MSc Chemistry
Literature Thesis
Ortho-Phenylene-Bridged Frustrated Lewis Pairs
An overview
by
Michael van den Brink
1016446401 August 2016
Research Institute Supervisor
Department of Chemistry F. Holtrop MSc
Research group Examiner
2
1. List of abbreviations
BBN Borabicyclononane BuLi Butyllithium C6F5 Pentafluorophenyl Cy CyclohexaneDFT Density Functional Theory
DMAP Dimethylaminopyridine
duryl 2,3,5,6- tetramethylphenyl
ee Enantiomeric excess
FLP Frustrated Lewis pair
Flu Fluorene
IDipp 1,3-bis(diisopropylphenyl)imidazol-2-ylidene
ItBu 1,3-bis(t-butyl)imidazol-2-ylidene
LA Lewis acid
LB Lewis base
LDA Lithium diisopropylamide
ma Maleic anhydride
Mes Mesityl
MTBE Methyl tert-butyl ether
nbd 2,5-norboranediene
NHC N-heterocyclic carbene
NMR Nuclear Magnetic Resonance
Ph Phenyl
TEMPO (2,2,6,6-tetramethylpiperidin-1-yl)oxyl
TMEDA Tetrametylethylenediamine
TMP 2,2,6,6-tetramethylpiperidine
TOF Turnover frequency
TON Turnover number
3
2. Abstract
Ortho-phenylene-bridged frustrated Lewis pairs (FLPs) are a separate class in the field
of intramolecular FLPs. Their syntheses and applications have been studied based on the Lewis bases nitrogen and phosphorus. Most syntheses are based on a lithiation followed by borylation of the phenylene linker. These aminoborane/phosphinoborane FLPs are used in various applications. They can coordinate to gold and palladium to form complexes. Furthermore, small molecules as molecular hydrogen, molecular oxygen, CO2
and azides can be activated and used in catalysis by these systems. Hydrogenation of alkynes and CO2 has been reported with good conversions and yields. Even asymmetric
hydrogenation of enamines and imines is known with an ee of 37%. A lot of topics have not been explored yet, as there are no known examples of aluminium-based o-phenylene-bridged FLPs. In addition, coordination to first-row transition metals, activation of small molecules as CO, NO and SO2 and catalytic reactions involving these
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3. Table of contents
1. List of abbreviations 2 2. Abstract 3 3. Table of contents 4 4. Introduction 54.1. Inter versus intramolecular 6
4.2. Frustrated Lewis pairs 8
4.3. Phenylene-bridged frustrated Lewis pairs 12
5. Synthesis 13
5.1. Synthesis of nitrogen-based Lewis pairs 13
5.2. Synthesis of phosphorus-based Lewis pairs 17
6. Applications 21
6.1. Transition metal coordination 23
6.2. Small molecule activation 23
6.2.1. Molecular hydrogen 23 6.2.2. (Hydrogen) fluoride 27 6.2.3. Molecular oxygen 27 6.2.4. Carbon dioxide 28 6.2.5. Azides 29 6.3. (Organo)catalysis 30
6.3.1. Hydrogenation of carbon dioxide 30
6.3.2. Hydrogenation of imine/enamine compounds 34
6.3.3. Alkyne hydrogenation 36 6.3.4. C-C bond formation 39 6.3.5. C-H activation 40 7. Future prospects 42 8. Conclusion 45 9. References 47 10. Acknowledgements 52
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4. Introduction
One of the first records on catalytic activity was in 1823 when Pierre Dulong found a pattern in several metals when used for the decomposition of ammonia.1 Since that
moment catalysts have become one of the most important components in industrial processes. Over the years catalysts became more complex, using rare transition metals as palladium, platinum and ruthenium as their centre, surrounded by ligands. These developments increased the efficiency of processes as well making reactions possible that seemed impossible.
The downside to this success is that we are rapidly depleting the natural supply of the rare transition metals, a problem that is not easily resolved. One of the solutions is to work with abundant first-row transition metals as iron or nickel, while another solution is to use no metal centres at all, which is called organocatalysis. In order to make organocatalysis effective you need both a Lewis acid and a Lewis base in the catalyst: something that is present in normal catalytic systems where the metal centre is the Lewis acid and the ligands act as a Lewis base.2 One of the interesting techniques
uses frustrated Lewis pairs (FLPs), where the Lewis acid and the Lewis base are unable to react with each other.
The technique of FLPs is based on a combination of Z-type ligands and L-type ligands. As is shown in Scheme 1, there are several ways to describe a ligand: L, X and Z, where the Z-type ligand is a two electron acceptor.3 A Lewis acid is such a Z-type ligand
and can coordinate unsupported towards for example a metal centre, and supported, where an L-type ligand also coordinates to the same centre to create a bidentate coordination.
Scheme 1 Various types of metal-ligand interactions, including L-Z ligands
An intermolecular FLP coordinated to a transition metal consists of two
unsupported ligands, whereas an intramolecular FLP is one supported ligand, also called ambiphilic ligand, which is the combination of two opposites into one molecule. Besides
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being able to form complexes with metal centres, FLPs are mostly interesting as organocatalysts, which is discussed in Chapter 6.3.
4.1. Inter versus intramolecular
As has been mentioned before there are two different types of FLPs: intermolecular and intramolecular. The systems of Stephan et al.4,5 are intermolecular Lewis pairs: two
separate molecules form a complex based on the chemical attraction of a Lewis acid and a Lewis base. The other systems on the other hand are intramolecular: both the Lewis acid as the Lewis base is present in the same molecule. Table 1 shows the advantages and disadvantages of both inter- and intramolecular systems, divided into five categories: collision dependency, kinetics, lifetime, reaction site and synthesis.
Table 1 Advantages and disadvantages of both inter- and intramolecular FLPs
Intermolecular Intramolecular
Three molecules Collision dependency Two molecules
More difficult Kinetics Easier
Self-repair Lifetime No self-repair
Diffusion controlled Reaction site Pre-organised
Easier Synthesis Extra coupling step
Table 1 shows that an intramolecular system has the advantage of only depending on two molecules, namely the catalyst and the substrate, colliding for any reaction to occur instead of three molecules with an intermolecular system. In addition, a kinetic analysis of the system is expected to be more facile as fewer components are involved in the reaction. Such an analysis can provide valuable information on the mechanism, which can lead to a more thorough understanding and further improvement of the system. Intermolecular systems can, in theory, have a self-repair mechanism as the FLP consists of two separate components. If one of these components, for example the Lewis base, becomes inactive another Lewis base can replace it in the active catalyst. This construction can also shorten the synthetic route, because an extra step is required to couple the Lewis acid and Lewis base. The most important feature is the catalytic reactivity, which can be better controlled in intramolecular systems. The reaction site is pre-organised, controlling the binding of the substrate and possibly enhancing the
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reactivity. This is less controlled with intermolecular systems, as they consist of two components.
