chem soc rev - imperial college london · 2018. 7. 10. · borane), this means that flps are...
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Chem Soc Rev
TUTORIAL REVIEW
This journal is © The Royal Society of Chemistry 2017 Chem. Soc. Rev., 2017, 00, 1-3 | 1
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Department of Chemistry, Imperial College London, SW7 2AZ, UK. E-mail: [email protected]
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Designing Effective ‘Frustrated Lewis Pair’ Hydrogenation Catalysts
Daniel J. Scott,* Matthew J. Fuchter and Andrew E. Ashley*
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
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.
Introduction to FLP chemistry
Since the earliest days of the field, the study of homogeneous
catalysis has been all but synonymous with the study of
transition metal (TM) catalysis, particularly in the activation of
relatively inert small molecules or of strong chemical bonds.
The privileged reactivity demonstrated by TM compounds can
be attributed to their characteristic electronic structures, with
partially occupied sets of d-orbitals leading to the
simultaneous presence of both nucleophilic/Lewis basic and
electrophilic/Lewis acidic frontier orbitals located on the same
atom. It is the ability of both types of orbital to interact
synergistically with a substrate that allows for the activation of
functional groups that would normally be kinetically inert,
even where these groups would be unreactive towards a Lewis
acidic or Lewis basic site on its own (illustrated for H2 in Fig.
1a). Comparable electronic structures are uncommon for
stable main group compounds, which explains their general
inability to mediate similar catalytic reactions. Nevertheless,
some examples do exist (notably the various well-known
carbenes and related group IV R2E species) and in recent years
there has been great interest in the isolation and study of such
compounds in the hope that they may demonstrate a similar
potential for catalysis, and ultimately provide counterparts or
alternatives to TMs (many of which suffer from high toxicity,
high cost, or low abundance).1 Indeed, some such compounds
have been shown to readily undergo a variety of ‘TM-like’
reactions. For example, Bertrand et al. were able to
demonstrate activation of inert E—H bonds (E = N, H) by
addition to singlet carbenes, with the observed reactivity
attributed to simultaneous interaction of the substrate with
the electrophilic 2p and nucleophilic sp2 orbitals on the
reactive carbon centre, in a manner clearly reminiscent of TMs
(Fig. 1b).2
Nevertheless, the adaptation of stoichiometric bond
activation chemistry by main group compounds into useful
catalytic cycles has proven highly challenging, and only very
few such examples have been reported. This can broadly be
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
initial isolation and handling.
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.
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In 2006 Stephan and co-workers described results that
have led to an alternative and much simpler approach for
obtaining TM-like reactivity using main group compounds.3
The authors observed that under an atmosphere of H2 a
solution of an intramolecular phosphine-borane was converted
to into the zwitterionic phosphonium borohydride, via
activation and cleavage of the homopolar H—H bond (Fig. 2a).
It was quickly realised that this reactivity could be generalised
to simple intermolecular phosphine/borane combinations,
provided that their steric bulk was sufficient to prevent adduct
formation between the Lewis acid (LA) and base (LB).4
Because of their sterically-induced inability to quench one
another, such systems have come to be known as ‘frustrated’
Lewis pairs (FLPs).5 Subsequent work by many groups has
shown that FLP reactivity can be observed with a much wider
variety of both inter- and intramolecular LA and LB
combinations [e.g. boranes, boreniums, alanes, carbocations,
silyliums and stannyliums; phosphines, amines and N-
heterocyclic carbenes (NHCs)], and can lead to activation of a
great many other small molecules and chemical bonds (e.g.
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,
unlike the other examples discussed so far, in FLPs these
orbitals are spatially separated from one another, and
localised on different functional groups. As a consequence, it
is typically relatively easy to fine-tune the properties of one
(e.g. sterics or electronics) without having a significant impact
on the other. Given also that FLPs are readily constructed from
robust, well-understood functional groups (usually an amine or
phosphine combined with a strong fluoroaryl-substituted
borane), this means that FLPs are uniquely well-suited among
unsaturated p-block compounds for the development of
catalytic applications. Indeed, within two years of the first
report of FLP H2 activation, the same authors also described
the first example of FLP-catalysed hydrogenation; the
conversion of simple imines to amines (Fig. 2b).8 Subsequent
rapid progress has expanded the scope of FLP-catalysed
hydrogenations to include substrates ranging from alkenes and
aromatics to aldehydes and ketones.6 FLPs have thus provided
the first general methodology for catalytic hydrogenation that
does not require the use of a TM.
Dr Matthew Fuchter is a Reader in
Chemistry at Imperial College. The
Fuchter group has a wide-ranging
track record in the design, synthesis
and application of organic molecules
in chemistry, medicine and materials.
Representative examples include the
design and development of novel
bioactive probes, the study of novel
chiral semiconducting molecules, and
the development of novel FLP catalysts.
Daniel Scott is an EPSRC doctoral
prize fellow currently working in the
group of Dr Andrew E. Ashley at
Imperial College, where he had
previously obtained his PhD studying
the development of FLP catalysis. His
current research focuses on the
development of Fe-based catalysts
for homogeneous N2 fixation.
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Fig. 3 H2 activation by intramolecular and intermolecular FLPs. For
the latter, the termolecular reaction step is facilitated by formation
of a weakly-bound ‘encounter complex’ between the LA and LB,
into which H2 can add.
A note on FLPs and other branches of chemistry
Given the simplicity of the FLP concept, it is perhaps not
surprising that it has begun to be invoked in relation to quite a
broad range of chemical processes. This includes discussion of
newly developed or discovered reactions, but also of many
that pre-date the FLP formalism. Notable examples in the
latter category include Piers-type hydrosilylation,9 metal-ligand
cooperative catalysis,10
and the chemistry of solid surfaces,11
among many others. In one particularly dramatic example,
KOR (R = alkyl) was reported to catalyse ketone hydrogenation
under very forcing conditions, with H2 activated by ‘the joint
action of a […] base and a Lewis-acid […] on the H2 molecule’,
clearly foreshadowing the development of FLP-catalysed
hydrogenation.12
An analogy can also be drawn between FLP
H2 activation and the chemistry of TM·(H2) complexes, where
binding to a Lewis acidic TM creates a Brønsted acidic H2
moiety that can be deprotonated by LBs.13
As a consequence,
it can sometimes be unclear where the formal boundaries of
the ‘FLP catalysis’ field should be placed (for example, where it
may overlap with LA catalysis, especially in reactions that do
not involve a co-catalytic LB). Ultimately, it is up to the
individual chemist to decide whether invocation of the FLP
concept is helpful in understanding the system in question, as
is the case for many other descriptive models of chemistry
(e.g. valence bond versus molecular orbital theory).
