Asymmetric hydrogenation is a chemical reaction that adds two atoms of hydrogen to a target (substrate) molecule with three-dimensional spatial selectivity. Critically, this selectivity does not come from the target molecule itself, but from other reagents or catalysts present in the reaction. This allows spatial information (what chemists refer to as chirality) to transfer from one molecule to the target, forming the product as a single enantiomer. The chiral information is most commonly contained in a catalyst and, in this case, the information in a single molecule of catalyst may be transferred to many substrate molecules, amplifying the amount of chiral information present. Similar processes occur in nature, where a chiral molecule like an enzyme can catalyse the introduction of a chiral centre to give a product as a single enantiomer, such as amino acids, that a cell needs to function. By imitating this process, chemists can generate many novel synthetic molecules that interact with biological systems in specific ways, leading to new pharmaceutical agents and agrochemicals. The importance of asymmetric hydrogenation in both academia and industry contributed to two of its pioneers — William Standish Knowles and Ryōji Noyori — being collectively awarded one half of the 2001 Nobel Prize in Chemistry.
History In 1956 a heterogeneous catalyst made of palladium deposited on silk was shown to effect asymmetric hydrogenation. Later, in 1968, the groups of William Knowles and Leopold Horner independently published the examples of asymmetric hydrogenation using a homogeneous catalysts. While exhibiting only modest enantiomeric excesses, these early reactions demonstrated feasibility. By 1972, enantiomeric excess of 90% was achieved, and the first industrial synthesis of the Parkinson's drug L-DOPA commenced using this technology.
The field of asymmetric hydrogenation continued to experience a number of notable advances. Henri Kagan developed DIOP, an easily prepared C2-symmetric diphosphine that gave high ee's in certain reactions. Ryōji Noyori and co-workers introduced ruthenium–BINAP catalysts for the asymmetric hydrogenation of polar substrates, including functionalized ketones. Robert H. Crabtree demonstrated the ability for Iridium compounds to catalyse asymmetric hydrogenation reactions in 1979 with the invention of Crabtree's catalyst. In the early 1990's, the introduction of P,N ligands by several groups independently then further expanded the scope of the C2-symmetric ligands, although they are not fundamentally superior to chiral ligands lacking rotational symmetry.
Today, asymmetric hydrogenation is a routine methodology in laboratory and industrial scale organic chemistry. The importance of asymmetric hydrogenation was recognized by the 2001 Nobel Prize in Chemistry awarded to William Standish Knowles and Ryōji Noyori.
Mechanism
Asymmetric hydrogenations operate by conventional mechanisms invoked for other hydrogenations. This includes inner sphere mechanisms, outer sphere mechanisms and the σ-bond metathesis mechanisms. The type of mechanism employed by a catalyst is largely dependent on the ligands used in a system, which in turn leads to certain catalyst-substrate affinities.
Inner sphere mechanisms The so-called inner sphere mechanism entails coordination of the alkene to the metal center. Other characteristics of this mechanism include a tendency for a homolytic splitting of dihydrogen when more electron-rich, low-valent metals are present while electron-poor, high valent metals normally exhibit a heterolytic cleavage of dihydrogen assisted by a base.
The diagram below depicts purposed mechanisms for catalytic hydrogenation with rhodium complexes which are inner sphere mechanisms. In the unsaturated mechanism, the chiral product formed will have the opposite mode compared to the catalyst used. While the thermodynamically favoured complex between the catalyst and the substrate is unable to undergo hydrogenation, the unstable, unfavoured complex undergoes hydrogenation rapidly. The dihydride mechanism on the other hand sees the complex initially hydrogenated to the dihydride form. This subsequently allows for the coordination of the double bond on the non-hindered side. Through insertion and reductive elimination, the product's chirality matches that of the ligand.
The preference for producing one enantiomer instead of another in these reactions is often explained in terms of steric interactions between the ligand and the prochiral substrate. Consideration of these interactions has led to the development of quadrant diagrams where "blocked" areas are denoted with a shaded box, while "open" areas are left unfilled. In the modeled reaction, large groups on an incoming olefin will tend to orient to fill the open areas of the diagram, while smaller groups will be directed to the blocked areas and hydrogen delivery will then occur to the back face of the olefin, fixing the stereochemistry. Note that only part of the chiral phosphine ligand is shown for the sake of clarity.
Outer sphere mechanisms Some catalysts operate by "outer sphere mechanisms" such that the substrate never bonds directly to the metal but rather interacts with its ligands, which is often a metal hydride and a protic hydrogen on a ligand. As such, in most cases dihydrogen is split heterolytically, with the metal acting as a Lewis acid and either an external or internal base "deprotonating" the hydride.
