)-BIA R R' DG is a directing group (lone pair bond to catalyst)
hydrogenation of ketones provides an example of double asymmetric induction Step 2 Step 1 cat. S-BIA Cl 2 2, cat. S-BIA Cl 2 2, 98 x 98 (S,S) 98 (S) 98 x 2 meso 2 (R) Enantiomer ratio S,S : R,R - 98 2 : 2 2 = 2400 :1; e.e. = 99.9 % Diastereomer ratio S,S : meso = ca 50 : 1 2 x 2 (R,R)
igh diastereoselectivity and fast keto-enol tautomerisation lead to Dynamic Kinetic Resolution Boc Et I BETWEE R-BIA Br 2 2, C 2 Cl 2 Et Boc FAST trace acid or base via Et Boc 99% syn, 98% ee. Et Boc 2 VERY SLW X 18 Draw this out in detail to make sure that you understand it
In a related case the two diastereomers do not interconvert quickly and react separately Compare : Et R-BIA Br 2 2, Et SLW 97% ee. Et R-BIA Br 2 2, Et 96% ee. Explain the difference from the last example?
2 2 complexes; a further breakthrough in catalysis of hydrogenation h 2 Cl 2 h 2 (dimer) 1st generation catalyst h 2 h 2 Cl Cl 2 2 h h 2nd generation catalyst Completely different mechanism
In the presence of base, metal hydrides are formed that change the reaction pathway C 2 250 times faster, condition A C 3 1500 times faster, condition B Allow competition for catalyst and reagent A B Cl 2 (h 3 ) 3, 2, i-r, toluene as A, add K, 2 (C 2 ) 2 2. In B; - is formed from -Cl by the base; how?
The method is useful for asymmetric reductions in the absence of a directing group R cat 2 R X K, i-r R =, i-r, t-bu X =, t-bu,, Cl, C() X (R)-isomer > 90% e.e. (S)-(S,S) h 2 h 2 Cl Cl 2 2 h h cat (or p-tolyl for h)
Getting close to a universal method for selective reduction of ketones 2 2 catalysts Br i-r, 2 (4-8 atm) Br 99.7% e.e. cat 2 90% e.e. cat 2 94% e.e. C=C Double bonds are unaffected; simple ketones are reduced by the same catalysts
ow it works 1. The precatalyst needs to be reduced first to replace Cl by to make the active catalyst Cl Cl 2 2 deprotonation 2 Cl Cl 2 Cl elimination 2 x 2 i-r Cl Cl 2 R 2 18-electron hydride 24 Cl Cl 2 2 Cl elimination Cl 2 creates vacant coordination site Second Cl replacement can occur as well; gives A on next slide
ow it works 2. nce the catalyst has formed a very simple mechanism ensues; the ketone is never bound to 2 RR'C= R R' 2 2 Make a comparison with the simple BIA hydrogenation mechanism? 2 A 2 R R'
Basics of iridium asymmetric hydrogenation; - catalysts, chelate forming F 6 Crabtree's original catalyst 1977-1980. Fast hydrogenation even of tetrasubstituted alkenes in non-protic solvents. Cx 3 ever used commercially; limited turnover before deactivation vary Bu t h 2 F 6 faltz introduced a family of chelate X-based analogues for asymmetric hydrogenation. Similar limitations; high pressures needed for satisfactory e.e.s vary igh sensitivity to water; annulled by switching to the hydrophobic BARf counter-ion.