Tutorial review aims and scope
In this tutorial review we will outline the key factors that can
determine the outcome of FLP-catalysed hydrogenation
reactions, and illustrate how these principles can be used in
the design of effective catalysts. Note that while they will not
be discussed here explicitly, most of these principles will also
be directly applicable to the development of various other FLP-
catalysed reactions.
Key aspects of FLP catalyst design
Understanding the reaction mechanism
As with any chemical transformation, the rational
development of effective FLP hydrogenation catalysis is above
all dependent upon a basic understanding of the key steps
underlying the reaction mechanism. Understanding the
mechanism by which FLPs are able to activate H2 is thus clearly
central for considerations of hydrogenation catalysis. As
already discussed, H—H cleavage is believed to occur through
simultaneous interaction with both the LA and LB (Fig. 1c).
While for intramolecular FLPs this leads to a feasible
bimolecular reaction, for intermolecular systems it implies the
need for an entropically unfavourable termolecular step. This
in turn indicates that some transient interaction must form
between two of the reaction components prior to the
involvement of the third, in order to render the bond cleavage
step kinetically accessible. At first it was supposed that this
was likely to be either a weak LA←H2 or LB→H2 interaction.
However, after initial attempts to find either experimental or
computational evidence for such interactions were
unsuccessful, further theoretical studies instead suggested
formation of so-called ‘encounter complexes’ in which the LA
and LB are held together by weak intermolecular interactions
in such a way that they are pre-organised for subsequent H2
activation (Fig. 3).14
Subsequent experimental work has
confirmed the existence of intramolecular interactions for two
PR3/B(C6F5)3 FLPs (R = tBu, or Mes; 2,4,6-trimethylphenyl),
through NMR spectroscopic techniques (e.g. observation of
intermolecular 1H/
19F correlations via 2D HOESY; Fig. 3), and as
such this is believed to be the general mechanism by which H2
activation is effected by a diverse range of FLPs.15
Nevertheless, it should be emphasised that these
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investigations have largely been limited to ‘typical’
amine/borane or phosphine/borane FLPs, and alternative
mechanisms cannot conclusively be ruled out in other
intermolecular systems.
Following H2 activation, catalytic hydrogenation requires
transfer of the resulting H+ and H
– fragments to the substrate
in order to close the catalytic cycle. In almost all examples, this
is believed to involve initial protonation of the substrate in
order to activate it towards subsequent hydride transfer (Fig.
4a). This can be attributed to the ubiquitous use in FLP
hydrogenation catalysts of boranes incorporating very strongly
electron-withdrawing fluoroaryl-substituents as LAs; following
H2 activation these form relatively stable [Ar3BH]– anions that
are not sufficiently powerful hydride donors to reduce the
unactivated substrate. Only after protonation (or, at a
minimum, hydrogen-bonding to [LB·H]+) does the substrate
become sufficiently electrophilic for further reaction to occur.
Nevertheless, some hydrogenations can proceed via
alternative mechanisms, particularly where less ‘typical’ LAs
are used. These may involve hydride transfer prior to
protonation (if the substrate is sufficiently electrophilic and
can stabilise the resulting negative charge), direct
hydroelementation of the substrate, or activation of the
substrate through coordination of the LA rather than H+ (Fig.
4b). In some cases it is also possible that hydrogenation can
proceed without the need to add an auxiliary LB catalyst (‘LA-
only catalysis’), if the substrate is sufficiently basic and can act
as the basic component to activate H2 directly in combination
with the LA (Fig. 4c; imines, for example, are commonly
hydrogenated by this mechanism). When attempting to
rationally design or optimise a reaction it is crucial to
determine if one of these alternative mechanisms might be
operative. This can usually be achieved fairly simply through
stoichiometric reaction of the substrate with pre-formed
[LA·H]– reagents (e.g. [Bu4N]
+[LA·H]
– salts, which contain an
inert countercation) in the presence and absence of possible
activators (such as additional LA or ‘H+[WCA]
–’, where [WCA]
–
is a weakly-coordinating anion; Fig. 5). Likewise, computational
studies may be used to provide additional insight.
Tailoring LA and LB strength
The ‘strength’ of the LA and LB components used to construct
an FLP are of crucial importance to the success of FLP-
catalysed hydrogenation reactions. FLP H2 activation has been
reported using LBs that vary in strength by over 20 pKa units,
and LAs whose calculated hydride ion affinities (G for LA+H–
→[LA·H]–) vary by more than 140 kcal/mol. In an important
study, Pápai and co-workers analysed the thermodynamics by
FLP H2 activation by considering it as the sum of five separate
conceptual steps (Fig. 6):16
Heterolytic cleavage of H2 into H+ and H
–
The size of this term will depend on factors such as the solvent
(with more polar solvents making ionisation more favourable),
but is independent of the FLP used.
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Separation of any LA←LB adduct into the uncoordinated Lewis
pair
For an FLP this term must, by definition, be close to zero. In
some instances FLP reactivity can be observed for Lewis pairs
that do form a weak adduct (discussed in the next section);
however, even in these cases this term would not typically be
expected to be too large.
Attachment of H+ and H
– to the LB and LA, respectively
These terms are highly variable and depend above all on the
choice of LA and LB.
