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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.

Journal Name ARTICLE

This journal is © The Royal Society of Chemistry 20xx J. Name., 2013, 00, 1-3 | 3



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





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.





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





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





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.





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





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





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





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





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.

chem soc rev - imperial college london · 2018. 7. 10. · borane), this means that flps are...

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