Intermolecular FLPs have different types of coordination: direct or indirect. When the Lewis acid and the Lewis base are connected in an adduct-fashion (Scheme 5b) this is called direct coordination, whereas indirect coordination happens when the Lewis base coordinates with one of the substituents of the Lewis acid, for example the fluorinated phenyl in Scheme 5a. For intramolecular FLPs there are four possible coordination modes that are different in the way the acceptor, the Lewis acid, interacts with the metal, as depicted in Scheme 2.6
Scheme 2 Possible coordination modes of an ambiphilic ligand. Information below the modes is based on the interactions of the LA (LA: Lewis acid and LB: Lewis base)
Besides interaction with a metal and the ligand(s) it is also possible to observe interaction between the Lewis acid and the Lewis base. Balueva et al. proposed three possible interactions between the Lewis acid and the Lewis base (Scheme 3): a shift in electron density (a), intramolecular interactions of phosphorus and boron (b) or intermolecular P→B interactions (c).7 Electron density shift seemed unlikely due to the
π-system of the phenyl, whereas molecular interactions were not viable either due to the distorted bond angles of boron and phosphorus. This left intermolecular interactions as the most sensible solution at that time.
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Scheme 4 gives an overview of the various bridging molecules and conformations of FLPs, including (dimeric) methylene (a, b, h and j)8–14, ethylene and longer,
sometimes cyclised, carbon chains (c, d and e)15–17, N-heterocyclic carbenes (NHCs,
f)18,19 and fluorinated benzene (i)4. Although this is not a bridging molecule, k5 is
mentioned at the bottom of the main scheme as it will be discussed with the other FLPs later on.
Scheme 4 An overview of frustrated Lewis pair bridges and conformations
4.2. Frustrated Lewis pairs
The interest for FLPs increased in 2006 when Stephan et al. described the first non-transition metal system that is able to react in a reversible fashion with hydrogen (Scheme 5a).4 The system binds only 0.25 weight % of H2, which is a very low
percentage, but it showed early capabilities of FLP systems in activating small molecules, starting a new type of chemistry.
A next step was to explore the reactivity of FLPs based on Scheme 5a which led to the study of Stephan et al. towards the formation of [R3PH][HB(C6F5)3] (Scheme 5b).5
Unlike the intramolecular system there was no adduct formation observed due to the steric nature of the phosphines and boranes that prohibit substitution at the para position as seen in Scheme 5a and therefore it was surprising that hydrogen uptake was
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detected. However, the hydrogen could not be released upon aggressive heating in toluene.5 This led to the assumption that an optimal combination of both acidity/basicity
and steric factors is needed for reversible hydrogen activation.20
Scheme 5 Frustrated Lewis pairs (de)activating molecular hydrogen
Erker et al. explored bridging molecules for intramolecular FLPs by synthesising the ethylene analogue 1 (Scheme 6).21 It was shown that this compound exists in
equilibrium between a four-membered heterocycle and the open form, which can react with molecular hydrogen to yield zwitterion 2. Benzaldehyde can react with this H2-FLP
2, demonstrating that FLPs can be used for hydrogenation. An important feature of the
system reported by Erker et al.21 is that there is an alterable bridge between the Lewis
acid and the Lewis base, giving the opportunity towards variations on this system, for example elongating the alkyl chain. However this is not easily achieved.15,16 In addition,
1 is one of the most active FLPs reported to date for molecular hydrogen cleavage, being
able to reach full conversion when hydrogenating alkynes en imines within hours at mild conditions.17,22
Scheme 6 Four-membered heterocyclic FLP adduct as reported by Erker et al.
On the topic of C2-bridges there is a recent paper of Erker et al.
focusing on a methylene side group, which combines the properties of saturated and unsaturated C2-bridges as the double bond is
located outside of the C2-basis of the linker that bears both a sp2 and a
sp3 carbon centre.17 This should give both the stability of the ethene
Figure 1 Ethylene-bridged FLP with a methylene side group
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linker as the rotational freedom of the ethane linker.
Lammertsma et al. focused on geminal P/Al-based FLPs which can be formed by reacting functionalised alkynes with aluminium hydrides (Scheme 7).8 The
Z-configuration that is expected by hydroalumination due to the polarised alkyne bond has been confirmed by X-ray crystallography. Also, no P-Al interaction was observed in the monomeric species 3 on the left of Scheme 7, which can be related to formation of a strained three-membered ring. Several types of molecules have successfully been activated by using 3 such as alkynes8, ammonia, ammonia-borane adducts, borane
itself9, carbonyl compounds10 and metal hydrides.14 In addition, the dimeric compound
with just the simple methylene bridge (Scheme 7, 4) has shown reactivity towards carbon dioxide.11 The dimeric species form when the steric hindrance of the linker is
minimal, such as the methylene bridge in 4. 3 has a substituted linker that has as consequence that no dimeric species can be formed.
Scheme 7 P/Al-based FLP chemistry performed by Lammertsma et al.
Yu et al. reported the hydroboration of a P-enyne with Piers’ borane, yielding a P/B geminal FLP that underwent rapid intramolecular ring closure due to conjugated double bonds.12 Also, Wagner et al. reported on the first and highly reactive geminal P/B
FLP for C-halogen bond activation.13 During the synthesis a ring formation was
observed, yielding the five-membered heterocycle 5 shown in Scheme 8, effectively deactivating the FLP properties at both the boron and the phosphorus. As this was an unwanted reaction, different substituents were used to avoid this ring formation as is shown in Scheme 8, where the change from -C6F5 to –xyl allowed for the synthesis of the
11
Scheme 8 Formation of P/B FLP reported by Wagner et al. (A: conventional method and B: newly designed method)
The final FLP discussed here is a NHC and a coupled Lewis acid as reported by Stephan et al. in 2008.19 Reaction of the NHC-IDipp with B(C6F5)3 resulted in the
FLP-adduct 7 shown in Scheme 9, which was not reactive towards molecular hydrogen. On the left side of Scheme 9 the unsuccessful reaction of the NHC ItBu with B(C6F5)3 is
displayed. However after treatment with molecular hydrogen the intermolecular FLP 8 was observed having activated molecular hydrogen, which can be used in the catalytic cleavage of N-H bonds to form aminoboranes. This proves that the NHCs can also be used in FLP chemistry.
12
4.3. Ortho-phenylene-bridged frustrated Lewis pairs
Almost all bridging molecules and other types of FLPs have been discussed, except the o-phenylene-bridge, which is the main focus of this overview. O-phenylene-bridged FLPs have the advantage that they are not saturated through intramolecular boron-nitrogen bond formation, although sometimes interaction between those centres is observed. In addition, the distance between the amino and borane moieties is not too large, which is especially important for small molecule activation as the reactive centres (Lewis acid/base) need to be in close proximity.23
The first o-phenylene bridged compound was reported in 1959 when Wittig et al. showed the then surprising synthesis of the o-phenylene bridged FLP-like compound 9 depicted in Figure 2.24 The
initial plan was to form an adduct of PPh3 and BPh3 using a Grignard
reagent in presence of o-F-(C6H4Br), but the observed product was
o-PPh3(C6H4BPh3). This was the result of huge steric effects that prohibited the direct
adduct formation of phosphorus to boron or the para position on one of the phenyl-substituents as we saw earlier.25
The goal of this report is to give an overview of the known literature for
o-phenylene-bridged FLPs, with FLP combinations P/B, P/Al, N/B and N/Al (Scheme
10). First the syntheses of these compounds will be discussed listed on their Lewis base: phosphorus and nitrogen. This will be followed by their applications in transition-metal coordination, small molecule activation and (organo)catalysis. This report will conclude with an outlook of FLP chemistry that will include suggestions for follow-up research.