Any stabilising interaction between the resulting [LA·H]– and
[LB·H]+ moieties (e.g. ion pairing, dihydrogen bonding)
Computational studies have suggested that this term, while
not negligible in magnitude, does not vary significantly across a
selection of intermolecular FLPs (only neutral LAs and LBs were
considered; it is not clear to what extent this conclusion will
hold for charged species).16
For intramolecular systems the
[LA·H]–/[LB·H]
+ pairing term is typically larger, as enthalpically-
favourable ion pairing can be achieved without such a
significant entropic penalty. H2 activation in these systems is
thus generally more favourable than in intermolecular systems
of equivalent LA/LB strength. The magnitude of this additional
stabilisation can be highly variable, and depends on the linker
used (often unpredictably; vide infra). Again, the size of this
term can also be expected to depend appreciably on factors
such as solvent polarity. In particular, apolar solvents may lead
to precipitation of [LB·H]+[LA·H]
– salts; in these cases the ion
pairing term becomes effectively very large, and may provide
the main thermodynamic driving force for H2 activation.
In general, of the five terms outlined above, only two are
expected to vary very significantly upon variation of the FLP:
H+ attachment and H
– attachment. Thus, the thermodynamic
ability of any FLP to activate H2 will critically depend on the
magnitude of these terms, and hence with the combined
‘strength’ of the LB and LA; a conclusion that has been found
to compare very well with experimental results. In particular, it
can be seen that when designing FLP hydrogenation catalysts,
the key measures by which the ‘strength’ of the LB and LA
should be judged are their proton affinity (PA) and hydride ion
affinity (HA), respectively. Experimentally-determined proxies
for PA have been extensively tabulated in the form of pKa
values.17
Importantly, these are often available for a variety of
different solvents (solvation having a significant effect not just
on PA and pKa but also HA; in general, more polar solvents are
expected to render FLP activation of H2 by neutral LA/LB
combinations more favourable, by stabilising the ionic
products relative to the neutral reactants). Experimental
values for HA are unfortunately far less abundant and so
alternative measures of LA strength are often used as
alternatives to aid FLP design (for example the commonly-
employed Gutmann-Beckett method, which uses changes in 31
P chemical shift to probe the strength of binding between
LAs and Et3PO).18
Nevertheless, the relationships between HA
and other measures of abstract ‘Lewis acidity’ or
‘electrophilicity’ are not always trivial and may show very
different sensitivity to other relevant parameters such as steric
bulk (other chemical probes will have different steric profiles
than H–).
19 As such, these values are often most reliable (and
so most useful) as guidelines when comparing structurally-
similar LAs that show variation in positions distant from the
acidic centre, rather than for comparison of more diverse LAs
from different ‘families’. It is also often useful to consider such
values in conjunction with calculated estimates of HA;
fortunately, values for a fairly diverse collection of FLP-
relevant main-group LAs were recently reported by Heiden
and Latham.20
Taken together, PA and HA values afford an invaluable
predictive tool for the design of FLP hydrogenation catalysts.
By comparing the values for prospective FLPs with those of
systems already reported in the literature, it is possible to
anticipate their likely degree of reactivity towards H2. If the
combined PA and HA are very low, then H2 activation will be
highly disfavoured, and successful hydrogenation catalysis is
likely to be infeasible. Conversely, for effective catalysis the
combined PA and HA of the FLP should also not be excessively
high, as this will lead to a very stable and hence unreactive
[LB·H]+[LA·H]
– H2 cleavage product. In such cases either H
+ or
H– transfer (or both) to the substrate will be unfavourable, and
turnover will again be limited. If the reaction mechanism
involves LA activation of the substrate (Fig. 4b) this also
requires that H2 activation be sufficiently reversible to ensure
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the presence of some ‘free’ LA (assuming 1:1 LA:LB
stoichiometry). It should be noted that a number of ‘weak’
FLPs have actually been observed to effect successful catalytic
hydrogenation despite not activating H2 to a sufficient extent
for it to be observed by standard NMR spectroscopic
techniques. In these cases the ability of a FLP to effect
transient, reversible H2 cleavage can often be demonstrated by
admitting HD gas or a mixture of H2 and D2, and observing
isotopic scrambling to form the statistical 2:1:1 mixture of HD,
H2 and D2 (Fig. 7). Thus, B(C6F5)3 has been found to effect
successful catalytic hydrogenation in combination with LBs as
weak as simple ethers (aqueous pKaH < 0).21
In contrast, FLPs
consisting of the same LA and very powerful LBs such as N-
heterocyclic carbenes (NHCs; aqueous pKaH ~ 20-25) have not
yet found use in hydrogenation catalysis, even though they
readily activate H2.22
In this context, it is noteworthy that the
pKa of H2 itself has been experimentally estimated to be
approximately 35 in THF.23
In principle, the LA-free
deprotonation of H2 could be thought of as a conceptual
limiting case for FLP H2 activation, where a very large PA term
is necessary in order to compensate for negligible HA.
In addition to combined PA and HA, it is important that the
PA affinity alone (and, in principle, HA alone) is tailored to
those of the substrate and product (analogous to the
electronic fine-tuning typically required of TM catalysts). As
shown in Fig. 4a, the standard mechanism for FLP-catalysed
hydrogenation requires that the [LB·H]+ intermediate be a
sufficiently strong Brønsted acid to protonate the substrate (or
else activate it appreciably through hydrogen-bonding), which
places an upper limit on the strength of the LB that can be
used. These principles were elegantly illustrated by Paradies
and co-workers during the development of phosphine/B(C6F5)3
FLPs for alkene hydrogenation, where it was found that sub-
optimal rates were obtained when using phosphine LBs that
were either too weak (where disfavourable H2 activation is
rate-limiting) or too strong (where substrate protonation to
form an intermediate carbocation becomes rate-limiting
instead).24
Notably, different optimum LB strengths were
found when the basicity of the substrate was changed,
highlighting the need to tailor LB strength to the specific
substrate under investigation.
The basicity of the substrate is of even more importance in
LA-only catalyst systems, where it is directly involved in H2
activation (Fig. 4c). Typically, this reaction pathway is feasible
for more strongly basic substrates, while less basic analogues
benefit strongly from addition of a stronger auxiliary LB which
can speed H2 activation and act as an intermediate ‘proton
shuttle’.
