Hydroformylation and oxidation of olefins

1. Hydroformylation and oxidationof olefins Chapters 16 and 18

2. Outline Hydroformylation Thermodynamics Mechanism Phosphine-modified catalysts Wacker reaction Monsanto process Katsuki-Sharpless asymmetric epoxidation of allylic alcohols Jacobsen asymmetric epoxidation of olefins Sharpless asymmetric dihydroxylation of olefins

3. Hydroformylation: Thermodynamics

4. Mechanism of the Co-catalyzed hydroformylation

5. Other mechanistic details

6. Phosphine-modified catalysts Alkylphosphines are strong electron donors and thus dissociation of CO is retarded, leading to more stable, but also slower catalysts. A very effective ligand for Co is a phobane derivative: The reaction is 100 times slower; The selectivity to linear products increases; The catalyst is more stable; The catalyst acquires activity for hydrogenation Order of activity (195 �C, 36 bar) Ph2EtP > PhBu2P > Bu3P > Et3P > PhEt2P > Cy3P Linear : branched ratio: Bu3P > Et3P = PhEt2P = Cy3P = PhBu2P > Ph2EtP For Rh, PPh3 works very well. HRh(CO)L3 complexes are 100 to 1000 times more active than Co complexes and they operate under milder conditions (15 � 25 atm and 80 �C � 120 �C).

7. Acetic acid and acetyl chemicals Principal application of acetyl chemicals: solvents and vinyl acetate monomer for polymerization. Early production routes (ca 1850s): fermentation or wood distillation (still used in the USA in the mid-1960s). First synthetic route: Hg2+ catalyzed H2O addition to HC=CH to form CH3CHO.

8. The Wacker reaction: oxidation with O2

9. Vinyl acetate synthesis Overall yields: 90 � 95% based on both ethylene and acetic acid. Homogeneous process was abandoned due to corrosion associated with the presence of acetic acid. Heterogeneous process uses PdCl2 / CuCl2 / C or PdCl2 / alumina.

10. Monsanto carbonylation of methanol

11. Katsuki-Sharpless asymmetric epoxidation of allylic alcohols T-Butyl hydroperoxide, a well known source of oxygen atoms for a variety of organic oxidations is possibly the best source of oxygen atoms, being a selective reagent, relatively stable, and easy to handle. It is regarded as one of the most stable organic peroxides and is much safer to handle than peracetic acid or H2O2. It was known for some time that allylic alcohols are very reactive towards epoxidation by t-BuOOH (no oxidation of the alcohol). Early experiments for the purpose of accomplishing asymmetric epoxidation were run with V catalysts bearing chiral hydroxamic acids as ligands. The Katsuki-Sharpless epoxidation is a Ti-catalyzed asymmetric epoxidation of allylic alcohols with tartaric esters as chiral ligands, giving high ees (> 90% ee). The necessary compounds are L-(+)- or D-(-)-diethyl tartrate, Ti(OiPr)4, and water-free solutions of t-BuOOH. The natural and the unnatural DET are commercially available, as is Ti(OiPr)4. The required water-free solution of t-BuOOH is easy to prepare from the commercially available 70% solution (containing 30% water as a stabilizer). Two main advantages became clear from the first few examples of the chiral oxidation: The reaction gives uniformly high asymmetric induction for a wide range of primary allylic alcohols. It seems that the epoxide oxygen is always delivered from the same enantioface of the olefin given a specific tartrate isomer. If the olefin is drwan as shown, the oxygen is delivered from the bottom using D-(-)-DET and from the top using L-(+)-DET.T-Butyl hydroperoxide, a well known source of oxygen atoms for a variety of organic oxidations is possibly the best source of oxygen atoms, being a selective reagent, relatively stable, and easy to handle. It is regarded as one of the most stable organic peroxides and is much safer to handle than peracetic acid or H2O2. It was known for some time that allylic alcohols are very reactive towards epoxidation by t-BuOOH (no oxidation of the alcohol). Early experiments for the purpose of accomplishing asymmetric epoxidation were run with V catalysts bearing chiral hydroxamic acids as ligands. The Katsuki-Sharpless epoxidation is a Ti-catalyzed asymmetric epoxidation of allylic alcohols with tartaric esters as chiral ligands, giving high ees (> 90% ee). The necessary compounds are L-(+)- or D-(-)-diethyl tartrate, Ti(OiPr)4, and water-free solutions of t-BuOOH. The natural and the unnatural DET are commercially available, as is Ti(OiPr)4. The required water-free solution of t-BuOOH is easy to prepare from the commercially available 70% solution (containing 30% water as a stabilizer). Two main advantages became clear from the first few examples of the chiral oxidation: The reaction gives uniformly high asymmetric induction for a wide range of primary allylic alcohols. It seems that the epoxide oxygen is always delivered from the same enantioface of the olefin given a specific tartrate isomer. If the olefin is drwan as shown, the oxygen is delivered from the bottom using D-(-)-DET and from the top using L-(+)-DET.