Scheme 10 Discussed o-phenylene bridged frustrated Lewis pairs
Figure 2 FLP-like compound discovered by Wittig et al.
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5. Synthesis
5.1. Synthesis of nitrogen-based Lewis pairs
One of the first FLPs have been reported by Piers et al. and the synthesis is straightforward. Lithiation of the o-bromophenyldiphenylamine and subsequent boronation with bis(pentafluorophenyl)chloroborane (C6F5)2BCl resulted in
aminoborane 10 in 73% yield.23
Scheme 11 Reaction performed by Piers et al. in 2003, including possible side reaction with HX
The aminoborane 10 proved to be extremely sensitive towards HX compounds such as water and hydrogen chloride, yielding the zwitterion 11 shown in Scheme 11. This reaction shows that the molecule exhibits frustrated Lewis pair reactivity by functioning as a Lewis acid/Lewis base trap.23,26 Stephan et al. reported a similar
synthesis with the boronation of 2-dimethylaminophenyl lithium using dimesitylborane halogen in toluene, which is depicted in Scheme 12.27 A possible side reaction (depicted
in red) is the loss of mesityl group from 12 after heating for 72 h at 80 °C under 4 atm H2
pressure.
Scheme 12 Synthesis of 2-(dimethylamino)phenyl-(dimesityl)borane27
A reaction for the simple and effective synthesis of fluorescent organoboranes that has some similarities with those previously mentioned was reported by Kaufmann
et al. in 2000. This synthetic route goes via the boronic ester and a second organolithium
reagent instead of the direct coupling of the boron substituent. By deprotonation with n-butyllithium in the presence of TMEDA and a subsequent reaction with dimethyl boronate the boronic ester 13 was obtained, which was easily displaced by reacting with
14
an organolithium reagent (Scheme 13) and workup with brine. Interestingly, if only one equivalent of R5Li was added the boronic ester was selectively reduced to the boronic
acid, confirming a stepwise transition and opening up the possibility to synthesise boron compounds with three different substituents.28 These organoboranes have proven to be
stable in the solid phase, but when diluted in isooctane the boron-aminophenyl bond breaks slowly.
Scheme 13 Reaction performed by Kaufmann et al. in 2000
More recently, Whiting et al. developed a synthetic route that starts with treatment of diisopropylbenzamide with n-BuLi and TMEDA, followed by addition of triisopropyl borate resulting in the boronated benzamide 14 (Scheme 14). Treating 14 with pinacol gave the boronic ester and subsequent amide reduction with NaBH4 resulted in the
boronic acid 15 in a total yield of 25-70%, depending on the isolated intermediate after the first two steps. For structural insight the boronic acid derivate was treated with KHF2 yielding the B/N FLP in 82% yield that mostly exists in the heterocycle-state.29
Although boronic acids can be used in FLP chemistry, it must be noted that their FLP reactivity is lower than other mentioned FLPs due to the back-bonding effect that partly saturates the boron atom through the boron-oxygen bond.30
15
In 2008, Repo et al. reported the synthesis of a nitrogen/boron FLP, using 2-bromobenzylbromide as the scaffold (Scheme 15).25,26,31 Amination of the
bromobenzyl in the presence of a base yielded compound 16, while the coupling of the boron fragment is achieved by lithiation and subsequent boronation with (C6F5)2BCl. It
is mentioned that fluorinated benzenes are used in these so-called ‘Molecular Tweezers’, as their electron withdrawing properties result in the formation of a highly Lewis acidic boron moiety.
Scheme 15 Reaction performed by Repo et al. using 2-bromobenzylbromide as scaffold
A variation of this synthesis was reported in 2012 in which the methylene group has been removed and the substituents on the nitrogen can vary. Starting from iodobenzene a reaction with LiTMP couples the Lewis base at the o-position, yielding
18.1. Subsequent lithiation and boronation yielded the aminoborane 19.1 (Scheme
16).32 Interesting is that the similar NMe2 compound exists as an intramolecular Lewis
adduct with the four-membered C-N B-C heterocycle 20.33 The same type of reaction,
only differing in substituents on both boron and nitrogen was reported by Stephan et al.: the nitrogen bears two methyl groups as above, but the boron substituents are mesityl or 2,4,5-trimethylbenzene in 72%, respectively 64% yield.27
16
In 2015 subsequent research by was reported on BH3 as the Lewis acid
precursor34, showing a trans-dimer with two μ-H bridges and the same type of reactivity
towards molecular hydrogen splitting as reported before.26,31 The lithiated compound
was treated with two equivalents BH3∙SMe2, replacing the lithium for BH3-, and Me3SiBr
to capture the hydride at -80°C with a yield of 56% (21, Scheme 17).
Scheme 17 Mechanism of BH3SMe2 with the lithiumaryl compound
Whiting et al. reported a similar synthesis in which the amine is treated with
n-BuLi and trimethoxyborane, followed by hydrolysis to form the boronic acid, as is
shown in Scheme 18.35 The aminoboronic acids could also be synthesised starting from
the aldehyde and work towards the amine with reductive amination. It is interesting to see the variety of compounds based on 22 that have been synthesised using direct
ortho-lithiation. Table 2 shows the synthesised FLPs with the o-phenyl bridge.
Scheme 18 Synthesis of aminoborane 22 reported by Whiting et al.35
Table 2 Synthesis of aminoboronic acids by o-lithiation as described by Whiting
et al.35
product yield (%) product yield (%)
45 52
17
Scheme 19 illustrates the synthesis of the bulky N/B FLP in which TMP reacts with n-BuLi and iodobenzene to form 1-iodo-2-TMP-benzene (23). A lithium-halogen exchange is followed by replacement by 9-BBN to yield the final compound 23 in 73% yield.36 Interesting is that the NMR data shows that there is no rotation of the nitrogen
substituent as the methyl substituents pointing towards and away from boron have different chemical shifts. On the other hand, the rotation of the boron substituent is much faster as is indicated by only three carbon peaks for the substituent.
Scheme 19 Synthesis of the bulky ligand 1-(BBN)-2-(TMP)-benzene
5.2. Synthesis of phosphorus-based Lewis pairs
In 1963 Hartley et al. reported the synthesis of 2-bromophenyldiphenylphosphine (24), which is one of the most used precursors in the synthesis of phosphine-based
o-phenylene bridged FLPs.37 2-bromobenzenediazonium reacts with PCl3 and
magnesium to yield (2-bromophenyl)dichlorophosphine in 21% yield, which is followed by a reaction with the Grignard reagent to form the final product in 36% yield (Scheme 20).
Scheme 20 Synthesis of 2-(diphenylphosphine)phenylbromide by Hartley et al.
Since then new synthetic routes have been developed, improving the yield dramatically by using 1,2-iodophenylbromide as the starting material. In 1987 this was first reported with (trimethylsilyl)diphenylphosphine as reagent and a palladium catalyst (Scheme 21, left).38 The reaction was performed cleanly with 82% yield, a big
improvement on the reaction in Scheme 20. A few years later Stelzer et al. performed the reaction with diphenylphosphine and a different catalyst that only needed 0.1 mol%
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loading (Scheme 21, right).39 With 75% yield this proved to be an effective reaction, but
the yield was lower than when (trimethylsilyl)diphenylphosphine was used. One of the reasons for this lower yield could be that the reactivity on the phosphorus is enhanced by the trimethylsilyl by considering it as a bulky proton.
