Journal of the American Chemical Society
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(13) Piers, W. E.; Marwitz, A. J. V.; Mercier, L. G. Inorg. Chem. 2011,
50, 12252.
pearance of the resonances attributed to the aldehyde in the H
1
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NMR spectrum, concomitant with the appearance of sharp resoꢀ
nances at ca. −2.5 ppm in the 11B NMR spectra, consistent with
formation of the 1a·alkoxide adducts;34 this suggests an alternaꢀ
tive, Lewis acidꢀcatalysed reaction pathway may also be feasible
for these substrates (Scheme 4b). In fact, similar reactivity is
observed for these aldehydes even without addition of 1a,35 sugꢀ
gesting that their reductions may even proceed without any prior
activation of the carbonyl (Scheme 4c). Nevertheless, Brønsted or
Lewis acid catalysis cannot be ruled out, and further studies are
needed to confirm the validity and generality of our proposed
mechanisms.
(14) Lindqvist, M.; Sarnela, N.; Sumerin, V.; Chernichenko, K.; Leskela,
M.; Repo, T. Dalton Trans. 2012, 41, 4310.
(15) Longobardi, L. E.; Tang, C.; Stephan, D. W. Dalton Trans. 2014, doi:
10.1039/C4DT02648A
(16) Spies, P.; Erker, G.; Kehr, G.; Bergander, K.; Frohlich, R.; Grimme,
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J.; Geier, S. J.; Farrell, J. M.; Brown, C. C.; Heiden, Z. M.; Welch, G. C.;
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2002, 124, 8693.
(27) Confirmed by independent addition of iPrOH and iPr2O to 1b in d8ꢀ
THF in the appropriate molar ratios.
(28) Ashley, A. E.; Herrington, T. J.; Wildgoose, G. G.; Zaher, H.;
Thompson, A. L.; Rees, N. H.; Kraemer, T.; O'Hare, D. J. Am. Chem. Soc.
2011, 133, 14727.
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In conclusion, we have developed a protocol for TMꢀfree, FLPꢀ
mediated catalytic hydrogenation of aliphatic and aromatic
ketones and aldehydes to their respective alcohols; the first such
system to be reported. Preliminary mechanistic studies suggest
that ketone reduction likely occurs via Brønsted acid activation of
the substrate followed by hydride transfer, but that alternative
mechanisms may be feasible for more electrophilic aldehyde
substrates; competitive coordination of the solvent then facilitates
dissociation of the product from the Lewis acid catalyst. We
anticipate that with further rational variation of both the solvent
and borane catalyst, hydrogenation of more challenging carbonyl
substrates should be possible using systems of this type.
Investigations in this area are ongoing, and will be reported in due
course.
ASSOCIATED CONTENT
Supporting Information
(29) At no point during the course of our studies was any evidence for
ringꢀopening or polymerisation of the solvent observed.
(30) The different outcome in 1,4ꢀdioxane may simply be attributable to
its reduced polarity (ε1,4ꢀdioxane = 2.22, εTHF = 7.52) and lower Brønsted
basicity relative to THF. This should reduce the concentration of ionic
species, including solvated ‘H+’, present in the reaction mixture. Since the
condensation mechanisms are likely to proceed via carbocationic intermeꢀ
diates in the acidic media, condensation/dehydration pathways are more
likely to be supressed in 1,4ꢀdioxane over THF.
(31) For our previous 1b/THF system the hydrogen activation product
[(THF)nH][H·1b] could be observed directly by low temperature 11B NMR
spectroscopy.24 Such direct observation is not possible in this case due to
the high melting point of 1,4ꢀdioxane. However, admission of HD (1 bar)
to a solution of 1a in 1,4ꢀdioxane leads to formation of H2 (clearly visible
by 1H NMR spectroscopy) over several hours at room temperature, clearly
demonstrating that reversible activation must occur (see SI).
(32) No resonances attributable to [1a·H]− are observed by 1H, 19F or 11B
NMR spectroscopy for solutions of 1a in 1,4ꢀdioxane under H2 (5 bar) at
100 °C.
Supplementary information includes full experimental details and
spectroscopic characterization of products. This material is availꢀ
AUTHOR INFORMATION
Corresponding Author
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We would like to thank GreenCatEng, Eli Lilly (Pharmacat conꢀ
sortium) and the EPSRC for providing funding for a PhD studentꢀ
ship (DJS), and the Royal Society for a University Research Felꢀ
lowship (AEA).
(33) This activation is perhaps best characterised as a hydrogen bonding
interaction in which the substrate enters the inner coordination sphere of
the solvated proton. The pKa of protonated acetone, for example, is much
lower than that of protonated 1,4ꢀdioxane (−7.2 vs. −2.9223 in H2O), but its
acidity is known to drop appreciably upon interaction with hydrogen bond
acceptors such as H2O. See: Campbell, H.J.; Edward, J.T. Can. J. Chem.,
1960, 38, 2109; Palm, V. A.; Haldna U. L.; Talvik A. J.; Patai, S. Basicity
of carbonyl compounds, in The Carbonyl Group: Volume 1, John Wiley &
Sons, Ltd., Chichester, UK, 1966; and references therein.
REFERENCES
(1) de Vries, J. G.; Elsevier, C. J., The Handbook of Homogeneous Hydro-
genation, WileyꢀVCH: Weinheim, Germany, 2008.
(2) Darwish, M.; Wills, M.; Catal. Sci. Technol. 2012, 2, 243.
(3) Welch, G. C.; Juan, R. R. S.; Masuda, J. D.; Stephan, D. W. Science
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(4) Chase, P. A.; Welch, G. C.; Jurca, T.; Stephan, D. W. Angew. Chem.
Int. Ed. 2007, 46, 8050.
(5) Hounjet, L. J.; Stephan, D. W. Org. Proc. Res. Dev. 2014, 18, 385.
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1
(34) The product resonances are not observed in the H NMR spectrum,
due to precipitation of [nBu4N][1a·OCH2Ar] from the reaction mixture;
however removal of the solvent in vacuo and subsequent addition of
CD2Cl2 allows the products to be clearly observed, most notably by their
diagnostic CH2 singlet resonances at ca. 4.5 ppm.
(35) For 2,6ꢀdichlorobenzaldehyde the reduction is significantly slower in
the absence of additional 1a, and for neither substrate does the reaction
proceed to completion. Both observations may simply be attributable to
coꢀprecipitation of [nBu4N][1a·OCH2Ar] and [nBu4N][1a·H] from the
1,4ꢀdioxane solvent, which results in separation of the substrate and reꢀ
ductant into different phases. Repeating the experiments using CD2Cl2 as
the solvent (or removing 1,4ꢀdioxane in vacuo and replacing it with
CD2Cl2) prevents phase separation, and complete reduction is observed to
occur immediately for both substrates.
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