In some cases it may also be important to consider the
basicity of the intended reaction product. In a particularly
extreme example, Stephan et al. reported that while B(C6F5)3 is
capable of mediating the stoichiometric hydrogenation of
simple anilines to cyclohexylamines, catalytic turnover is
prohibited due to the high basicity of the product (amine pKaH
~ 10 in H2O), which prevents protonation of the much less
basic aromatic substrate (aniline pKaH ~ 5 in H2O; note that
while this value relates to protonation at nitrogen, the initial
site of protonation required for reduction is actually at carbon,
which will be less basic). In effect, the Brønsted acidity is
‘levelled’ to the weak cyclohexylammonium species (Fig. 8a).25
Conversely, Paradies et al. have described a degree of
autocatalysis in certain borane-catalysed imine
hydrogenations.26
This is attributed to the increased basicity of
the product amines, which means that rate-limiting H2
activation becomes more favourable as the reaction proceeds
(Fig. 8b; both of these examples involve LA-only catalysis).
Balancing steric bulk
Perhaps the most obvious variables in the design of FLP
catalysts are the steric bulk of the acidic and basic centres. The
fundamental FLP concept clearly requires that the LA and LB
possess sufficient combined bulk to prevent formation of a
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strong classical adduct. If these functional groups are too small
then mutual quenching will eliminate the ability of the FLP to
engage in the H—H cleavage step that is crucial to catalysis
(even if PA/HA and other factors would otherwise be
favourable, the unfavourable separation term in Fig. 6 will
become insurmountably large). Steric bulk, particularly around
the LA, is also a key factor in determining substrate scope and
functional group tolerance for FLP hydrogenation catalysts.
Soós and co-workers have emphasised the value of the ‘size-
exclusion principle’ in FLP design, where the use of especially
bulky LAs can allow for the effective hydrogenation of less
bulky imine substrates, for example, by limiting unproductive
adduct formation between the LA and product amines.27
Use
of a bulkier LA also means an FLP can be formed using a less
bulky LB (or vice versa).
Nevertheless, is it not simply the case that using bulkier
components will lead to a more active FLP catalyst. Extremely
bulky LAs will lead to similarly bulky [LA·H]– reductants, whose
size can lead to low kinetic reactivity, particularly if the hydride
needs to be transferred to a relatively bulky substrate. In
particularly extreme cases steric bulk may even inhibit H2
activation. For example, while investigating the very hindered
LA MesB(C6F5)2, Soós et al. found that H2 activation was much
slower when using LBs that were also very bulky (e.g. 2,2,6,6-
tetramethylpiperidine), compared to when less hindered LBs
of comparable pKa were employed (e.g. quinuclidine).27
As a
result, and perhaps counterintuitively, it can sometimes be
productive to pursue the use of less bulky LAs, even if this
appears to lead to the formation of a classical LA←LB adduct.
Provided that any such dative interaction is reversible,
transient cleavage can generate the active FLP in situ. In
particular, Lewis pairs that appear to form a strong adduct at
room temperature may dissociate significantly at elevated
temperatures: this has come to be known as ‘thermally-
induced frustration’.28
While the need to separate the LA and
LB provides an additional energetic barrier that must be
overcome prior to H2 activation (the LA←LB separation term in
Fig. 6 in no longer negligible), this is potentially outweighed by
the kinetic advantages of generating a less bulky and more
reactive [LA·H]– reductant (Fig. 9).
Reversible adduct formation can also have significant
implications for the stability of the catalytic Lewis pair. In
particular, the decomposition of highly reactive FLPs may be
suppressed by allowing them to form a reversible adduct. For
example, while investigating the use of NHC LBs in FLP
chemistry, Tamm et al. found that, while an NHC/B(C6F5)3 FLP
undergoes rapid rearrangement to form an unreactive
‘abnormal NHC’ adduct over the course of a few hours at room
temperature, the equivalent less hindered NHC/B(FXyl)3 pair
[FXyl = 3,5-bis(trifluoromethyl)phenyl)] forms a reversible
normal adduct that is stable up to significantly elevated
temperatures, while still retaining its FLP-type reactivity
towards H2 (Fig. 10a).22
Taking the concept of thermally-induced frustration to its
extreme, it can actually be possible for a classical adduct to
display FLP-like reactivity without ever achieving complete
separation of the Lewis pair. Ashley et al. have previously
described how the adduct [iPr3Si←PtBu3]+[B(C6F5)4]
–, which
Fig. 10 Reversible adduct formation can stabilise FLPs against
decomposition, for example in the systems shown in (a). FLP-like
reactivity can also sometimes be observed by Lewis pairs without
even transient separation (b). This can be compared with direct
addition of H2 across certain polar chemical bonds (c; this is
another strategy that has recently been used to achieve TM-free
catalytic hydrogenation).
Fig. 9 A qualitative summary of how catalytic activity can typically
vary as a function of FLP steric bulk, assuming combined HA/PA
and other parameters are suitable for catalysis. The ideal catalyst
must be neither too large nor too small, but the ideal mid-point
will be substrate-dependent.
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does not dissociate to form PtBu3 + [iPr3Si]+[B(C6F5)4]
– even at
high temperature, is nevertheless capable of activating H2 in
an FLP-like manner.29
This is attributed to transient
lengthening and weakening of the Si←P interaction, which
generates a structure analogous to an FLP encounter complex
that is capable of inserting H2. From here, it is possible to see
an analogy between FLP H2 activation and the direct
hydrogenolysis of certain weak or polar chemical bonds, which
has also recently begun to be exploited to develop mild
protocols for TM-free catalytic hydrogenation of alkenes (Fig.