Scheme 21 More recent syntheses of 2-(diphenylphosphine)phenylbromide
The first case of using such an o-phenylene linker between a Lewis acid and a Lewis base was reported in 1991 by Balueva et al.7,40 The reaction was a metallation
with n-BuLi of (2-bromophenyl)diphenylphosphine and subsequent electrophilic trapping using n-Bu2BCl (Scheme 22). A low yield of 25 was observed (4,5%) due to
incomplete lithiation, a problem that was not resolved using a longer reaction time or adding more niBuLi.7 Isolation of the lithiated intermediate could achieve higher yields,
as is reported by for the N/B FLP 17 in Scheme 15.31 There are no P/B FLP syntheses in
this report that mention isolation of the lithiated intermediate. This does not have to be a problem, as the similarity with the reaction of Piers et al.23 (Scheme 11) is clearly
visible, however Piers et al. used nitrogen as the Lewis base rather than phosphorus.
Scheme 22 Reaction performed by Balueva in 1991
The reaction performed by Balueva et al. (Scheme 22) has been used by the group of Bourissou, researching the coordinating properties of such FLP derivatives.41 A
variety of substituents on boron has been reported, all following the same reaction path: lithiation with n-BuLi, electrophilic trapping with Cl-BR2 and workup.41–43 It is shown
that there is a difference in yields across the substituents, as the fluoreneborane has only 28% yield compared with the ‘standard’ diphenylborane yield of 94% (Scheme 23), which can be explained by the extreme air- and temperature sensitive of the fluorene, that has an higher electron deficiency at the boron centre.43
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Scheme 23 Different substituents for 1-P(iPr)2-(C6H4)-2-BR2
Variation of the substituents on boron also has an effect on the amount of P→B interaction. This closed form is favoured by BPh2 (28) and BFlu (27), whereas the open
form is mostly seen on BCy2 (26) and BMes2 (29).40,41,43 The preferred form can be
deduced by investigating the steric interactions of the boron substituents: 27 and 28 have a planar character, while 26 and 29 are more sterically encumbered which inhibits the phosphorus-boron interaction around the linker and boron. This space is needed for the interaction with phosphorus, leading to less interaction when the substituents have larger steric effects.
The same technique has been utilised to synthesise boronate esters.44–47 After lithiation, the lithiated phenyl
phosphine compound reacts with the corresponding boron reagent to form the phosphine boronate ester. Several boronate esters are depicted in Scheme 24. The yield appears to be quite variable as it ranges from 41 to 94% yield (Table 3). In general the diphenylphosphine side group ensures higher conversion, but in the case of the pinacol coupling (32) this is not the case. It could be that the inconsistency is due to the way these numbers are obtained, because these yields are spread out in four papers
over five years. Another explanation could be that in the case of the pinacol coupling the reactivity with isopropyl as side group is higher, resulting in better yields. What we can conclude is that high yields are obtained and this is a suitable method of producing boronate esters.
Table 3 Obtained yields by Bourissou et al. compound yield 1.30 94% 1.31 80% 1.32 61% 1.33 41% 2.30 70% 2.31 49% 2.32 76%
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Scheme 24 Syntheses of phosphine-boronate esters by the group of Bourissou et al.
The group of Liu et al. reported the first general synthesis of boron-substituted 1,4-azaborines, which is shown in Scheme 25. By using an earlier mentioned coupling reaction7, (diphenylphosphino)phenylbromide is coupled to the azaborines and upon
release of lithium methoxide the desired compound 34 is obtained in 66% yield.48 As the
scope of substitution at the azaborines is broad, there is an opportunity for different combinations of azaborines and phenylenes.
Scheme 25 Synthesis of 1,4-azaborine substituted phenylene
The methods described above are all dependent on the unstable o-lithiated bromobenzene intermediate to make the phosphine bromobenzene. Jugé et al. has developed a synthetic route (Scheme 26) that circumvents this intermediate by using a one-pot synthesis. Via deprotonation of the secondary phosphine borane and subsequent LiBr elimination benzyne is formed49, which is trapped by the phosphorus
reagent. Even more remarkable is that the yields of this method are similar to the conventional method used by Balueva (±40-70% towards borane coupled, 60-90% yield for the last step) and that the measured ee is 99%.50 In summary, this is a facile
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technique to circumvent unstable intermediates and achieve high enantioselectivity on the chiral phosphorus, giving possibilities for asymmetric catalysis.
Scheme 26 One-pot synthesis for formation of o-boronatophenylphosphines
5.3. Other Lewis pairs
Stephan et al. reported a frustrated Lewis pair consisting of phosphorus and nitrogen. This can be achieved by the formation of a phosphonium cation, which can function as a Lewis acid combined with a counter-ion in the coordination sphere. Compound 36 in Scheme 27, pathway a, was tested towards activation of CO2, but unfortunately no
reaction was observed. However treatment with t-BuLi yielded compound 37 with a P-N interaction (Scheme 27, pathway b), which is in equilibrium with two other resonance structures, showing the possible FLP type reactivity in the amido donor and phosphonium acceptor.51 Synthesis is quite similar to other syntheses we have seen so
far: metallation with lithium and electrophilic trapping with a phosphorus compound.52
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A schematic overview of this chapter is given in Scheme 28, including possible side groups for the phosphorus/nitrogen and boron substituents. All of these groups have been included in one of the described syntheses, although not all combinations have been reported. This could be a topic of further research, which can include variations in sterics, electronic effects and functionalisation. In the next chapter the reactivity of these systems will be discussed.
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6. Applications
FLPs can be used in a variety of applications, which can differ from simple coordination towards transition metals to complex organocatalysis. This chapter will discuss all of the reported applications, starting with the transition metal coordination, followed by the activation of small molecules and at the end (organo)catalysis will be discussed.
6.1. Transition metal coordination
The first application of FLPs that will be discussed is the coordination as a ligand to transitions metals. This will help in understanding the reactivity of the FLPs and it can create systems that have the possible ability to use their ligands cooperatively. As mentioned in the introduction (Scheme 2), this coordination can exist in three different ways: interaction between Lewis base and a substrate, a ligand or the metal centre.6,53
Figure 3 Coordination of PdII and AuI metal centres to ambiphilic ligands
Reactions of Bourissou’s phosphinoboranes 26 and 27 with AuI and PdII gave the
coordination complexes of Figure 3.41 In the Pd-complex there is an interaction between
the Lewis acid (boron) and the chloride, as is indicated by the short B-Cl distance of 2.615 Å obtained from DFT calculations. This is different at the Au-complex, where the B-Cl distance of 4.08 Å, combined with an Au-B distance of 2.66-2.90 Å indicates an interaction of boron with gold, as depicted in the structure in Figure 3. It is possible that this is due to the more nucleophilic character of gold with respect to palladium.41,53 In
addition, sterics can play a significant role in the geometry of these complexes, as there is an additional ligand on palladium.
