Frustrated Lewis pair
A frustrated Lewis pair (FLP) is a compound or mixture containing a
The discovery that some FLPs split H2
This reactivity has been exploited to produce FLPs which catalyse hydrogenation reactions.[5]
Small molecule activation
Frustrated Lewis pairs have been shown to activate many small molecules, either by inducing heterolysis or by coordination.
Hydrogen
The discovery that some FLPs are able to split, and therefore activate, H2[4] triggered a rapid growth of research into this area. The activation and therefore use of H2 is important for many chemical and biological transformations. Using FLPs to liberate H2 is metal-free, this is beneficial due to the cost and limited supply of some transition metals commonly used to activate H2 (Ni, Pd, Pt).[6] FLP systems are reactive toward substrates that can undergo heterolysis (e.g. hydrogen) due to the "unquenched" reactivity of such systems. For example, it has been previously shown that a mixture of tricyclohexylphosphine (PCy3) and tris(pentafluorophenyl)borane reacts with H2 to give the respective phosphonium and borate ions:
In this reaction, PCy3 (the Lewis base) and B(C6F5)3 (the Lewis acid) cannot form an adduct due to the steric hindrance from the bulky cyclohexyl and pentafluorophenyl groups. The proton on the phosphorus and hydride from the borate are now ‘activated’ and can subsequently be ‘delivered’ to an organic substrate, resulting in hydrogenation.
Mechanism of dihydrogen activation by FLP
The mechanism for the activation of H2 by FLPs has been discussed for both the intermolecular and intramolecular cases. Intermolecular FLPs are where the Lewis base is a separate molecule to the Lewis acid, it is thought that these individual molecules interact through secondary London dispersion interactions to bring the Lewis base and acid together (a pre-organisational effect) where small molecules may then interact with the FLPs. The experimental evidence for this type of interaction at the molecular level is unclear. However, there is supporting evidence for this type of interaction based on computational density functional theory studies. Intramolecular FLPs are where the Lewis acid and Lewis base are combined in one molecule by a covalent linker. Despite the improved ‘pre-organisational effects’, rigid intramolecular FLP frameworks are thought to have a reduced reactivity to small molecules due to a reduction in flexibility.
Other small molecule substrates
FLPs are also reactive toward many unsaturated substrates beyond H2. Some FLPs react with CO2, specifically in the deoxygenative reduction of CO2 to methane.[7]
For acid-base pairs to behave both nucleophilically and electrophilically at the same time offers a method for the ring-opening of cyclic ethers such as THF, 2,5-dihydrofuran, coumaran, and dioxane.[9]
Use in catalysis
Imine, nitrile and aziridine hydrogenation
Reduction of imines, nitriles, and aziridines to primary and secondary amines traditionally is effected by metal hydride reagents, e.g. lithium aluminium hydride and sodium cyanoborohydride. Hydrogenations of these unsaturated substrates can be effected by metal-catalyzed reactions. Metal-free catalytic hydrogenation was carried out using the phosphonium borate catalyst (R2PH)(C6F4)BH(C6F5)2 (R = 2,4,6-Me3C6H2) 1. This type of metal-free hydrogenation has the potential to replace high cost metal catalyst.
The mechanism of imine reduction is proposed to involve protonation at nitrogen giving the iminium salt. The basicity of the nitrogen centre determines the rate of reaction. More electron rich imines reduce at faster rates than electron poor imines. The resulting iminium center undergoes
Enantioselective imine hydrogenation
A chiral boronate
Although conceptually interesting, the protocol suffers from lack of generality. It was found that increasing steric bulk of the imine substituents lead to decreased yield and ee of the amine product. methoxy-substituted imines exhibit superior yield and ee's.[10]
Asymmetric hydrosilylations
Frustrated Lewis pairs of chiral alkenylboranes and phosphines are beneficial for asymmetric Piers-type hydrosilylations of 1,2-dicarbonyl compounds and alpha-keto esters, giving high yield and enantioselectivity. However, in comparison to conventional Piers-type hydrosilyations, asymmetric Piers-type hydrosilylations are not as well developed.
In the following example, the chiral alkenylborane is formed in situ from a chiral diyne and the HB(C6F5)2. Heterolytic cleavage of the Si-H bond from PhMe2SiH by the FLP catalyst forms a silylium and hydridoborate ionic complex.[11]
Alkyne hydrogenation
Metal free hydrogenation of unactivated internal alkynes to cis-alkenes is readily achieved using FLP-based catalysts.[12] The condition for this reaction were relatively mild utilising 2 bar of H2. In terms of mechanism, the alkyne material is first hydroborated and then the resulting vinylborane-based FLP can then activate dihydrogen. A protodeborylation step releases the cis-alkene product, which is obtained due to the syn-hydroborylation process, and regenerating the catalyst. While active for alkyne hydrogenation the FLP-based catalysts do not however facilitate the hydrogenation of alkenes to alkanes.
The reaction is a syn-hydroboration, and as a result a high cis selectivity is observed. At the final stage of the catalytic cycle the C6F5 group is cleaved more easily than an alkyl group, causing catalyst degradation rather than alkane release. The catalytic cycle has three steps:
- Substrate binding (the hydroboration of alkyne)
- H2 cleavage with vinylborane, followed by intramolecular protodeborylation of vinyl substituent, recovering N,N-Dimethyl-2-[(pentafluorophenyl)boryl]aniline
- Release of the cis-alkene
With internal alkynes, a competitive reaction occurs where the proton bound to the nitrogen can be added to the fluorobenzenes. Therefore, this addition does not proceed that much, the formation of the alkene seems favoured.
But terminal alkynes do not bind to the boron through hydroboration but rather through C-H activation. Thus, the addition of the proton to the alkyne will result in the initial terminal alkyne. Hence this hydrogenation process is not suitable to terminal alkynes and will only give pentafluorobenzene.
The metal free hydrogenation of terminal alkynes to the respective alkenes was recently achieved using a pyridone borane based system.[13] This system activates hydrogen readily at room temperature yielding a pyridone borane complex.[14] Dissociation of this complex allows hydroboration of an alkyne by the free borane. Upon protodeborylation by the free pyridone the cis alkene is generated. Hydrogenation of terminal alkynes is possible with this system, because the C-H activation is reversible and competes with hydrogen activation.
Borylation
Amine-borane FLPs catalyse the borylation of electron-rich aromatic heterocycles (Scheme 1).[15] The reaction is driven by release of hydrogen via C-H activation by the FLP. Aromatic borylations are often used in pharmaceutical development, particularly due to the abundance, low cost and low toxicity of boron compounds compared to noble metals.,