Facile Protocol for Water-Tolerant "Frustrated Lewis Pair"-Catalyzed Hydrogenation

Article abstract of DOI:10.1021/acscatal.5b01417

Despite rapid advances in the field of metal-free, "frustrated Lewis pair" (FLP)-catalyzed hydrogenation, the need for strictly anhydrous reaction conditions has hampered wide-scale uptake of this methodology. Herein, we report that, despite the generally perceived moisture sensitivity of FLPs, 1,4-dioxane solutions of B(C₆F₅)₃ actually show appreciable moisture tolerance and can catalyze hydrogenation of a range of weakly basic substrates without the need for rigorously inert conditions. In particular, reactions can be performed directly in commercially available nonanhydrous solvents without subsequent drying or use of internal desiccants.

Full text of DOI:10.1021/acscatal.5b01417

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Letter
A Facile Protocol for Water-Tolerant ‘Frustrated
Lewis Pair’-Catalyzed Hydrogenation
Daniel J Scott, Trevor R. Simmons, Elliot J. Lawrence, Gregory
G. Wildgoose, Matthew J Fuchter, and Andrew E. Ashley
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.5b01417 • Publication Date (Web): 17 Aug 2015
Downloaded from http://pubs.acs.org on August 19, 2015
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A Facile Protocol for WaterꢀTolerant ‘Frustrated
Lewis Pair’ꢀCatalyzed Hydrogenation
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Daniel J. Scott,a Trevor R. Simmons,b Elliot J. Lawrence,b Gregory G. Wildgoose,b Matthew J.
Fuchter,a and Andrew E. Ashleya,*
aDepartment of Chemistry, Imperial College London, London, SW7 2AZ, U.K.
bEnergy Materials Laboratory, School of Chemistry, University of East Anglia, Norwich
Research Park, Norwich, NR4 7TJ, U.K.
KEYWORDS: ‘frustrated Lewis pairs’, catalytic hydrogenation, water tolerance, solvent effects,
metalꢀfree.
ABSTRACT: Despite rapid advances in the field of metalꢀfree, ‘frustrated Lewis pair’ (FLP)
catalyzed hydrogenation, the need for strictly anhydrous reaction conditions has hampered wideꢀ
scale uptake of this methodology. Herein we report that, despite the generallyꢀperceived
moistureꢀsensitivity of FLPs, 1,4ꢀdioxane solutions of B(C6F5)3 actually show appreciable
moisture tolerance, and can catalyze hydrogenation of a range of weakly basic substrates without
the need for rigorously inert conditions. In particular, reactions can be performed directly in
commerciallyꢀavailable nonꢀanhydrous solvents, without subsequent drying or use of internal
desiccants.
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With the advent of ‘frustrated Lewis pair’ (FLP) chemistry, metalꢀfree catalytic hydrogenation
has managed to progress, in less than a decade, from the first example of reversible metalꢀfree H2
activation,1 into an established area of active research.2 In this remarkably short space of time
the substrate scope of FLP hydrogenation methodologies (in which H2 is activated through the
cooperative action of a Lewis acid/base pair precluded from forming a strong classical adduct)
has expanded from the initial basic imines and aziridines3 to include a wide variety of other
functional groups2 including heterocycles,4 simple alkenes and alkynes,5 and most recently,
aldehydes and ketones.6
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As FLP chemistry becomes more established, focus has inevitably begun to shift from
early, ‘proofꢀofꢀconcept’ studies to the aim of developing more practical and widely applicable
FLP catalysts. To this end, recent reports have been seen emphasising the development of FLPs
that can operate with low catalyst loadings,5a, 7 or with high enantioselectivity.8 Despite these
advances, one factor that seriously limits the attractiveness of the FLP catalysts reported to date
is their extreme sensitivity (and perceived sensitivity) to moisture9 (as well as many other
functional groups),4, 9ꢀ10 requiring these reagents to be handled and employed under rigorously
inert conditions, through use of gloveboxes and Schlenk lines. This lack of H2O tolerance
represents a significant practical barrier to the uptake of FLP catalysis by the broader chemical
community, which must be overcome if FLPs are truly to become viable alternatives to transition
metal hydrogenation catalysts.
Several attempts have been made to mitigate this problem in recent years. For example,
we have reported the use of B(C6Cl5)(C6F5)211 as a benchꢀstable Lewis acid for FLP chemistry;12
however, this system still required the use of rigorously dry reaction conditions (including
freshly distilled, anhydrous solvent) during catalytic hydrogenations. Separately, Ingleson et al.