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Figure 4 Crystal structure of phosphinoborane with Pd(nbd)(ma)
It is interesting to see that upon reaction of the same phosphinoborane with Pd(nbd)(ma) the palladium centre coordinates to the Mes rings as is confirmed by the crystal structure in Figure 4.6 An η2 coordination is
observed, which is an important interaction regarding the stability of the complex.54 Buchwald et al.
mentioned that these interactions are not visible in
transition states, suggesting that the stabilisation of the palladium only occurs when the catalyst is not used in the catalytic cycle.54
The palladium complex in Figure 3 has been used for the synthesis of other palladium complexes by Bourissou et al. Upon reaction of 26-Pd with HCl at room temperature in DCM for 24 h the dinuclear complex 38 was obtained in 59% yield (Scheme 29).55 Crystal structure analysis showed that the Cl→B bond has been
weakened upon loss ofthe allyl ligand. The next step was to cleave the [Pd(μ-Cl)]2 bridge
with PPh3, as has been done before with the reaction of Lewis base DMAP with the
dinuclear complex [Rh(μ-Cl)(DPB)]2, where the chloro bridge was broken instead of the
Rh→B bond (39).56 Indeed the reaction was performed smoothly with a yield of 98%.
Scheme 29 Synthesis of palladium complexes performed by Bontemps et al. Top: bound Lewis acid. Bottom: free Lewis acid.
Replacing the chlorine with the more basic PPh3 resulted in an increased strength
of the Cl→B interaction. Steric factors were investigated by replacement of BCy2 for
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structure analysis showed that the bond distances of Cl-B and Pd-B are too long to contain any interaction. In addition, DFT calculations could not generate a minimum in which there is an interaction between the boron and the metal fragment. It is proposed that this interaction is not possible due to the increased steric hindrance around the boron centre.
6.2. Small molecule activation
Besides their ability of transition metal coordination, FLPs can be used in the activation of small molecules. Small molecule activation is important in many chemical processes as it allows for the utilisation of often abundant molecules as building blocks in the synthesis of more complex molecules. Many chemical processes are thus reliant on small molecule activation. For example, to perform a hydrogenation the system must be able to activate the hydrogen from a source as molecular hydrogen.
6.2.1. Molecular hydrogen
Repo et al.31 successfully applied their
‘Molecular Tweezers’ for the activation of molecular hydrogen. A rapid reaction with H2 was observed at just 20 °C in toluene.
Upon heating to 110 °C for 20h, hydrogen was released and the starting material regenerated (Scheme 30). According to the crystal structure, the H-H distance of 1.51 Å combined with the bond angles of N-H-H (154°) and B-H-H (125°) suggest that the
dihydrogen bond remains partly covalent (Figure 5).31 This is supported by the findings
of Grabowski et al., who report that partly covalent bonds have a distance of 1.2-1.7 Å.57
Scheme 30 Activation of molecular hydrogen with the aminoborane as reported by Repo et al.31
Figure 5 Crystal structure of the aminoborane with activated H2 as shown in Scheme 30
26
19.1 in Scheme 31 could also activate molecular hydrogen in a similar fashion.32
However regeneration of the starting compound was practically unsuccessful with 2.6% yield even after 4 days of reflux in toluene. The dimethylaminoborane 19.2 could activate molecular hydrogen within 12 hours and regeneration of the starting material was successful, as it regenerated with 10 mol%/day while stored under argon.
Scheme 31 Molecular hydrogen activation by the aminoboranes as reported by Repo et al.32
When FLP 21 in Scheme 32 was applied for hydrogen activation, a dynamic equilibrium was found. This was supported by kinetic studies focused on the dehydrogenation of 43. The Gibbs free energy value found was 18.3 ± 0.9, a number that is very close to the activation barrier of H2 (20.6 kcal mol-1). Further investigation
showed that by tweaking the reaction conditions the equilibrium can be shifted towards
43.34 At room temperature and 2.2 bar H2 the conversion is 5% in CD2Cl2, which
increases to 72% when the conditions are changed to -15 °C and 10 bar.
Computational studies have been done to investigate the effect of the solvents, as no reaction was observed in toluene. The results show clearly that polar solvents as CD2Cl2 are favoured over non-polar solvents for this reaction, because the zwitterion 43
is more stabilised in a polar solvent, driving the equilibrium towards the products.
27
6.2.2. (Hydrogen) fluoride
Bourissou et al. have done research on the trapping of hydrogen fluoride with FLPs using compound 44 shown in Scheme 33. This system was chosen because the mesityl groups on boron provide good stability to the system and the nitrogen adduct analogues have shown to form readily and possess stabilisation by intramolecular interactions.42,58
Scheme 33 Trapping of 3 equivalents of HF using a P/B FLP
Mechanistic studies revealed that the FLP reacts with HF to form intermediate 45. Subsequent protonolysis of the B-Mes bond the neutral intermediate 46 is yielded, which is susceptible for a second and third HF reaction. The final product is the zwitterionic compound 47, which is obtained in 74% yield after 24 hours. The crystal structure of this zwitterion in Figure 6 revealed that there are no intramolecular interactions between the phosphonium and the anionic borane.
6.2.3. Molecular oxygen
Bourissou et al. also reported the activation of molecular oxygen with phosphine-borane
44.44 Treatment with molecular oxygen did not work, but after addition of a
photosensitiser molecular oxygen was excited to the singlet state and split over both the phosphine as the boron to yield 45 (Scheme 34a). This happens via trapping of the molecular oxygen by the FLP, followed by rearrangement from boron to the mesityl group. Scheme 34b shows formation of a peroxoboronate moiety (46). It must be noted that this molecule can react with the starting pinacol borane to form two equivalents of phoshine-oxide compound, resulting in the same type of product as pathway A. Until now very little research is conducted on oxidation of FLPs with molecular oxygen, however recently a paper on intramolecular FLP-oxidation was published, which will be discussed in Chapter 7.59
Figure 6 Crystal structure of the zwitterionic FLP compound X
28
Scheme 34 Two different fixations of 1O2 by phosphinoboranes (TPP = tetraphenylporphyrin)
6.2.4. Carbon dioxide
The P/N FLP 37 depicted in Scheme 35 is capable of trapping carbon dioxide at ambient conditions (1 atmosphere, room temperature).51 1H-NMR data
showed that the P-N bond was broken by the presence of a singlet N-methyl signal, indicating the loss of coupling to phosphorus and fluorine. This is confirmed by the crystal structure shown in Figure
7, which clearly shows that the carbon of CO2 is bound to nitrogen and the phosphorus
forms a bond with one of the oxygen.
Scheme 35 Carbon dioxide trapping by P/N FLP at ambient conditions51
If we compare this coordination of CO2 towards the FLP with previous studies we
see that the role of phosphorus is different than normal, as you would expect that it would bind to the electrophilic carbon, which is shown by Erker et al. in Scheme 36.60
The difference is clarified if we look at the approaching CO2: in the left case the
phosphorus acts as a Lewis acid and thus is the CO2 oriented with the oxygen towards
Figure 7 Crystal structure of aminophosphorane as reported by Hounjet51
29
phosphorus. In the right example the phosphorus acts as the Lewis base, inverting the approach of the CO2 as the oxygen is now pointed towards the boron.