For an example of this mechanism we can consider the BINAP-Ru-diamine system. The dihalide form of the catalyst is converted to the catalysts by reaction of H2 in the presence of base: RuCl2(BINAP)(diamine) + 2 KOBu-t + 2 H2 → RuH2(BINAP)(diamine) + 2 KCl + 2 HOBu-t The resulting catalysts have three kinds of ligands: hydrides, which transfer to the unsaturated substrate diamines, which interact with substrate and with base activator by the second coordination sphere diphosphine, which confers asymmetry.
The "Noyori-class" of catalysts are often referred to as bifunctional catalysts to emphasize the fact that both the metal and the (amine) ligand are functional.
In the hydrogenation of C=O containing substrates, the mechanism was long assumed to operate by a six membered pericyclic transition state/intermediate whereby the hydrido ruthenium hydride center (HRu-NH) interacts with the carbonyl substrate R2C=O. More recent DFT and experimental studies have shown that this model is largely incorrect. Instead, the amine backbone interacts strongly with the base activator, which often is used in large excess. However in both cases, the substrate does not bond directly with the metal centre, thus making it a great example of an outer sphere mechanism. Metals Practical AH employ platinum metal-based catalysts.
Base metals Iron is a popular research target for many catalytic processes, owing largely to its low cost and low toxicity relative to other transition metals. Asymmetric hydrogenation methods using iron have been realized, although in terms of rates and selectivity, they are inferior to catalysts based on precious metals. In some cases, structurally ill-defined nanoparticles have proven to be the active species in situ and the modest selectivity observed may result from their uncontrolled geometries.
Ligand classes Phosphine ligands Chiral phosphine ligands, especially C2-symmetric ligands, are the source of chirality in most asymmetric hydrogenation catalysts. Of these the BINAP ligand is well-known, as a result of its Nobel Prize-winning application in the Noyori asymmetric hydrogenation.
Chiral phosphine ligands can be generally classified as mono- or bidentate. They can be further classified according to the location of the stereogenic centre – phosphorus vs the organic substituents. Ligands with a C2 symmetry element have been particularly popular, in part because the presence of such an element reduces the possible binding conformations of a substrate to a metal-ligand complex dramatically (often resulting in exceptional enantioselectivity).
Monodentate phosphines Monophosphine-type ligands were among the first to appear in asymmetric hydrogenation, e.g., the ligand CAMP. Continued research into these types of ligands has explored both P-alkyl and P-heteroatom bonded ligands, with P-heteroatom ligands like the phosphites and phosphoramidites generally achieving more impressive results. Structural classes of ligands that have been successful include those based on the binapthyl structure of MonoPHOS or the spiro ring system of SiPHOS. Notably, these monodentate ligands can be used in combination with each other to achieve a synergistic improvement in enantioselectivity; something that is not possible with the diphosphine ligands.
Chiral diphosphine ligands The diphosphine ligands have received considerably more attention than the monophosphines and, perhaps as a consequence, have a much longer list of achievement. This class includes the first ligand to achieve high selectivity (DIOP), the first ligand to be used in industrial asymmetric synthesis (DIPAMP) and what is likely the best known chiral ligand (BINAP). Chiral diphosphine ligands are now ubiquitous in asymmetric hydrogenation.
P,N and P,O ligands
The use of P,N ligands in asymmetric hydrogenation can be traced to the C2 symmetric bisoxazoline ligand. However, these symmetric ligands were soon superseded by monooxazoline ligands whose lack of C2 symmetry has in no way limits their efficacy in asymmetric catalysis. Such ligands generally consist of an achiral nitrogen-containing heterocycle that is functionalized with a pendant phosphorus-containing arm, although both the exact nature of the heterocycle and the chemical environment phosphorus center has varied widely. No single structure has emerged as consistently effective with a broad range of substrates, although certain privileged structures (like the phosphine-oxazoline or PHOX architecture) have been established. Moreover, within a narrowly defined substrate class the performance of metallic complexes with chiral P,N ligands can closely approach perfect conversion and selectivity in systems otherwise very difficult to target. Certain complexes derived from chelating P-O ligands have shown promising results in the hydrogenation of α,β-unsaturated ketones and esters.
NHC ligands
Simple N-heterocyclic carbene (NHC)-based ligands have proven impractical for asymmetrical hydrogenation.
Some C,N ligands combine an NHC with a chiral oxazoline to give a chelating ligand. NHC-based ligands of the first type have been generated as large libraries from the reaction of smaller libraries of individual NHCs and oxazolines. NHC-based catalysts featuring a bulky seven-membered metallocycle on iridium have been applied to the catalytic hydrogenation of unfunctionalized olefins and vinyl ether alcohols with conversions and ee's in the high 80s or 90s. The same system has been applied to the synthesis of a number of aldol, vicinal dimethyl and deoxypolyketide motifs, and to the deoxypolyketides themselves.
C2-symmetric NHCs have shown themselves to be highly useful ligands for the asymmetric hydrogenation.
Acyclic substrates Substrates can be classified according to their polarity. Nonpolar substrates are dominated by alkenes. Polar substrates include ketones, enamines ketimines. Nonpolar substrates