12. Mechanistic considerations for the Katsuki-Sharpless asymmetric epoxidation The kinetics of the reaction show� This is in accordance with replacement of two i-PrO anions by a t-butylperoxyanion and an allyloxy anion. This intermediate has a very low concentration and has not been observed directly. The Ti alkoxide systems have several unique properties crucial to the success of asymmetric epoxidation reactions: Exchange of the monodentate alkoxide ligands is rapid in solution. Ti(IV) has a somewhat flexible coordination sphere. Ti(IV) alokxides are weak Lewis acids: they activate to a certain extent a coordinated alkylperoxo ligand towards nucleophilic attack by the double bond of the allylic alcohol. Some observations help understanding the mechanism and the highly ordered transition state which leads to the high face selectivity of the asymmetric epoxidation: The coordinated distal peroxo-O is transferred to the olefin. The proximal peroxo-O interacts strongly with Ti in the TS. The olefin pi* orbital must be in position to overlap with one of the lone pairs of the peroxo-O that is being delivered. The attack is centered along the axis of the O-O sigma-bond being broken.The kinetics of the reaction show� This is in accordance with replacement of two i-PrO anions by a t-butylperoxyanion and an allyloxy anion. This intermediate has a very low concentration and has not been observed directly. The Ti alkoxide systems have several unique properties crucial to the success of asymmetric epoxidation reactions: Exchange of the monodentate alkoxide ligands is rapid in solution. Ti(IV) has a somewhat flexible coordination sphere. Ti(IV) alokxides are weak Lewis acids: they activate to a certain extent a coordinated alkylperoxo ligand towards nucleophilic attack by the double bond of the allylic alcohol. Some observations help understanding the mechanism and the highly ordered transition state which leads to the high face selectivity of the asymmetric epoxidation: The coordinated distal peroxo-O is transferred to the olefin. The proximal peroxo-O interacts strongly with Ti in the TS. The olefin pi* orbital must be in position to overlap with one of the lone pairs of the peroxo-O that is being delivered. The attack is centered along the axis of the O-O sigma-bond being broken.

13. Jacobsen asymmetric epoxidation of olefins In 1985, Kochi and coworkers reported that Cr(salen)s catalyzed the epoxidation of olefins via the corresponding oxo-Cr(V)(salen)s, the structures of which were determined by X-ray. In the subsequent year, they further reported that cationic Mn(salen)s were superior catalysts for epoxidation which was also proposed to proceed through oxo-Mn(V)(salen)s. In 1990, Jacobsen and Katsuki independently reported enantioselective epoxidation using optically active Mn(salen)s as catalysts. These Mn(salen)s are characterized by the presence of asymmetric centers at the ethyelendiamine unit and bulky and/or chiral 3- and 3�-substituents. Since then, several modified Mn(salen)s have been introduced and high enantioselectivities have been achieved in the epoxidation of conjugated cis- di-, tri-, and some tetra-substituted olefins. In 1985, Kochi and coworkers reported that Cr(salen)s catalyzed the epoxidation of olefins via the corresponding oxo-Cr(V)(salen)s, the structures of which were determined by X-ray. In the subsequent year, they further reported that cationic Mn(salen)s were superior catalysts for epoxidation which was also proposed to proceed through oxo-Mn(V)(salen)s. In 1990, Jacobsen and Katsuki independently reported enantioselective epoxidation using optically active Mn(salen)s as catalysts. These Mn(salen)s are characterized by the presence of asymmetric centers at the ethyelendiamine unit and bulky and/or chiral 3- and 3�-substituents. Since then, several modified Mn(salen)s have been introduced and high enantioselectivities have been achieved in the epoxidation of conjugated cis- di-, tri-, and some tetra-substituted olefins.