Scheme 36 Different coordination and interaction possibilities for CO2 when approaching different FLPs
47 is, to our knowledge, the only o-phenylene bridged FLP-system that is able to
form a stable, detectable complex with CO2. A simple explanation can be found in DFT
modelling predicting that the interaction with CO2 would be disfavoured by an enthalpy
change of 9.9 kcal mol-1.61 Despite this, the hydrogenation of CO2 has proven to be very
effective, which will be described in section 6.3.1.
6.2.5. Azides
Bourissou et al. investigated the capabilities of phosphinoborane 44 with respect to azides. In 2007 Bourissou et al. showed that the phosphonium borane reacted cleanly with a six-equivalent excess of phenylazide in toluene at room temperature towards 50 in 94% yield.42 After observing complexation with methyl iodide62 and sodium
hydroxide at pH > 3.5 in a biphasic system (chloroform/water) they started to investigate other anions as well and the only new species observed was after a reaction with 2 equivalents of sodium azide 51 with 66% yield and 8% of the hydroxide species (Scheme 37).63 The structure observed during the experiment is in agreement with the
DFT calculations, which can be seen in the distance between phosphorus and the first nitrogen (2.799 Å with DFT, 2.790 in the crystal structure).
30
6.3. (Organo)catalysis
6.3.1. Hydrogenation of carbon dioxide
Using aminoborane 52 in Scheme 38 an attempt was made to hydrogenate CO2 and with
success: 0.37 equivalents of boron-bound acetals were formed after 72h at room temperature.27 DFT calculations revealed that the substituents of boron could be
replaced by hydrogen during the molecular hydrogen activation. It must be said that the aminoborane is attached with two equivalents, effectively forming an acetal-coupled dimer (53), in which one of the original substituents of boron is attached again.
Scheme 38 Hydrogenation of CO2 with possible products: carbonic acid, acetal and/or methoxy. Top: structure of dimer
acetal
The hydrogenation of CO2 to methanol produces ‘waste’ products as water and
formic acid and in order to develop a catalyst it must be stable in presence of these compounds. This is what Fontaine et al.36 researched by reacting aminoborane 23 from
Scheme 39 with water and formic acid. When it was exposed to water a new compound was detected that indicated the splitting of water. The NMR spectra also indicated hydrogen bonding between the N-H and B-O-H. Surprisingly, the splitting of water turned out to be reversible, as the starting compound was obtained after the solution was stored with 4Å molecular sieves overnight. An excess of water resulted in hydrolysis of the aminoborane.
Similar results were found when the FLP was reacted with formic acid: the compound showed similar splitting and over 50% was reverted back to the starting compound when treated with K2CO3. Interesting was that an excess of formic acid
showed low degradation (<5%), even after heating for 24h. In contrast, there was no reactivity observed for carbon dioxide, molecular hydrogen and formaldehyde, suggesting that only O-H bonds can be broken by this FLP-system.
31
Scheme 39 Stability experiments performed by Fontaine et al.36 for the catalytic hydrogenation of CO2
One of the most effective methods to hydrogenate CO2 with FLP chemistry is via
hydroboration with HBcat (54, Scheme 40). The hydroborane HBcat is exposed to the catalyst at 1 atmosphere CO2 while heated to 70 °C to yield 55 and by-product 56, which
precipitates. Methanol can be retrieved by addition of an excess of water to 55 and in the process 54 is regenerated. In addition, NaBH4 can be used to break down 56 to 54.64
54 can be replaced by other hydrogen sources such as BH3∙SMe2 that has proven to be
even better performing under similar conditions.46,47
Scheme 40 Standard reaction scheme for the hydrogenation of CO2 via the hydroboration mechanism46
Table 4 lists selected experiments of CO2 hydrogenation via the hydroboration
mechanism. A TON of 86 was observed after 36 min, which corresponds to a TOF of 143 h-1. After running the same experiment for a longer time an increased TON has been
observed of 92, indicating that the conversion of CO2 is dependent on the concentration
of the hydroborane. The earlier mentioned hydroborane BH3∙SMe2 was tested under
similar conditions and it showed a significantly higher TOF of 242, a difference of 99 with 54 in entry 1. Using a catalyst loading from 1 to 0.1% for a 4 hour reaction resulted in excellent results (entries 9 and 11). With 54 a TOF of 166 was observed and using BH3∙SMe2 resulted in frequencies exceeding 737, which is even more impressive
considering that the highest TOF reported before was 495 h-1 by using a nickel
32
Table 4 selected CO2 hydrogenation entries using the catalyst of Scheme 40 as reported by Fontaine et al. 46
entry# borane equivalents time TONα TOF (h-1)
1 54 100 36 min 86 143
2 54 100 98 min 92 56
5 BH3∙SMe2 100 67 min 271 242
9β 54 1000 240 min 664γ 166
11β BH3∙SMe2 1000 240 min >2950γ >737
Standard conditions: 2 mg (0.0053 mmol) of catalyst in 0.6 mL of D-benzene at 70 °C
α based on mole B-H consumed per mole of catalyst; β 2.0 mg (0.0053 mmol) of catalyst in 9 mL of benzene at 70 °C under ~2 atm of CO2 pressure; γ quenched with excess H2O and analysed by GC-FID with iPrOH as a
standard
# entry number of the original paper
Using computational studies a proposed catalytic cycle is reported regarding this hydrogenation via hydroboration, which is depicted in Scheme 41.66 In cycle A is first
coordination of the hydroborane and CO2 observed, after which a hydride transfer
results in the first intermediate. A rearrangement leads to two pathways: release of the boronated formic acid or the coordination of a second hydroborane, which leads to cycle
B. The process of hydride transfer and rearrangement is repeated, resulting is the
release of [B]OCH2O[B], a compound that can reversibly release [B]O[B] to yield
formaldehyde to start cycle C. Coordination of formaldehyde to the catalyst is followed by insertion of a hydroborane, hydride migration and rearrangement, yielding the boronated methanol and regeneration of the catalyst.
33
Scheme 41 Proposed mechanism for the hydrogenation of CO2 via hydroboration 66
34
6.3.2. Hydrogenation of imine/enamine compounds
The ‘Molecular Tweezers’ reported by Repo et al. can activate molecular hydrogen and this is used in imine reductions.31 With 4% catalyst loading refluxed in toluene for 6h a
yield was obtained of 99%. The most important step of the catalytic cycle (Scheme 42) is the coordination of the imine to the borane and it is reported that subtle changes at the α-position of the imine can significantly change the reactivity. This is confirmed later by Stephan and Erker, who mention that sterically less-hindered substrates react only with 4% yield.67 In addition, changes at the aminoborane can also alter the reactivity as the
acidity and basicity of the system must be in balance as this will affect the molecular hydrogen activation time. This is shown by subsequent research when the addition of electron donating groups, such as methyl, to the o-phenylene linker slowed down the activation of molecular hydrogen drastically from a few minutes to a week.26
Scheme 42 Catalytic cycle of the imine/enamine hydrogenation reported by Repo et al.31 and reviewed by Stephan and Erker67
35
In 2011 the first asymmetric catalysts were described by Repo et al.68 The
catalysts of Scheme 43 were tested and after tuning the steric and electronic properties of CAT they found that the liberation of molecular hydrogen was significantly faster when the basicity of the aminoboranes was lowered due to the weaker N+-H bonds. This
had also a positive effect on the catalytic activity as lower catalyst loading and/or shorter reaction times were needed.
