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| title | chunk | source | category | tags | date_saved | instance |
|---|---|---|---|---|---|---|
| Asymmetric hydrogenation | 3/4 | https://en.wikipedia.org/wiki/Asymmetric_hydrogenation | reference | science, encyclopedia | 2026-05-05T10:46:00.770091+00:00 | kb-cron |
Conversely to the case of olefins, asymmetric hydrogenation of enamines has favoured diphosphine-type ligands; excellent results have been achieved with both iridium- and rhodium-based systems. However, even the best systems often suffer from low ee's and a lack of generality. Certain pyrrolidine-derived enamines of aromatic ketones are amenable to asymmetrically hydrogenation with cationic rhodium(I) phosphonite systems, and I2 and acetic acid system with ee values usually above 90% and potentially as high as 99.9%. A similar system using iridium(I) and a very closely related phosphoramidite ligand is effective for the asymmetric hydrogenation of pyrrolidine-type enamines where the double bond was inside the ring: in other words, of dihydropyrroles. In both cases, the enantioselectivity dropped substantially when the ring size was increased from five to six.
=== Imines and ketones ===
Ketones and imines are related functional groups, and effective technologies for the asymmetric hydrogenation of each are also closely related. Early examples are Noyori's ruthenium-chiral diphosphine-diamine system. For carbonyl and imine substrates, end-on, η1 coordination can compete with η2 mode. For η1-bound substrates, the hydrogen-accepting carbon is removed from the catalyst and resists hydrogenation. Iridium/P,N ligand-based systems have been effective for some ketones and imines. For example, a consistent system for benzylic aryl imines uses the P,N ligand SIPHOX in conjunction with iridium(I) in a cationic complex to achieve asymmetric hydrogenation with ee >90%. An efficient catalyst for ketones, (turnover number (TON) up to 4,550,000 and ee up to 99.9%) is an iridium(I) system with a closely related tridentate ligand.
The BINAP/diamine-Ru catalyst is effective for the asymmetric reduction of both functionalized and simple ketones, and BINAP/diamine-Ru catalyst can catalyze aromatic, heteroaromatic, and olefinic ketones enantioselectively. Better stereoselectivity is achieved when one substituent is larger than the other (see Flippin-Lodge angle).
== Aromatic substrates == The asymmetric hydrogenation of aromatic (especially heteroaromatic), substrates is a very active field of ongoing research. Catalysts in this field must contend with a number of complicating factors, including the tendency of highly stable aromatic compounds to resist hydrogenation, the potential coordinating (and therefore catalyst-poisoning) abilities of both substrate and product, and the great diversity in substitution patterns that may be present on any one aromatic ring. Of these substrates the most consistent success has been seen with nitrogen-containing heterocycles, where the aromatic ring is often activated either by protonation or by further functionalization of the nitrogen (generally with an electron-withdrawing protecting group). Such strategies are less applicable to oxygen- and sulfur-containing heterocycles, since they are both less basic and less nucleophilic; this additional difficulty may help to explain why few effective methods exist for their asymmetric hydrogenation.
=== Quinolines, isoquinolines and quinoxalines === Two systems exist for the asymmetric hydrogenation of 2-substituted quinolines with isolated yields generally greater than 80% and ee values generally greater than 90%. The first is an iridium(I)/chiral phosphine/I2 system, first reported by Zhou et al.. While the first chiral phosphine used in this system was MeOBiPhep, newer iterations have focused on improving the performance of this ligand. To this end, systems use phosphines (or related ligands) with improved air stability, recyclability, ease of preparation, lower catalyst loading and the potential role of achiral phosphine additives. As of October 2012 no mechanism appears to have been proposed, although both the necessity of I2 or a halogen surrogate and the possible role of the heteroaromatic N in assisting reactivity have been documented. The second is an organocatalytic transfer hydrogenation system based on Hantzsch esters and a chiral Brønsted acid. In this case, the authors envision a mechanism where the isoquinoline is alternately protonated in an activating step, then reduced by conjugate addition of hydride from the Hantzsch ester.
Much of the asymmetric hydrogenation chemistry of quinoxalines is closely related to that of the structurally similar quinolines. Effective (and efficient) results can be obtained with an Ir(I)/phophinite/I2 system and a Hantzsh ester-based organocatalytic system, both of which are similar to the systems discussed earlier with regards to quinolines.
=== Pyridines === Pyridines are highly variable substrates for asymmetric reduction (even compared to other heteroaromatics), in that five carbon centers are available for differential substitution on the initial ring. As of October 2012 no method seems to exist that can control all five, although at least one reasonably general method exists. The most-general method of asymmetric pyridine hydrogenation is actually a heterogeneous method, where asymmetry is generated from a chiral oxazolidinone bound to the C2 position of the pyridine. Hydrogenating such functionalized pyridines over a number of different heterogeneous metal catalysts gave the corresponding piperidine with the substituents at C3, C4, and C5 positions in an all-cis geometry, in high yield and excellent enantioselectivity. The oxazolidinone auxiliary is also conveniently cleaved under acidic conditions as a second step.
Methods designed specifically for 2-substituted pyridine hydrogenation can involve asymmetric systems developed for related substrates like 2-substituted quinolines and quinoxalines. For example, an iridium(I)\chiral phosphine\I2 system is effective in the asymmetric hydrogenation of activated (alkylated) 2-pyridiniums or certain cyclohexanone-fused pyridines. Similarly, chiral Brønsted acid catalysis with a Hantzsh ester as a hydride source is effective for some 2-alkyl pyridines with additional activating substitution.
=== Indoles and pyrroles === The asymmetric hydrogenation of indoles has been established with N-Boc protection.
A Pd(TFA)2/H8-BINAP system achieves the enantioselective cis-hydrogenation of 2,3- and 2-substituted indoles.
Akin to the behavior of indoles, pyrroles can be converted to pyrrolidines by asymmetric hydrogenation.
=== Oxygen- and sulfur-containing heterocycles === The asymmetric hydrogenation of furans and benzofurans is challenging.
Asymmetric hydrogenation of thiophenes and benzothiophenes has been catalyzed by some ruthenium(II) complexes of N-heterocyclic carbenes (NHC). This system appears to possess superb selectivity (ee > 90%) and perfect diastereoselectivity (all cis) if the substrate has a fused (or directly bound) phenyl ring but yields only racemic product in all other tested cases.
== Heterogeneous catalysis == No heterogeneous catalyst has been commercialized for asymmetric hydrogenation. The first asymmetric hydrogenation focused on palladium deposited on a silk support. Cinchona alkaloids have been used as chiral modifiers for enantioselectivity hydrogenation.