Unlike the Rh analogy, a series of stable hydride complexes are formed by the active species Cx 3 2, CD, 80 C CD 2 Cl 2 a b Cx 3 h 3 h 3 2, 80 C CD 2 Cl 2 h 3 h 3 2, CD, 20 C CD 2 Cl 2 h 3 h 3 Dppe complex reacts similarly to (h 3 ) 2 [MR at 80 C]
The relative rates of hydrogenation of alkenes vs. degree of substitution alkene <1 mol% L 2 (CD) F 6 C 2 Cl 2, zero degrees alkane L 2 = 2 x h 2 ot 100% hydrogenation
Compare with the hydrogenation of the same set of alkenes using a - catalyst - faster than 2 alkene <1 mol% L 2 (CD) F 6 C 2 Cl 2, zero degrees alkane L 2 = ir 3, pyridine
A reason for the lower popularity of iridium hydrogenation is competitive deactivation of the catalyst Cx 3 F 6 2, low substrate Inactive trimer 3 3 3 7 2 F 6 Crabtree's catalyst 108 references h 3 h 3 Rh Cl h 3 Wilkinson's catalyst 2839 references 2 2 2 () 2 Suggest why this is not a hydrogenation catalyst 2 F 6 30
idium asymmetric hydrogenation follows naturally from the Crabtree catalyst (>20 years later)
The counter-ion is critical, and the solution must be anhydrous as well 2 consumption 0% Tf BF 4 F 6 small B(C 6 5 ) 4 BARF Al(C(CF 3 ) 3 ) 4 large, hydrophobic 100% 0 500 1500 2500 3500 time, secs Bu t (o-tol) 2 0.1 mol% 2 [14 bar], 4 C, C 2 Cl 2 What s BARF? (look up non-coordinating anion in Wiki)
idium has a strong affinity for 2 and the initial chemistry is different from Rh (and ). nly limited mechanistic information is available here: r i h 2 BArF d 8 -thf -40 C 2 r i h 2 BArF 40 C 0 C r i S S h 2 BArF one species by 31 MR S = d 8 -thf major of two species
Examples of iridium asymmetric hydrogenation catalysts; normally chelates R 2 R" R" R" R" R" R 2 R" R 2 R' R 2 X Almost all examples are based on the 6-ring chelate shown; different ligands have different selectivities and so reactions are tested empirically (small "libraries" of ligands in the testing stage.
Some examples of asymmetric hydrogenation with catalysts - di, tri- and even tetrasubstituted alkenes 1 mol% catalyst 50 bar 2, C 2 Cl 2 2 h. RT. 99% e.e. Bn Bn h 2 ligand h Compare: 1 mol% catalyst 50 bar 2, C 2 Cl 2 2 h. RT. 99% e.e. (o-tol) 2 ligand Bu t C 2 1 mol% catalyst 1 bar 2, C 2 Cl 2 2 h. RT. 94% e.e. Bn Bn Cx 2 ligand h
A hydrogenation-based enantioselective synthesis of Vitamin E. Two crucial stereocentres introduced without directing groups Ac (R)- preexisting from the synthesis 1 mol% catalyst; BArF 50 bar 2, C 2 Cl 2 2 h. RT. (o-tol) 2 h as ligand Ac > 98% (R,R,R) isomer 36
idium catalysts are also effective for the reduction of imines (B catalysts) catalyst 2, Bu 4 I C 2 Cl atropisomers Fe h 2 2 ligand - has both central and planar chirality Classic example is the synthesis of the herbicide metolachlor produced on a multi-ton scale
Dehydrogenation. Reverse of hydrogenation is possible (in principle) but we must include an energy sink enthalpy enthalpy 2 Bu t Bu t The dehydrogenation of an alkene is highly endothermic! 0 = ca. 120 KJmol 1 An acceptor alkene can make the reaction mildly exothermic Cyclooctane is more strained than cyclohexane - why is this?
incer iridium complexes have provided the most successful application of catalytic dehydrogenation Bu t 2 Bu t 2 Cl Bu t 2 16e LiBEt 3 then 2 Bu t 2 18e (I)Cl vacuum Bu t 2 Bu t 2 Bu t 2 Bu t 2 16e eed to transfer 2 to added alkene to generate the active catalyst. pincer ligand; electron-rich catalyst for dehydrogenation
Even in this case the reaction requires high temperatures and turnovers are limited (ca. 200) Reactant Bu t Bu t 2 Bu t 2 Reductive cycle Bu t Bu t Bu t 2 Bu t Bu t 2 Bu t ----roducts---- Bu t Bu t Bu t 2 Bu t Bu t 2 Bu t 2 Bu t 2 xidative cycle Reactant