Please do not adjust margins Chem Soc Rev TUTORIAL REVIEW Designing Effective ‘Frustrated Lewis Pair’ Hydrogenation Catalysts Received 00th January 20xx, Accepted 00th January 20xx Daniel J. Scott,* Matthew J. Fuchter and Andrew E. Ashley* DOI: 10.1039/x0xx00000x The past decade has seen the subject of transition metal-free catalytic hydrogenation develop incredibly rapidly, transforming from a largely hypothetical possibility to a well-established field that can be applied to the reduction of a www.rsc.org/ diverse variety of functional groups under mild conditions. This remarkable change is principally attributable to the development of so-called ‘frustrated Lewis pairs’: unquenched combinations of bulky Lewis acids and bases whose dual reactivity can be exploited for the facile activation of otherwise inert chemical bonds. While a number of comprehensive reviews into frustrated Lewis pair chemistry have been published in recent years, this tutorial review aims to provide a focused guide to the development of efficient FLP hydrogenation catalysts, through identification and consideration of the key factors that govern their effectiveness. Following discussion of these factors, their importance will be illustrated using a case study from our own research, namely the development of FLP protocols for successful hydrogenation of aldehydes and ketones, and for related moisture-tolerant hydrogenation. Key learning points 1. Rational FLP design must be based on an understanding of the relevant key mechanistic steps. 2. H+ and H– affinities are crucial parameters and must be balanced relative to both the substrate and each one another. 3. Reactivity can be inhibited by either exceedingly high or low steric bulk, and the ideal profile will be substrate-dependent. 4. Intramolecular FLPs offer the possibility of improved reactivity, but at the cost of more challenging catalyst development. 5. Successful FLP design requires an understanding of inhibition/decomposition mechanisms, which are often LA-related. some examples do exist (notably the various well-known Introduction to FLP chemistry carbenes and related group IV R2E species) and in recent years there has been great interest in the isolation and study of such Since the earliest days of the field, the study of homogeneous compounds in the hope that they may demonstrate a similar catalysis has been all but synonymous with the study of potential for catalysis, and ultimately provide counterparts or transition metal (TM) catalysis, particularly in the activation of alternatives to TMs (many of which suffer from high toxicity, 1 relatively inert small molecules or of strong chemical bonds. high cost, or low abundance). Indeed, some such compounds The privileged reactivity demonstrated by TM compounds can have been shown to readily undergo a variety of ‘TM-like’ be attributed to their characteristic electronic structures, with reactions. For example, Bertrand et al. were able to partially occupied sets of d-orbitals leading to the demonstrate activation of inert E—H bonds (E = N, H) by simultaneous presence of both nucleophilic/Lewis basic and addition to singlet carbenes, with the observed reactivity electrophilic/Lewis acidic frontier orbitals located on the same attributed to simultaneous interaction of the substrate with 2 atom. It is the ability of both types of orbital to interact the electrophilic 2p and nucleophilic sp orbitals on the synergistically with a substrate that allows for the activation of reactive carbon centre, in a manner clearly reminiscent of TMs 2 functional groups that would normally be kinetically inert, (Fig. 1b). even where these groups would be unreactive towards a Lewis Nevertheless, the adaptation of stoichiometric bond activation chemistry by main group compounds into useful acidic or Lewis basic site on its own (illustrated for H2 in Fig. 1a). Comparable electronic structures are uncommon for catalytic cycles has proven highly challenging, and only very stable main group compounds, which explains their general few such examples have been reported. This can broadly be inability to mediate similar catalytic reactions. Nevertheless, attributed to the typical low stability of unsaturated p-block compounds, which leads to difficulties in catalyst regeneration (and thus prevents closure of the catalytic cycle) and tendency towards decomposition, as well as more general difficulties in Department of Chemistry, Imperial College London, SW7 2AZ, UK. E-mail: [email protected] initial isolation and handling. This journal is © The Royal Society of Chemistry 2017 Chem. Soc. Rev., 2017, 00, 1-3 | 1 Please do not adjust margins Please do not adjust margins ARTICLE Journal Name CO2 and other p-block oxides; alkenes and alkynes; acidic and