14. Mechanistic considerations for the Jacobsen asymmetric epoxidation Due to the flexibility of the ethane bridge, the catalyst adopts a non-planar conformation. Half of the ligand is bent upwards and half of the ligand is bent downwards. The oxo-intermediate is also considered to adopt a bent conformation. If the oxo species has a non-planar structure of stepped conformation, the olefin is expected to approach the Mn-oxo center over a downwardly bent benzene ring of the salen ligand, directing its bulkier substituent (L) away from the 3�-substituent to minimize repulsion between them. The substituents on the benzylic carbons in the 3 or 3� positions are directed away from the incoming olefin and strong repulsion cannot be expected. In order to improve enantioselectivities, a binaphtyl unit as the chiral element was used. Trans-Olefins are not good substrates for usual Mn(salen)-catalyzed epoxidation. This is partly because the desired orientation of the incoming olefin is destabilized by the interaction of the downward substituent (S) with the salen ligand, expecially when the ligand adopts a shallow stepped conformation. Therefore, deeply-folded Mn(salen)s are expected to be the catalyst suitable for the epoxidation of trans-olefins. Symmetric epoxides such as cyclohexene oxide would be an interesting source of chiral compounds if one would be able to open the epoxide ring in an enantioselective fashion. Jacobsen reasoned that there might be a relationship between the final stage of an epoxidation process and the binding of an epoxide to a Lewis acid. Thus the question was whether chiral salen complexes would do the job. Indeed, it was found that salen complexes containing Cr(III) or Co(III) catalyze the asymmetric ring opening of epoxides. The catalyst structure is the same as that used for epoxidation. Due to the flexibility of the ethane bridge, the catalyst adopts a non-planar conformation. Half of the ligand is bent upwards and half of the ligand is bent downwards. The oxo-intermediate is also considered to adopt a bent conformation. If the oxo species has a non-planar structure of stepped conformation, the olefin is expected to approach the Mn-oxo center over a downwardly bent benzene ring of the salen ligand, directing its bulkier substituent (L) away from the 3�-substituent to minimize repulsion between them. The substituents on the benzylic carbons in the 3 or 3� positions are directed away from the incoming olefin and strong repulsion cannot be expected. In order to improve enantioselectivities, a binaphtyl unit as the chiral element was used. Trans-Olefins are not good substrates for usual Mn(salen)-catalyzed epoxidation. This is partly because the desired orientation of the incoming olefin is destabilized by the interaction of the downward substituent (S) with the salen ligand, expecially when the ligand adopts a shallow stepped conformation. Therefore, deeply-folded Mn(salen)s are expected to be the catalyst suitable for the epoxidation of trans-olefins. Symmetric epoxides such as cyclohexene oxide would be an interesting source of chiral compounds if one would be able to open the epoxide ring in an enantioselective fashion. Jacobsen reasoned that there might be a relationship between the final stage of an epoxidation process and the binding of an epoxide to a Lewis acid. Thus the question was whether chiral salen complexes would do the job. Indeed, it was found that salen complexes containing Cr(III) or Co(III) catalyze the asymmetric ring opening of epoxides. The catalyst structure is the same as that used for epoxidation.