Scheme 43 Designed catalysts for the hydrogenation of imines
The next step was the development of enantioselective catalysts for asymmetric hydrogenation of imines. The most reactive catalysts of Scheme 43 were synthesised enantiopure and a new compound was added to the tests (CarCAT). iPrI*CAT racemises upon abstraction of a α-hydrogen, forming the imine. This leaves Q*CAT and CarCAT for asymmetric catalysis testing.
Scheme 44 Enantioselective catalysts based on the best performing catalysts of Scheme 43
Q*CAT showed full conversion in all entries of Table 5, irrespectively of solvent
or temperature with 4 mol% catalyst loading and 2 atm H2 pressure. The best results
were obtained at ambient temperature in MTBE, with a maximum ee of 37%.68 CarCAT
on the other hand showed both lower conversion (30-70%) as ee (8-17%) for the model substrate in different solvents. No reaction in MTBE was reported for unknown reasons. It is expected that an increase of basicity at the nitrogen centre will lead to higher catalyst activity.
36
Table 5 Selected imine hydrogenation substrates using the catalysts of Scheme 44 as reported by Repo et al.68
entry# substrate catalyst solvent time temp conversionα eeβ
1 Q*CAT toluene 1 h 80 °C 100 % 4 % 3 Q*CAT Et2O 1 h 60 °C 100 % 12 % 4 Q*CAT Et2O 1 h 20 °C 100 % 19 % 5 Q*CAT MTBE 1 h 20 °C 100 % 26 % 8 Q*CAT MTBE 12 h 20 °C 100 % 35 % 11 Q*CAT MTBE 12 h 20 °C 100 % 37 % 12 CarCAT toluene 20 h 80 °C 70 % 8 % 14 CarCAT Et2O 20 h 60 °C 35 % 17 %
Standard conditions: 4 mol% catalyst, 2 atm H2.
α determined by 1H-NMR; β determined by chiral HPLC
# entry number of the original paper
6.3.3. Alkyne hydrogenation
Alkyne hydrogenation is studied by Repo et al. by using an aminoborane as catalyst.33
Various alkynes have been hydrogenated with almost full conversions under mild conditions (80 °C, 2 bar H2, 3h). In Table 6 a selection of substrates is presented, while
Scheme 45 shows the proposed catalytic cycle.
First one pentafluorophenyl ligand is replaced with a hydride, which is followed by insertion of the alkyne. Another dihydrogen molecule is used to form the zwitterionic compound , resulting in alkene formation and regeneration of the starting catalyst.69 The
mechanism of catalyst activation can be interpreted as a rearrangement with as result elimination of the pentafluorobenzene or as an intramolecular deprotonation of the nitrogen atom.
37
Table 6 Selected alkyne hydrogenation substrates using the catalyst of Scheme 45 as reported by Repo et al.33
entry# substrate product conversion
1.1α 100% 1.2 100% 1.3β - no reaction 1.6α 100% 1.7γ 100% 1.12 100% 1.16 88% cis 12% trans 1.21δ 42% 10% 10.5% 10.2% 1.22 - no reaction
Standard conditions: 5 mol% catalyst, 2.2 bar H2, D-benzene, 80 °C, 3h.
α 7 mol% catalyst; β 15 h; γ 10 mol% catalyst; δ 15 mol% catalyst, 120 °C, 10h # entry number of the original paper
As can be seen in Table 6 there are two types of alkynes that are not hydrogenated by this system: terminal alkynes and alkynes that bear a terminal double bond. The terminal alkynes can still easily be hydrogenated using silylation via organometallic reagents and LDA, followed by the reaction of the alkyne with a silicon halogen compound.49 No over-reduction to alkanes was observed and only the Z-alkene
38
was formed selectively, making this system a possible alternative for the Lindlar catalyst. The cis-selectivity is the result of selective syn-hydroboration that is retained during the reaction.
Scheme 45 Catalytic cycle of the alkyne hydrogenation reported by Repo et al.33 and reviewed by Stephan69
A turnover frequency of 297 h-1 was reported, which is very impressive given the
fact that this is a metal-free catalytic system. However, with a turnover number of only 91 there is still a lot of work to be done, as the system is now only active for only 20 minutes. Catalyst deactivation is the result of intramolecular protonation of the C6F5
instead of the vinyl. This is also the reason that a double bond could not be hydrogenated using this system, because the C6F5 is a better leaving group than an alkyl.
Nevertheless, this system is unique in its capability of hydrogenating unactivated alkynes.
39
6.3.4. C-C formation
The Michael addition has been studied by Bourissou et al. using the phosphine-boronates shown in Scheme 46.45 Two different Michael additions were studied:
coupling of dimethylmalonate (57.1) or methyl dimethylmalonate (57.2) to methylvinylketone. The best results of 57.1 were obtained using methyl-substituted phosphine-boronates for 1 hour with yields between 58-69%. For 57.2 the reaction time was longer (5 hours) due to the sterically more challenging methyl dimethylmalonate. Nevertheless good conversions were detected of 80-95%, however the Bpin catalysts were performing with 34-50% yield. These lower yields emphasise that the steric influence of the boron group has a role in the catalytic activity of the system.
Scheme 46 Catalytic Michael addition with the studied phosphine-boronates
Another important reaction is the Suzuki-Miyaura reaction, a palladium-catalysed cross coupling reaction. Bourissou et al. investigated the use of FLPs as potential cooperative ligands for the palladium-catalysed reaction with the ligands 44 and 58 as depicted in Scheme 47.70 After formation of the catalyst in situ the coupling of
4-bromoanisole and phenyl boronic acid was investigated under mild conditions (80-100 °C).
Scheme 47 Top: FLP-based ligands used in the Suzuki-Miyaura cross coupling reaction. Bottom: Suzuki-Miyaura coupling
Table 7 shows selected catalytic results of the system in Scheme 47. In general high yields are obtained, where the difference between 2 and 20 hours is small. When higher phenyl boronic acid/4-bromoanisole ratios are used (entry 3) a drop in yield is recorded. In addition upon lowering the L/Pd ratio an increase in activity was observed
40
(entries 4 and 8). A control experiment with triphenylphosphine showed a significantly lower activity (67%), suggesting that the dimesityl boron plays an important role in enhancing the catalytic activity. For a better insight in the behaviour of the boron moiety 44-Pd (Figure 8) was synthesised. X-ray diffraction showed interaction of palladium
with phosphorus and a mesityl group, confirming the importance of the dimesityl boron group. 44-Pd was used in a catalytic experiment (entry 8) and a conversion of 82% was obtained.70
Table 7 Selected C-C cross coupling entries using the catalyst of Scheme 47 as reported by Bourissou et al.70
entry ligand temperature (°C) time (h) L/Pd ratio yield I (%)
1 1 80 2 2 81 2 1 100 20 2 86.5 3 1 80 2 2 58α 4 1 80 2 1 81 [87]β 5 2 100 20 2 85.6 8 1-Pd 80 20 1 82 [72]β
Standard conditions: 1 mmol 4-bromoanisole; 2 mL toluene; K3PO4/boronic acid/4-bromoanisole =
2.1/1.1/1; 0.01 mmol Pd(OAc)2 or 1-Pd
α Ph-B(OH)2/substrate = 2; β In square brackets, data after 6h of reaction
6.3.5. C-H activation
C-H activation is one of the most important reactions studied at the moment, as the functionalisation of simple carbon chains can be of great value in synthetic routes. For example, by using C-H activation synthetic routes can be shortened. Recently the C-H activation of heteroarenes was studied following the reaction and the corresponding catalytic cycle that is depicted in Scheme 48.71
The catalytic cycle displays the proposed mechanism of this type of C-H activation. Monomerisation leads to the active catalyst (21), which can coordinate the heteroarene and eventually lead to breaking of the C-H bond and the formation of the
41
zwitterionic intermediate. Loss of molecular hydrogen, followed by a reaction with HBpin yields the activated heteroarene and regenerates the catalyst. The monomeric catalyst 21 formed from the precursor and the first intermediate are not observed.