10b,c).30
Choosing between intramolecular, intermolecular and ‘LA-only’
FLPs
As noted previously, tethering the LA and LB together to form
an intramolecular FLP transforms H2 activation from a formally
termolecular into a bimolecular reaction step, which is
expected to have a much lower entropic barrier. As such,
optimised intramolecular FLPs might intuitively be expected to
be superior catalysts than their intermolecular counterparts
(cf. TM catalysts, where the acidic and basic functionalities are
by necessity also localised on a single molecule). Indeed, many
investigations of intramolecular FLPs have appeared to support
this conclusion. For example, in 2008 Erker et al. reported one
of the first such systems: an ethylene-linked P/B system that
showed far greater activity as an imine hydrogenation catalyst
than previous intermolecular P/B FLPs.31
Nevertheless, it is important to acknowledge that the
development of intramolecular FLP catalysts suffers from
some significant drawbacks. In particular, the activity of such
systems is typically highly sensitive to the nature of the linker
used to connect the LA and LB, in a manner that is not easily
predictable. As such Erker et al., expanding on their earlier
work, have shown that P/B FLPs with a variety of simple alkyl
linkers show dramatically different reactivities towards H2.32
For example, in the series of oligo(methylene) linked FLPs
Mes2B(CH2)nP(C6F5)2, the members with n = 2 and n = 4 are
both active hydrogenation catalysts, while the intermediate
member with n = 3 is unreactive towards H2. Similarly, Aldridge
and co-workers have reported that while a dimethylxanthene-
linked P/B FLP readily activates H2 under mild conditions (room
temperature, 1 bar H2), no such activation is observed using an
otherwise identical dibenzofuran-linked system (Fig. 11).33
Such differences in reactivity can be attributed to
thermodynamic changes that arise when using different linkers
(for example if the resulting ‘H+’ and ‘H
–’ moieties are held too
far apart for effective ionic stabilisation) or, in other cases, to
kinetic factors that relate to the ease with which different
intramolecular FLPs are able to preorganise themselves into a
conformation suitable for H2 activation. In extreme cases, if no
such conformation is energetically accessible, then formally
intramolecular FLPs may in fact only activate H2 in an
intermolecular fashion, as is the case for the original, rigid
systems reported by Stephan et al. (see Fig. 2a).34
Further complicating the design of intramolecular FLPs, the
choice of linker will also directly impact both the steric and
electronic properties of the attached LA and LB centres, which
can lead to difficulties in their rational fine-tuning.
Intramolecular FLPs also typically require longer, more
demanding synthetic routes for their preparation than
unlinked LAs and LBs (of which many of the most commonly
used are commercially available). Thus, the expectation that
intramolecular FLPs might ultimately provide superior catalysis
must be balanced against the much greater ease and speed
with which intermolecular catalysts can be developed (note
that translating a successful intermolecular catalyst into an
intramolecular analogue is also not necessarily trivial, for
similar reasons). In particular, intermolecular FLPs lend
themselves very well to screening efforts that can rapidly
identify promising catalytic leads (especially valuable when the
optimum catalyst is highly substrate-dependent). By contrast,
even a rather modest screen of five acidic and five basic
moieties would require the synthesis of 50 separate
intramolecular FLPs, even if only two possible linkers were
investigated. Mechanistic investigations are also often simpler
using intermolecular systems, for similar reasons, as it is
easier to synthesise possible intermediates, or to exclude
either the acidic or basic component (cf. Fig 5; for an
intramolecular system these investigations would require the
further synthesis of separate monofunctional model
compounds).
The advantages enjoyed by intermolecular FLPs are even
more apparent in the ‘LA-only’ catalytic systems discussed
previously, where only one reaction component needs to be
varied and the overall reaction mixture is significantly
simplified. For example, the groups of Stephan and Crudden
have shown how simple screening studies can be used to
rapidly optimise the structure of borenium LAs for imine
hydrogenation catalysis.35,36
Again, however, this advantage
must be weighed against the expectation that, with fewer
variables available for optimisation, the best LA-only system
may be less effective than the best inter- or intramolecular
equivalent. As an example, it has been reported that, while
hydrogenation of weakly-basic imines such as PhCH=NSO2Ph
can proceed using B(C6F5)3 as the sole catalyst, greatly
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improved rates can be achieved upon addition of P(Mes)3 as a
co-catalytic LB.37
Understanding and controlling inhibition and decomposition
pathways
Just as important as designing an FLP that will be able to
perform all the component steps of a catalytic cycle (H2
activation; H+ and H
– transfer) is ensuring that the potential
catalyst can avoid any irreversible inhibition or decomposition
steps that might hinder catalysis. Several general
considerations have already been mentioned in earlier
sections with respect to catalyst inhibition. For example, steric
tuning can be used to avoid adduct formation between the
LA/LB and any other basic or acidic functional groups present,
while reversible adduct formation can be exploited to help
stabilise overly reactive FLPs.
A large number of chemical bonds aside from H—H are
known to be susceptible to cleavage by FLPs, which can lead to
quenching of the LA and LB. As such, if any of these
functionalities are present in the substrate and/or product
then efforts should be made to minimise the reactivity of the
FLP towards them. In practice, given the overwhelming
reliance of FLP hydrogenation catalysis on boron-based LAs
and early p-block LBs, reducing reactivity towards other
functional groups without a concomitant reduction in
reactivity towards H2 is not always easy, and may require the
use of less typical FLP components. An example of this will be
discussed in the case study at the end of this review.
Inevitably, relevant decomposition routes will be highly
dependent on the precise system under study. Nevertheless,
because most of the FLP hydrogenation catalysts reported to
date are based on bulky, electrophilic fluoroaryl-substituted
boranes it is worth specifically considering the decomposition
of these compounds, which typically involves loss of an aryl
group to an electrophile (Fig. 12a). A specific example is the
decomposition of the ubiquitous B(C6F5)3 in the presence of
simple alcohols (or H2O) which is believed to occur via initial
coordination to form ROH→B(C6F5)3 adducts in which the O—H
has been dramatically acidified, prompting intramolecular
protodeborylation (Fig. 12b; note that the decomposition
products ROBAr2 have much lower HAs, so are considerably
less likely to activate H2 than the initial BAr3).38,39
In general,
aryl group transfer of this type should be particularly facile
from anionic, 4-coordinate borate intermediates. Any catalytic
protocol that involves a build-up of such intermediates in the
presence of a suitable electrophile (which may simply be more
of the initial borane LA, leading to sequestration of a second
equivalent of borane in the form of a BAr4– anion) is therefore
likely to be particularly susceptible to decomposition,
particularly if the reaction is required to run at significantly
elevated temperatures.
Case study: C=O hydrogenation and moisture tolerance
Over the past several years we have focused on the
development of some of the first FLP systems capable of
catalysing the hydrogenation of aldehydes and ketones, and of
moisture-tolerant FLP hydrogenation catalysis. In this section
we will discuss the rational development of these systems in
order to illustrate the use of the principles that have been
outlined so far (and which are summarised in the learning
points listed at the start of this review).