15. Sharpless asymmetric dihydroxylation of olefins About a decade after the discovery of the asymmetric epoxidation of allylic alcohols, another discovery was reported from the laboratories of Sharpless, namely the asymmetric dihydroxylation of alkenes using OsO4. OsO4 in water by itself will slowly convert alkenes into 1,2-diols, but an amine ligand accelerates the reaction (Ligand-Accelerated Catalysis) and if the amine is chiral, the reaction is enantioselective. Hydroxylation of alkenes using high-valent metal oxides occurs in two steps, firstly the formation of a metal dialkoxylate (or metallate ester) and secondly the hydrolysis of this species to a 1,2-diol and the low-valent metal hydroxide. The amine plays a role in the first step, the formation of the osmate ester. The stoichiometric process can be made catalytic when the latter is reoxidized to the high-valent species. In older literature, the common oxidant used in stoichiometric reactions is KMnO4, but in the last decades the focus has been on OsO4, especially since the discovery of enantioselective, catalytic variants.About a decade after the discovery of the asymmetric epoxidation of allylic alcohols, another discovery was reported from the laboratories of Sharpless, namely the asymmetric dihydroxylation of alkenes using OsO4. OsO4 in water by itself will slowly convert alkenes into 1,2-diols, but an amine ligand accelerates the reaction (Ligand-Accelerated Catalysis) and if the amine is chiral, the reaction is enantioselective. Hydroxylation of alkenes using high-valent metal oxides occurs in two steps, firstly the formation of a metal dialkoxylate (or metallate ester) and secondly the hydrolysis of this species to a 1,2-diol and the low-valent metal hydroxide. The amine plays a role in the first step, the formation of the osmate ester. The stoichiometric process can be made catalytic when the latter is reoxidized to the high-valent species. In older literature, the common oxidant used in stoichiometric reactions is KMnO4, but in the last decades the focus has been on OsO4, especially since the discovery of enantioselective, catalytic variants.

16. Mechanistic considerations for the Sharpless AD The mode of addition of alkene to OsO4 has been the subject of debate since initially it was thought that a 2+2 reaction occurred and that the metal atom was involved (Os=O + C=C, Sharpless). This gives a metallaoxetane that subsequently will have to rearrange to a metalla-dioxolane. Computational chemistry is fully supporting the 3+2 mechanism (Criegee), which has a much lower barrier than the 2+2 mechanism. Amine complexation lowers the addition barrier only slightly in the calculations, while its accelerating function in catalysis has been well recognized. Initially, it was thought more likely that the electron poor metal center would be involved in the electrophilic attack at the alkene and also the metal-carbon bond would bring the alkene closer to the chiral metal-ligand environment. This mechanism is analogous to alkene metathesis in which a metallacyclobutane is formed. Later work, though, has shown that for Os the actual mechanism is the 3+2 addition. Besides molecular modelling, KIE support this. Oxetane formation should lead to a different KIE for the two carbon atoms involved. Both experimentally and theoretically, an equal KIE was found for both carbons and thus it was concluded that an effectively symmetric addition, such as the 3+2 addition, is the actual mechanism for Os. The mode of addition of alkene to OsO4 has been the subject of debate since initially it was thought that a 2+2 reaction occurred and that the metal atom was involved (Os=O + C=C, Sharpless). This gives a metallaoxetane that subsequently will have to rearrange to a metalla-dioxolane. Computational chemistry is fully supporting the 3+2 mechanism (Criegee), which has a much lower barrier than the 2+2 mechanism. Amine complexation lowers the addition barrier only slightly in the calculations, while its accelerating function in catalysis has been well recognized. Initially, it was thought more likely that the electron poor metal center would be involved in the electrophilic attack at the alkene and also the metal-carbon bond would bring the alkene closer to the chiral metal-ligand environment. This mechanism is analogous to alkene metathesis in which a metallacyclobutane is formed. Later work, though, has shown that for Os the actual mechanism is the 3+2 addition. Besides molecular modelling, KIE support this. Oxetane formation should lead to a different KIE for the two carbon atoms involved. Both experimentally and theoretically, an equal KIE was found for both carbons and thus it was concluded that an effectively symmetric addition, such as the 3+2 addition, is the actual mechanism for Os.