Scheme 48 Catalytic C-H activation of heteroarenes as is reported by Fontaine et al.71
This reaction is tested on various heteroarenes including pyrroles, thiophenes and furanes and all showed high conversions and yields. Side groups play a role in the effectiveness of the reaction, as more electron withdrawing groups can lower the conversion and the yield. In addition, the selectivity is comparable with previously reported transition metal catalysts.72
42
7. Future prospects
Next to the chemistry discussed in Chapters 5 and 6 there are a lot of applications proven to be effective using other linkers than the o-phenyl. In this Chapter several systems will be discussed that are able to activate small molecules and perform catalytic reactions that are not reported yet for o-phenyl bridged FLPs, illustrating the possibilities for future research.
No aluminium-based o-phenylene bridged FLPs are reported to date, questioning why this class of FLPs has not been researched yet. There could be several reasons for this and one assumption is that the aluminium could have a non-covalent interaction with the phenyl, turning the phenyl into a ligand instead of a bridge. Another problem could be the (in)stability of the FLP during or after the synthesis. A final possibility is that simply nobody reported it, because nobody has done research towards Al-based
o-phenylene-bridged FLPs.
However, several examples of Al-based FLPs have been reported, both inter as intramolecular, confirming the possibility of synthesising this type of FLPs.8,11,14,73–76 A
possible synthetic route is shown in Scheme 49, basically following the same steps as mentioned earlier and used earlier for other aluminium-based syntheses73,77: lithiation
of o-bromophenyldiphenylphosphine and subsequent treatment with R2AlX to yield FLP
59. This type of synthesis could also be used to yield N/Al-based FLPs.
Scheme 49 Proposed synthesis of P/Al-based FLPs
Transition-metal coordination can be interesting in order to get more insight into the FLP chemistry, however only palladium and gold complexes are reported to date. It could be interesting to look into first-row transition metal coordination as these metals are more abundant and cheaper than the metals used nowadays. On the topic of small molecule activation several molecules are not reported yet with o-phenylene bridged FLPs. In Chapter 6.2.3 oxidation with molecular oxygen was discussed, however only after excitation towards the singlet state molecular oxygen capture was observed. Recently a paper was published by Erker et al. describing FLP 60 that is able to capture
43
molecular oxygen in the triplet state (Scheme 50).59 Although no direct application is
mentioned in the article it is clear that activating molecular oxygen is important for the replacement of artificial oxidants in oxidation reactions. Besides the reactivity towards molecular oxygen it is also reported that 60 can successfully activate both molecular hydrogen and boranes, emphasising the diversity of the aminoborane.
Scheme 50 Reactions of N/B FLP system with Piers’ borane, molecular hydrogen and molecular oxygen as reported by Erker
et al.59
It was reported in 2009 that the earlier mentioned FLP 1 (Scheme 51) could capture CO2 reversibly and a few years later the reaction with SO2 was observed.60,78 The
FLP 1 captures SO2 rapidly in pentane at -78 °C, forming the chiral adduct 61 due to the
stereogenic sulphur, resulting in the formation of two diastereomers in a ratio of 5.25:1. This reaction conditions are also used for the FLP analogue with a cyclohexane-bridge (62) and the norborane (63). In crystals the ratio of diastereomers for 62 is 3:1, whereas in solution this is changed to 1:1.3, while 63 exists in a 2.5:1 ratio.79 In addition,
DFT calculations revealed that the adduct formation has low kinetic barriers, an advantage for further studies.
Scheme 51 Reactions of Erker´s FLPs60 with CO2 and SO278
FLP 64, displayed in Scheme 52, is capable of fixating CO in an argon matrix at 35 K. This results in a similar interaction as a transition metal with CO, where the donor
44
and acceptor sites lie on the B and P atoms.79 The same FLP can also facilitate the
reduction of CO via hydroboration (Scheme 52, bottom).80,81 Via addition of CO and the
hydroborane HB(C6F5)2 a three-membered ring is formed (65), which after fixation of
molecular hydrogen is rearranged to a seven-membered heterocycle (66), breaking the C-O bond.
Scheme 52 Top: Fixation of CO at the FLP reported by Erker and Stephan79 Bottom: Reduction of CO via hydroboration
The final small molecule discussed is nitric oxide which can be activated by 1, reported by Erker et al.21 When treated with nitric oxide an N-oxyl radical is formed that
is similar as seen in TEMPO (64, Scheme 53). This activated NO-radical can easily abstract hydrogen from various compounds, which are depicted in Scheme 53.
45
8. Conclusion
Frustrated Lewis pairs have provided a new field of research since their re-introduction in 2006. FLPs consist of a Lewis acid and a Lewis base that are unable to react with each other, increasing their reactivity drastically. After confirming the ability to activate molecular hydrogen a lot of varieties of FLPs have been reported, both inter- and intramolecular. These two types of FLPs both have advantages and disadvantages, but a tuneable bridge between the Lewis acid and Lewis base, combined with a pre-organised reaction site, makes intramolecular FLPs more interesting in my opinion.
Several different bridging FLPs been reported since, for example methylene and ethylene. However, in this report specifically the ortho-phenylene-bridged FLPs are investigated as it provides the Lewis acid and the Lewis base in close proximity. Various Lewis pairs have been discussed, using aluminium/boron as Lewis acids and nitrogen/phosphorus as Lewis bases. From the start it was clear that no Al-based o-phenylene-bridged FLPs are reported to date, limiting the Lewis acids to boron.
There are different synthetic routes towards the desired FLPs, but the general reaction is based on lithiation of o-bromophenyl attached to the Lewis base and subsequent boronation with the Lewis acid. In some cases an amide reduction has been done after the boronation to yield the aminoborane. As the side-groups can vary, a lot of different FLPs can be synthesised, all with different reactivity.
FLP reactivity can be divided into three parts: transition metal coordination, small molecule activation and (organo)catalysis. Palladium and gold complexes are successfully formed and characterised, providing important information on how
o-phenylene FLPs react. For FLP systems to be of interest in catalysis they have to be
able to activate certain molecules. It has been reported that molecular hydrogen, molecular oxygen (after excitation to the singlet state with a photosentisiser), carbon dioxide, azides and different HX compound can be activated, mostly with encouraging results.
The next step was to look into catalytic reactions that are of interest. Hydrogenation of CO2 has been reported successfully with high conversions and
turnover frequencies. In addition, the first asymmetric hydrogenation of imines and enamines is presented with ee values of 19-37%. Also alkynes have been hydrogenated