The first goal of our work was to develop a protocol for
FLP-catalysed hydrogenation of aldehydes and ketones to
alcohols, which had not previously been reported. Based on
the principles outlined above it was possible to identify the
following key factors:
The standard mechanism for FLP-catalysed hydrogenation
requires protonation of the substrate prior to H– transfer.
Because organic carbonyls are very poor bases (aqueous pKa
< 0), this suggests the LB employed in the FLP must also be
very weak. This in turn means a LA with fairly high HA will
be necessary so that H2 activation is feasible.
Unlike isoelectronic imines and amines, organic carbonyls
and alcohols lack steric bulk around their Lewis basic
oxygen atoms, which suggests that relatively bulky LAs
might be desirable to avoid inhibitory product→LA and
substrate→LA adduct formation. Conversely, however,
these neutral oxygen bases are much weaker donors than
their nitrogen-based counterparts, which could mitigate this
issue, and overly bulky [LA·H]– anions might lead to slow
hydride transfer. It therefore seemed sensible to investigate
LAs with a range of steric profiles.
The use of ‘LA-only’ systems for stoichiometric carbonyl
hydrogenation had been reported previously, using B(C6F5)3
as the catalyst.38
These investigations had confirmed that
direct H2 activation using the substrate as LB is feasible;
however, decomposition of the borane under these highly
acidic conditions meant that turnover could not be
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observed. It seemed likely that a stronger auxiliary LB might
lead both to improved H2 activation kinetics, and to more
stable Brønsted acidic intermediates. It was also speculated
that further improvements in stability might be observed
for a system with ‘thermally induced frustration’. Because
the desired reactivity lacks precedent, the initial goal was to
obtain a system that is catalytically competent, prior to full
optimisation. It therefore seemed sensible to investigate
intermolecular rather than intramolecular systems.
Though some FLPs are known to activate C=O bonds, it was
judged that the most significant inhibitory side-reaction was
likely to be activation of the product O—H bonds, as
previous borane-based FLPs had been reported to be very
sensitive to inhibition by hydroxylic species, including
alcohols.37
While this had typically been attributed in
general terms to the oxophilicity of boron, a closer analysis
of the literature suggested that the more specific problem
relates to irreversible deprotonation of the highly Brønsted
acidic borane-alcohol adduct (aqueous pKa < 0; Fig. 13).39
Developing boron-based FLP catalysts40
Based on the above considerations, and given the well-
established utility of highly electrophilic triarylborane LAs in
FLP hydrogenation catalysis, it was decided to begin
investigations by examining the boranes B(C6Cl5)n(C6F5)3-n (n =
0-3) whose chemistry we had investigated previously, and with
which we were therefore familiar.41
These also satisfied the
requirement of having large HAs and a range of different steric
bulk. To begin with, preliminary mechanistic investigations
were carried out in which pre-formed [Bu4N]+[HBAr3]
– salts
were reacted with a model substrate (acetone). These
confirmed that direct reactions of [HBAr3]– with the substrate,
either alone or in the presence of additional BAr3, were
unlikely to be feasible mechanistic steps (cf. Fig. 5). Thus,
catalytic hydrogenation would have to proceed via the
standard mechanism (Fig. 4a), which involves protonation of
the substrate. It was therefore decided to combine the initial
borane LAs with simple ethers as LBs (aqueous pKaH < 0; Fig.
14). The use of such weak bases should ensure that substrate
activation through protonation or hydrogen-bonding is
feasible, while also preventing irreversible deprotonation of
any ROH→BAr3 adducts (cf. Fig. 13). Reversible coordination
between the ethers and boranes might also reduce any
tendency towards decomposition (e.g. via alcoholysis; cf. Fig.
12b). Furthermore, combinations of this type had previously
been shown to be effective in the hydrogenation of other
weakly-basic substrates.41
Finally, because these LBs are
cheaply commercially available they are well-suited towards
catalyst screening efforts, and because they can be used as
solvents the entropic penalty faced by intermolecular FLPs
when activating H2 can be minimised.
The system chosen for initial investigation was the
B(C6Cl5)(C6F5)2/THF Lewis pair; previously studies had shown
that adduct formation in this system is highly reversible,
leading to effective catalysis in the hydrogenation of other
substrates.41
As hoped, this system was also able to achieve
successful catalysis in the hydrogenation of a model ketone
(acetone), but turnover in the reaction was unexpectedly
limited due to side-reactions of the product alcohol.
Fortunately, subsequent screening (made simple by the
decision to pursue an intermolecular system) was able to
rapidly identify commercially-available B(C6F5)3 and 1,4-
dioxane solvent as a superior protocol that avoids this issue.42
Having confirmed that catalytic systems of this type are
capable of tolerating simple alcohols, it was realised that
similar systems might also be tolerant of another significant
hydroxylic inhibitor of FLP catalysis: H2O (low air and moisture
tolerance have typically been severe limitations of early FLP
catalysis). This was quickly confirmed, although reactions were
observed to be significantly slower than under strictly
anhydrous conditions, which necessitated the use of increased
H2 pressures.43
Indeed, closer inspection of both the ‘wet’ and
anhydrous reactions suggested that, despite their apparent
tolerance, activation of O—H bonds remains a significant
limiting factor in the rates of these reactions (as indicated, for
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example, by 11
B NMR spectroscopy), even in the absence of
any very strong bases. Note that increased temperatures could
not be used to increase reaction rate as significant
hydrolysis/alcoholysis of the borane was observed in these
cases, consistent with the previously-anticipated
decomposition route.
The switch to Sn-based FLP catalysis44
Development of the borane-based systems described above
had emphasised the importance of O—H cleavage as a
mechanism for inhibition of the FLP catalyst. Because boron is
particularly oxophilic, even moderately strong LBs will cause
this reaction to be irreversible when using borane LAs. This
severely limits the scope of the ‘OH-tolerant’ reactions that
had been developed, as neither the substrates nor products
can contain any appreciably basic functional groups (Fig. 15).