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have described the use of the Nꢀmethylacridinium cation as a Lewis acid for FLP H2 activation in
wet 1,2ꢀdichlorobenzene,13 yet these reaction conditions were not extended to subsequent
hydrogenation catalysis. Additionally, significant hydrolysis (40 %) was observed. More
recently, Stephan et al. have reported an FLPꢀcatalyzed deoxygenation of aryl ketones and,
although this reaction produces H2O as a byꢀproduct, the use of molecular sieves as a reagent
ensures that the reaction mixture remains strictly anhydrous.6c As such, the challenge of
developing simple, H2Oꢀtolerant FLP catalytic systems remains an open one.14
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The origins of FLPs’ moisture sensitivity can be understood by considering as an
example the archetypal Lewis acid of FLP chemistry: commerciallyꢀavailable B(C6F5)3 (1). Due
to its high Lewis acidity, complexation of H2O is not only strong, but leads to significant
Brønsted acidification (the pKa of [1·OH2] has been found to be comparable to that of HCl)15 and
accordingly, deprotonation by even moderately strong bases (including the amines and
phosphines typically employed in FLP chemistry) is irreversible. Under more forcing
conditions, the adduct [1·OH2] is also prone to decomposition via B—C bond protonolysis
(Scheme 1).16
Scheme 1. Pathways for deactivation of 1 by H2O.
Recently we,6a and Stephan et al.,6b have independently reported the hydrogenation of
ketones and aldehydes to alcohols, catalyzed by 1 in ethereal solvents (Scheme 2). These
reactions are clearly tolerant of hydroxylic functionalities, which is attributed to the weak
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Brønsted basicity of the ethers employed, which inhibits irreversible deprotonation of the highly
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acidic [1·ROH] adducts.
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Scheme 2. Previouslyꢀreported hydrogenation of aldehydes and ketones catalyzed by 1.6a, b R =
aryl, alkyl; R’ = alkyl, H
Following on from these results, we reasoned that these systems might also be capable of
tolerating the presence of H2O, for similar reasons, which would represent an important advance
for the field of FLP chemistry. Initial investigations focused on the hydrogenation of acetone
(the simplest substrate previously examined under anhydrous conditions). Gratifyingly, when 1
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was replaced with the preꢀformed adduct 1·OH2 under identical conditions, selective
hydrogenation to 2ꢀpropanol was observed to proceed cleanly, and with good turnover number
(Table 1, entry 2). Although the rate of reaction is reduced (c.f. Table 1, entry 1), confirming
that H2O acts as a significant catalyst poison, inhibition by H2O is nonetheless clearly reversible.
At the time, this represented the first example of an FLPꢀcatalyzed hydrogenation that is tolerant
of stoichiometric (relative to catalyst) H2O.
Increasing the H2 pressure led to a significant rate enhancement, even at lower catalyst
loadings (Table 1, entry 3), and without any detectable catalyst decomposition (ascertained by
19F and 11B NMR spectroscopy). Under these conditions, several more equivalents of H2O could
be tolerated, with an attendant decrease in rate yet otherwise no major difference in reaction
outcome (Table 1, entries 4 & 5).
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Table 1. Metalꢀfree catalytic hydrogenation of acetone in the presence of various amounts of
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H2O.
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Entry [Me2CO] / M [1] / mol% [H2O] : [1] p / bar
t / h
6
Conv. / %a
TON
20
1b,c
2c
3e
4e
5e
6f
0.50
0.29
0.27
0.27
0.27
0.53
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0
1d
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99
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2.5
2.5
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2.5
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>1g
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b
a All conversions measured by H NMR integration. Result taken from Ashley et al.6a c 0.2
d
e
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mmol acetone. Added as [1·OH2]. 4.0 mmol acetone. 8 mmol acetone, ACS reagent grade
commercial solvent (Sigma Aldrich). g Confirmed by control experiments (see SI).
Based on the ability of this system to tolerate multiple equivalents of water, we reasoned
that the use of ‘undried’ solvents ought to be achievable; impressively the reaction could be
performed very effectively in nonꢀanhydrous commercial solvent17 even without any need for
subsequent drying, degassing, or other purification. Furthermore, doubling the substrate and
catalyst concentrations allowed for a significant decrease in reaction time (Table 1, entry 6).
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Scheme 3. Proposed mechanism for moistureꢀtolerant hydrogenation of acetone (possible
hydrogen bonding of solvent with [1·ROH] and [1·OH2] omitted for clarity)
The mechanism by which the hydrogenation is believed to occur is identical to that
proposed for the anhydrous reaction, with [1·OH2] acting as an offꢀcycle resting state (Scheme
3).18 As with previouslyꢀobserved alcohol tolerance, H2O tolerance is attributed to the lack of
any strong base, meaning irreversible deprotonation of [1·OH2] does not occur (c.f. Scheme 1).