hydridic E—H bonds).6 The TM-like reactivity of FLPs has again been attributed to the simultaneous action on the H2 molecule of energetically- accessible Lewis acidic and basic orbitals (Fig. 1c).7 However, In 2006 Stephan and co-workers described results that unlike the other examples discussed so far, in FLPs these have led to an alternative and much simpler approach for orbitals are spatially separated from one another, and 3 obtaining TM-like reactivity using main group compounds. localised on different functional groups. As a consequence, it The authors observed that under an atmosphere of H2 a is typically relatively easy to fine-tune the properties of one solution of an intramolecular phosphine-borane was converted (e.g. sterics or electronics) without having a significant impact to into the zwitterionic phosphonium borohydride, via on the other. Given also that FLPs are readily constructed from activation and cleavage of the homopolar H—H bond (Fig. 2a). robust, well-understood functional groups (usually an amine or It was quickly realised that this reactivity could be generalised phosphine combined with a strong fluoroaryl-substituted to simple intermolecular phosphine/borane combinations, borane), this means that FLPs are uniquely well-suited among provided that their steric bulk was sufficient to prevent adduct unsaturated p-block compounds for the development of 4 formation between the Lewis acid (LA) and base (LB). catalytic applications. Indeed, within two years of the first Because of their sterically-induced inability to quench one report of FLP H2 activation, the same authors also described another, such systems have come to be known as ‘frustrated’ the first example of FLP-catalysed hydrogenation; the 5 Lewis pairs (FLPs). Subsequent work by many groups has conversion of simple imines to amines (Fig. 2b).8 Subsequent shown that FLP reactivity can be observed with a much wider rapid progress has expanded the scope of FLP-catalysed variety of both inter- and intramolecular LA and LB hydrogenations to include substrates ranging from alkenes and combinations [e.g. boranes, boreniums, alanes, carbocations, aromatics to aldehydes and ketones.6 FLPs have thus provided silyliums and stannyliums; phosphines, amines and N- the first general methodology for catalytic hydrogenation that heterocyclic carbenes (NHCs)], and can lead to activation of a does not require the use of a TM. great many other small molecules and chemical bonds (e.g. Daniel Scott is an EPSRC doctoral Dr Matthew Fuchter is a Reader in prize fellow currently working in the Chemistry at Imperial College. The group of Dr Andrew E. Ashley at Fuchter group has a wide-ranging Imperial College, where he had track record in the design, synthesis previously obtained his PhD studying and application of organic molecules the development of FLP catalysis. His in chemistry, medicine and materials. current research focuses on the Representative examples include the development of Fe-based catalysts design and development of novel for homogeneous N2 fixation. bioactive probes, the study of novel chiral semiconducting molecules, and the development of novel FLP catalysts. 2 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx Please do not adjust margins Please do not adjust margins Journal Name ARTICLE A note on FLPs and other branches of chemistry As with any chemical transformation, the rational development of effective FLP hydrogenation catalysis is above Given the simplicity of the FLP concept, it is perhaps not all dependent upon a basic understanding of the key steps surprising that it has begun to be invoked in relation to quite a underlying the reaction mechanism. Understanding the broad range of chemical processes. This includes discussion of mechanism by which FLPs are able to activate H2 is thus clearly newly developed or discovered reactions, but also of many central for considerations of hydrogenation catalysis. As that pre-date the FLP formalism. Notable examples in the already discussed, H—H cleavage is believed to occur through latter category include Piers-type hydrosilylation,9 metal-ligand simultaneous interaction with both the LA and LB (Fig. 1c). cooperative catalysis,10 and the chemistry of solid surfaces,11 While for intramolecular FLPs this leads to a feasible among many others. In one particularly dramatic example, bimolecular reaction, for intermolecular systems it implies the KOR (R = alkyl) was reported to catalyse ketone hydrogenation need for an entropically unfavourable termolecular step. This in turn indicates that some transient interaction must form under very forcing conditions, with H2 activated by ‘the joint between two of the reaction components prior to the action of a […] base and a Lewis-acid