The use of very weak LBs also leads to the formation of very
powerful [LB·H]+ Brønsted acids after H2 cleavage, which
means that highly acid-sensitive functional groups also have to
be avoided.
In order to overcome these limitations and develop
protocols that include and tolerate stronger Lewis bases the
following further key factors were identified:
To minimise the problem of unproductive RO—H activation,
LAs should be incorporated that bind more weakly to –OR
moieties. However, in order to maintain the ability of the
FLP to activate H2, the HA of the LA must be preserved. In
other words, a LA is needed that is relatively less oxophilic,
but still hydridophilic.
The presence of stronger LBs will prevent protonation of
much more weakly basic substrates such as aldehydes and
ketones. Hydrogenation of such compounds is therefore
likely to require an atypical reaction mechanism, such as
activation of the substrate by the LA rather than H+ (Fig.
4b).
Based on this analysis, subsequent work was directed towards
investigating the use of previously-unexplored R3SnOTf LAs (R
= alkyl; these are surrogates for [R3Sn]+ cations, which are
valence isoelectronic with BAr3), in combination with typical
nitrogen LBs. Inspection of the literature indicated that these
acids should be significantly less oxophilic than boranes of
similar HA (such as B(C6F5)3),20
as indicated by the aqueous
pKa values of the respective LA·OH2 adducts (< 0 for B(C6F5)3
versus ~6 for [Bu3Sn]+; note that this is a specific example
where it is important to consider a measure of LA strength
other than just HA). In addition, R3SnOTf-catalysed addition of
R3SnH (which is generated following H2 activation by R3SnOTf-
based FLPs) to aldehydes and ketones is well established,
which suggested that the necessary atypical reaction
mechanism should be feasible (simple mechanistic
investigations were again performed to confirm this).
Gratifyingly, an optimised FLP consisting of iPr3SnOTf and
2,4,6-collidine was found to be capable not only of activating
H2, but also of both hydrogenating aldehydes and ketones and
performing hydrogenation catalysis in the presence of
moisture, despite the presence of fairly strong Brønsted
bases.
Conclusions and future outlook
Despite the enormous advances that have been made in field
of FLP catalysis in the decade since it was established, there
remains significant scope for further development. It is our
hope that the principles outlined in this review may provide a
useful framework for this ongoing work.
While the systems reported to date have provided a
dramatic proof-of-principle for TM-free catalytic
hydrogenation, it would be hard to argue that any of these
reactions yet constitutes a truly attractive synthetic tool. If
FLPs are eventually to take their place alongside TM complexes
as practical hydrogenation catalysts then future work must
increasingly be focused on ensuring broad functional group
tolerance, ‘open bench’ stability and well-defined
chemoselectivity, alongside optimised reactivity. In this vein, it
has been encouraging to see recent reports focusing on the
development of catalytic protocols that can achieve high
enantioselectivity,45
that use very low catalyst loadings,35
or
that catalyse reactions for which there is no existing TM-
catalysed alternative.46
Based on our own experiences with Sn-based systems, we
would suggest that achieving the above goals may require a
willingness to investigate a broader range of LAs and LBs than
have currently been investigated.47
In particular, s-block, late
p-block, and cheap d-block LAs all remain relatively unexplored
for applications in catalytic FLP chemistry. Detailed
experimental investigations into the kinetics and mechanisms
of most FLP-catalysed hydrogenation reactions are also still
needed, to provide the theoretical basis for rational future
development. Finally, it may be possible that FLP H2 activation
could find application in areas other than chemical
hydrogenation catalysis. Plausible examples include reversible
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hydrogen storage using very low molecular-weight FLPs, and
electrocatalytic H2 oxidation reactions for use in hydrogen fuel
cell applications.48
Acknowledgements
We would like to thank GreenCatEng, Eli Lilly (Pharmacat
consortium) and the EPSRC for providing funding (D. J. S.) and
the Royal Society for a University Research Fellowship (A. E.
A.).
Notes and references
1 For an excellent summary of this area, see P. P. Power, Nature, 2010, 464, 171. See also cited and citing references.
2 G. D. Frey, V. Lavallo, B. Donnadieu, W. W. Schoeller and G. Bertrand, Science, 2007, 316, 439.
3 G. C. Welch, R. R. S. Juan, J. D. Masuda and D. W. Stephan, Science, 2006, 314, 1124.
4 G. C. Welch and D. W. Stephan, J. Am. Chem. Soc., 2007, 129, 1880.
5 G. C. Welch, L. Cabrera, P. A. Chase, E. Hollink, J. D. Masuda, P. Wei and D. W. Stephan, Dalton Trans., 2007, 3407.
6 The field of FLP chemistry has seen a number of broad summaries in recent years. See, for example, D. W. Stephan, Science, 2016, 354, 1248, and references therein.
7 An alternative, electric-field-based model was also proposed, but has largely fallen out of favour and is not regularly invoked. See, for example, T. A. Rokob, I. Bakó, A. Stirling, A. Hamza and I. Pápai, J. Am. Chem. Soc., 2013, 135, 4425.
8 P. A. Chase and D. W. Stephan, Angew. Chem. Int. Ed., 2008, 47, 7433.
9 See W. E. Piers, A. J. V. Marwitz and L. G. Mercier, Inorg. Chem., 2011, 50, 12252, and references therein.
10 J. R. Khusnutdinova and D. Milstein, Angew. Chem. Int. Ed., 2015, 54, 12236.
11 K. K. Ghuman, L. B. Hoch, T. E. Wood, C. Mims, C. V. Singh and G. A. Ozin, ACS Catal., 2016, 6, 5764.
12 See A. Berkessel, T. J. S. Schubert and T. N. Müller, J. Am. Chem. Soc., 2002, 124, 8693, and references therein.
13 For a recent review, see R. H. Morris, Chem. Rev., 2016, 116, 8588.
14 T. A. Rokob, A. Hamza, A. Stirling, T. Soós and I. Pápai, Angew. Chem. Int. Ed., 2008, 47, 2435.
15 L. Rocchigiani, G. Ciancaleoni, C. Zuccaccia and A. Macchioni, J. Am. Chem. Soc., 2014, 136, 112.
16 T. A. Rokob, A. Hamza and I. Pápai, J. Am. Chem. Soc., 2009, 131, 10701.
17 See, for example: F. G. Bordwell, Acc. Chem. Res., 1988, 21, 456 and cited and citing references. Note that where pKa values are given in this review, they have typically been taken from the related cited work (or references therein).