Even so, it seems possible that reversible deprotonation does occur, which could be consistent
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with the acidity of this adduct (vide supra).19 Evidence for deprotonation comes from B NMR
spectroscopy: while [1·OH2] alone shows an 11B NMR resonance at 4.6 ppm in the nonꢀ
coordinating yet highly polar solvent 1,2ꢀdifluorobenzene (DFB), addition of 1,4ꢀdioxane leads
to a clear upfield shift, to −0.6 ppm with 1 equivalent of ethereal base, and −2.1 ppm with 10
equivalents (Figure 1).20 Typical nonꢀanhydrous reaction mixtures, which contain [1·OH2] in
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neat 1,4ꢀdioxane, produce resonances further upfield still, at −3.0 ppm. For comparison, the B
NMR shift of [NMe4][1·OH], which contains the ‘free’ conjugate base of [1·OH2], has been
reported as −2.1 ppm in CD2Cl2, with similar shifts for related salts.21 1H NMR analysis also
suggests an interaction between [1·OH2] and 1,4ꢀdioxane, with the 1,4ꢀdioxane resonance shifted
slightly downfield, from 3.56 ppm in the absence of [1·OH2], to 3.59 ppm in the presence of 1
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equivalent, indicating overall deshielding. Although displacement of H2O for 1,4ꢀdioxane could
also potentially explain these shifts in the NMR spectra, this possibility can be discounted:
addition of 1 and 10 equivalents of 1,4ꢀdioxane to dry 1 in DFB leads to 11B NMR resonances at
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1
9.8 ppm and 5.7 ppm respectively, and 1,4ꢀdioxane H resonances at 3.96 ppm and 3.59 ppm
respectively; in all cases significantly further downfield than when H2O is also present.
Figure 1. Variation in 11B NMR chemical shift of [1·OH2] upon addition of 1,4ꢀdioxane in
DFB.
Reversible deprotonation of [1·OH2], and the related [1·ROH] adducts, may partially
explain the large effect that pressure has been observed to have on both the anhydrous and nonꢀ
anhydrous reactions. Increasing H2 pressure will increase the solution concentration of H2 and,
in turn, the degree of H2 activation. The resulting increase in Brønsted acid concentration should
perturb the equilibrium between [1·OH2]/ [1·iPrOH] and [1·OH]−/ [1·OiPr] in favour of the
−
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more weakly bound neutral adducts, hence facilitating catalytic turnover via ROH/H2O
dissociation from 1.
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Table 2. Metalꢀfree hydrogenation of weaklyꢀbasic substrates in nonꢀanhydrous solvent.
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Entrya
Substrate
Product
[1] / mol%
t / h
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Conv. / %b
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1
2c
3d
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10
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50
>99
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>99
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>99
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6d
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8c
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>99 e
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0
5
0
a Standard conditions: 4.0 mmol substrate, 0.53 M. All conversions measured by H NMR
b
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integration. c 2.0 mmol substrate. d 8.0 mmol substrate. e Unquantified mixture of isomers.
Given that the rationale for H2O tolerance in this system depends primarily on the
absence of a strong base, it seemed reasonable that catalytic hydrogenation without the need for
rigorously dry conditions might also be achievable for other weakly basic substrates. To this end,
a variety of additional substrates (both carbonyls and nonꢀcarbonyls) were treated under similar
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conditions. For most, clean, efficient catalytic reduction was observed without the need for
extensive further optimisation (Table 2, entries 1ꢀ7), clearly indicating the generality of this
waterꢀtolerant methodology. As well as using undried solvent, reactions could be performed
under open bench conditions, without the need for inert atmosphere containment systems22
(although longꢀterm storage of 1 is best carried out in a glovebox). By contrast, the attempted
reduction of cyclohexanone under the same conditions was unsuccessful (Table 2, entry 8) which
is qualitatively consistent with previous observations made under dry conditions,6a where higher
pressures were required for hydrogenation than for the other carbonyl substrates. Collectively,
these results suggest a similar substrate scope for the anhydrous and nonꢀanhydrous reaction
protocols.
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As well as the advantages already discussed, moistureꢀtolerance should also allow FLPs
to catalyze reactions that produce H2O. To this end, acetophenone was exposed to our
anhydrous reaction conditions. Clean, catalytic reductive deoxygenation to ethylbenzene23 was
observed, despite the concomitant formation of H2O (5 equivalents relative to catalyst) that
necessarily occurs (Scheme 4).
Scheme 4. Hydrogenation of acetophenone to ethylbenzene and H2O catalyzed by 1.
In conclusion, we have demonstrated a number of examples of FLPꢀcatalyzed
hydrogenation reactions demonstrating appreciable water tolerance. As a result, a variety of
weakly basic substrates can be hydrogenated cleanly and in high yield, in the absence of a
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transition metal catalyst, in commercialꢀgrade ‘bench’ (undried) solvents. By removing the need
for both extensive, laborious drying of reaction solvents and inert atmosphere reaction
techniques, this development significantly increases the practicality of the FLP hydrogenation
methodology. These findings extend the current reach of FLP hydrogenation catalysis from
rigorously anhydrous research laboratory conditions into industriallyꢀrelevant, commerciallyꢀ
available solvent grades and reaction conditions.