17. Ligands used for AD The stoichiometric enantioselective reaction of alkenes and OsO4 was reported in 1980. As pyridine was known to accelerate the reaction, initial efforts concentrated on the use of py substituted with chiral groups, such as l-2-(2-menthyl)pyridine, but ees were below 18%. Besides, it was found that complexation was weak between py and Os. Griffith and coworkers reported that tertiary bridgehead amines, such as quinuclidine, formed much more stable complexes and this led Sharpless and coworkers to test this ligand type for the reaction of OsO4 and prochiral alkenes. The catalysts is a combination of a chemo-catalyst and a natural product taken from the cinchona alkaloids giving amazing results. In phosphine catalyzed asymmetric catalysis these types of structures are lacking, as nature does not produce phosphines and the phosphines used in the early days of development of asymmetric homogeneous catalysis lacked the complexity of cinchona alkaloids. Step by step, AD was converted into a very practical protocol and the most convenient oxidant found was K3Fe(CN)6 in t-BuOH/H2O and a variety of R groups (replacing H in the free alkaloid), each having an optimum performance for different substitution patterns of the alkene substrates. Especially �PHAL� (1,4-phthalazinediyl) as a connector, binding two alkaloid molecules was extremely effective as the second generation catalyst. Two convenient catalyst mixtures are available producing opposite diastereomers. In this �dimeric� catalyst only one OsO4 binds one bridgehead nitrogen atom in the U-shaped cavity that the molecule forms. The nitrogen ligand accelerates the addition step by orders of magnitude, but since the hydrolysis of the osmate esters becomes rate-determining, the maximum effect of this acceleration is usually not obtained in the catalytic system. Since the addition to unmodified OsO4 is so much slower, the rate of ligand-free complex is low and substoichiometric amounts of amine (versus Os) can be used. Various co-reagents have been tested and identified which can accelerate the hydrolysis step, for example MeSO2NH2. Air or O2 can be used as an oxidant with non-chiral amines to give a low cost catalyst for dihydroxylation of alkenes into racemic mixtures; dihydroquinidine modified catalysts with the air variant give lower ees than the AD-mix catalysts.The stoichiometric enantioselective reaction of alkenes and OsO4 was reported in 1980. As pyridine was known to accelerate the reaction, initial efforts concentrated on the use of py substituted with chiral groups, such as l-2-(2-menthyl)pyridine, but ees were below 18%. Besides, it was found that complexation was weak between py and Os. Griffith and coworkers reported that tertiary bridgehead amines, such as quinuclidine, formed much more stable complexes and this led Sharpless and coworkers to test this ligand type for the reaction of OsO4 and prochiral alkenes. The catalysts is a combination of a chemo-catalyst and a natural product taken from the cinchona alkaloids giving amazing results. In phosphine catalyzed asymmetric catalysis these types of structures are lacking, as nature does not produce phosphines and the phosphines used in the early days of development of asymmetric homogeneous catalysis lacked the complexity of cinchona alkaloids. Step by step, AD was converted into a very practical protocol and the most convenient oxidant found was K3Fe(CN)6 in t-BuOH/H2O and a variety of R groups (replacing H in the free alkaloid), each having an optimum performance for different substitution patterns of the alkene substrates. Especially �PHAL� (1,4-phthalazinediyl) as a connector, binding two alkaloid molecules was extremely effective as the second generation catalyst. Two convenient catalyst mixtures are available producing opposite diastereomers. In this �dimeric� catalyst only one OsO4 binds one bridgehead nitrogen atom in the U-shaped cavity that the molecule forms. The nitrogen ligand accelerates the addition step by orders of magnitude, but since the hydrolysis of the osmate esters becomes rate-determining, the maximum effect of this acceleration is usually not obtained in the catalytic system. Since the addition to unmodified OsO4 is so much slower, the rate of ligand-free complex is low and substoichiometric amounts of amine (versus Os) can be used. Various co-reagents have been tested and identified which can accelerate the hydrolysis step, for example MeSO2NH2. Air or O2 can be used as an oxidant with non-chiral amines to give a low cost catalyst for dihydroxylation of alkenes into racemic mixtures; dihydroquinidine modified catalysts with the air variant give lower ees than the AD-mix catalysts.