18 M. A. Beckett, G. C. Strickland, J. R. Holland and K. Sukumar Varma, Polymer, 2996, 37, 4629.
19 See, for example: A. E. Ashley, T. J. Herrington, G. G. Wildgoose, H. Zaher, A. L. Thompson, N. H. Rees, T. Krämer and D. O’Hare, J. Am. Chem. Soc., 2011, 133, 14727; or É. Dorkó, B. Kótai, T. Földes, Á. Gyömöre, I. Pápai and T. Soós, J. Organomet. Chem., 2017, doi: 10.1016/j.jorganchem.2017.04.031.
20 Z. M. Heiden and A. P. Latham, Organometallics, 2015, 34, 1818.
21 L. J. Hounjet, C. Bannwarth, C. N. Garon, C. B. Caputo, S. Grimme and D. W. Stephan, Angew. Chem. Int. Ed., 2013, 52, 7492.
22 See E. L. Kolychev, T. Bannenberg, M. Freytag, C. G. Daniliuc, P. G. Jones and M. Tamm, Chem. Eur. J., 2012, 18, 16938, and references therein.
23 See E. Buncel and B. Menon, J. Am. Chem. Soc., 1977, 99, 4457, and references therein.
24 See L. Greb, S. Tussing, B. Schirmer, P. Ona-Burgos, K. Kaupmees, M. Lokov, I. Leito, S. Grimme and J. Paradies, Chem. Sci., 2013, 4, 2788, and references therein.
25 T. Mahdi, Z. M. Heiden, S. Grimme and D. W. Stephan, J. Am. Chem. Soc., 2012, 134, 4088.
26 See S. Tussing, K. Kaupmees and J. Paradies, Chem. Eur. J., 2016, 22, 7422, and references therein.
27 See T. Soós, Pure Appl. Chem., 2011, 83, 667, and references therein.
28 T. A. Rokob, A. Hamza, A. Stirling and I. Pápai, J. Am. Chem. Soc., 2009, 131, 2029.
29 T. J. Herrington, B. J. Ward, L. R. Doyle, J. McDermott, A. J. P. White, P. A. Hunt and A. E. Ashley, Chem. Commun., 2014, 50, 12753.
30 See, for example, Y. Wang, W. Chen, Z. Lu, Z. H. Li and H. Wang, Angew. Chem. Int. Ed., 2013, 52, 7496.
31 P. Spies, S. Schwendemann, S. Lange, G. Kehr, R. Fröhlich and G. Erker, Angew. Chem. Int. Ed., 2008, 47, 7543.
32 See T. Özgün, K.-Y. Ye, C. G. Daniliuc, B. Wibbeling, L. Liu, S. Grimme, G. Kehr and G, Erker, Chem. Eur. J., 2016, 22, 5988, and references therein.
33 Z. Mo, E. L. Kolychev, A. Rit, J. Campos, H. Niu and S. Aldridge, J. Am. Chem. Soc., 2015, 137, 12227.
34 Y. Guo and S. Li, Inorg. Chem., 2008, 47, 6212. 35 J. M. Farrell, R. T. Posaratnanathan and D. W. Stephan,
Chem. Sci., 2015, 6, 2010. 36 P. Eisenberger, B. P. Bestvater, E. C. Keske and C. M.
Crudden, Angew. Chem. Int. Ed., 2015, 54, 2467. 37 See, for example, D. W. Stephan, S. Greenberg, T. W.
Graham, P. Chase, J. J. Hastie, S. J. Geier, J. M. Farrell, C. C. Brown, Z. M. Heiden, G. C. Welch and M. Ullrich, Inorg. Chem., 2011, 50, 12338, and references therein.
38 See L. E. Longobardi, C. Tang and D. W. Stephan, Dalton Trans., 2014, 43, 15723, and references therein.
39 C. Bergquist, B. M. Bridgewater, C. J. Harlan, J. R. Norton, R. A. Friesner and . Parkin, J. Am. Chem. Soc., 2000, 122, 10581.
40 In parallel with our own work described in this case study, very similar boron-based systems that address the same issues were independently developed by the groups of Stephan and Soós, and published near-simultaneously. See T. Mahdi and D. W. Stephan, J. Am. Chem. Soc., 2014, 136, 15809; and Á. Gyömöre, M. Bakos, T. Földes, I. Pápai, A. Domján and T. Soós, ACS Catal., 2015, 5, 5366.
41 See D. J. Scott, M. J. Fuchter and A. E. Ashley, Angew. Chem. Int. Ed., 2014, 53, 10218, and references therein.
42 D. J. Scott, M. J. Fuchter and A. E. Ashley, J. Am. Chem. Soc., 2014, 136, 15813.
43 D. J. Scott, T. R. Simmons, E. J. Lawrence, G. G. Wildgoose, M. J. Fuchter and A. E. Ashley, ACS Catal., 2015, 5, 5540.
44 D. J. Scott, N. A. Phillips, J. S. Sapsford, A. C. Deacy, M. J. Fuchter and A. E. Ashley, Angew. Chem. Int. Ed., 2016, 55, 14738.
45 For a recent review of enantioselective FLP-catalysed hydrogenation, see J. Paradies, Chiral Borane-Based Lewis Acids for Metal Free Hydrogenations, Top. Curr. Chem., Springer GmbH, Berlin, 2017, pp 1-24.
46 S. Wei and H. Du, J. Am. Chem. Soc., 2014, 136, 12261. 47 For a review of less standard main-group LAs in FLP
chemistry, see S. A. Weicker and D. W. Stephan, Bull. Chem. Soc. Jpn., 2015, 88, 1003.
48 See, for example, E. J. Lawrence, V. S. Oganesyan, D. L. Hughes, A. E. Ashley and G. G. Wildgoose, J. Am. Chem. Soc., 2014, 136, 6031.