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ASSOCIATED CONTENT
Supporting Information. Full experimental details are available in the Supporting Information.
This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Department of Chemistry, Imperial College London, London, SW7 2AZ, U.K. Email:
a.ashley@imperial.ac.uk. Tel: +44 (0)20 759 45810.
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We would like to thank GreenCatEng, Eli Lilly (Pharmacat consortium), and the EPSRC for
providing funding for a PhD studentship (D.J.S.), and Dr George Britovsek and Prof. Ramon
Vilar for access to high pressure equipment. G.G.W. and A.E.A. thank the Royal Society for
financial support through University Research Fellowships. The research leading to these results
has received funding from the European Research Council under the ERC Starting Grant
Agreement no.307061 (PiHOMER) and ERC PoC Grant Agreement no. 640988 (FLPower).
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REFERENCES
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Bergander, K.; Paradies, J. Angew. Chem. Int. Ed. 2013, 52, 5876ꢀ5879.
(11) Ashley, A. E.; Herrington, T. J.; Wildgoose, G. G.; Zaher, H.; Thompson, A. L.; Rees, N.
H.; Krämer, T.; O’Hare, D. J. Am. Chem. Soc. 2011, 133, 14727ꢀ14740.
(12) Scott, D. J.; Fuchter, M. J.; Ashley, A. E. Angew. Chem. Int. Ed. 2014, 53, 10218ꢀ10222.
(13) Clark, E. R.; Ingleson, M. J. Angew. Chem. Int. Ed. 2014, 53, 11306ꢀ11309.
(14) While this manuscript was under review, Soós et al. reported a moistureꢀtolerant protocol
for FLPꢀcatalysed hydrogenation of aldehydes and ketones using novel boranes specifically
designed for that purpose: Gyömöre, Á.; Bakos, M.; Földes, T.; Pápai, I.; Domján, A.; Soós, T.
ACS Catal. 2015, doi: 10.1021/acscatal.5b01299. Their approach – targeted design of new
catalysts, rather than adaptation of existing FLP hydrogenation protocols – complements the
work reported herein.
(15) pKa = 8.4 in MeCN, c.f. 8.5 for HCl: Bergquist, C.; Bridgewater, B. M.; Harlan, C. J.;
Norton, J. R.; Friesner, R. A.; Parkin, G. J. Am. Chem. Soc. 2000, 122, 10581ꢀ10590.
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(16) a) Bradley, D. C.; Harding, I. S.; Keefe, A. D.; Motevalli, M.; Zheng, D. H. J. Chem. Soc.,
Dalton Trans. 1996, 3931ꢀ3936. b) Ashley, A. E.; Thompson, A. L.; O'Hare, D. Angew. Chem.
Int. Ed. 2009, 48, 9839ꢀ9843.
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(17) ACS reagent grade 1,4ꢀdioxane purchased from Sigma Aldrich was used. Karl Fischer
titration indicated 220 ppm / 0.022% H2O (w/w) (advertised as up to 0.05%).
(18) We propose that 1,4ꢀdioxane acts as the main base for hydrogen activation due to the vast
excess (12 M) in which it is present. However, in principle, this role could also be played by
water or 2ꢀpropanol.
(19) The pKa of protonated 1,4ꢀdioxane has been measured as −2.92 in aqueous solution (see:
Arnett, E.; Wu, C. Y. J. Am. Chem. Soc. 1960, 82, 4999ꢀ5000). Although the aqueous pKa of
[1·OH2] has not been measured,15 our results indicate that it may be comparable .
(20) It should be noted that these observations could also be consistent with strong hydrogen
bonding to the solvent rather than full formal deprotonation; in practice the true situation might
be expected to lie somewhere between these two extremes.
(21) a) Hewavitharanage, P.; Danilov, E. O.; Neckers, D. C. J. Org. Chem. 2005, 70, 10653ꢀ
10659. b) Bibal, C.; Santini, C. C.; Chauvin, Y.; Vallee, C.; OlivierꢀBourbigou, H. Dalton Trans.
2008, 37, 2866ꢀ2870.
(22) For all experiments [H2O] > [1], as indicated by control experiments: see SI.
1
(23) H NMR analysis of an aliquot taken at partial conversion showed formation of styrene (in
addition to ethylbenzene and the expected alcohol intermediate), which is consistent with
previous observations made at lower pressure.6a At completion only ethylbenzene was observed,
however, indicating that the alkene undergoes further reduction (either directly, or via
rehydration to the alcohol).
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90x38mm (300 x 300 DPI)
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