6,6′-Dihydroxy terpyridine: A proton-responsive bifunctional ligand and its application in catalytic transfer hydrogenation of ketones

Article abstract of DOI:10.1039/c2cc36927c

The ligand 6,6′-dihydroxy terpyridine (dhtp) is presented as a bifunctional ligand capable of directing proton transfer events with metal-coordinated substrates. Solid-state analysis of a Ru(ii)-dhtp complex reveals directed hydrogen-bonding interactions of the hydroxyl groups of dhtp with a Ru-bound chloride ligand. The utility of dhtp was demonstrated by chemoselective transfer hydrogenation of ketones.

Full text of DOI:10.1039/c2cc36927c

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6,60-Dihydroxy terpyridine: a proton-responsive
bifunctional ligand and its application in catalytic
transfer hydrogenation of ketones†
Cite this: Chem. Commun.,
2013, 49, 400
Received 24th September 2012,
Accepted 14th November 2012
Cameron M. Moore and Nathaniel K. Szymczak*
DOI: 10.1039/c2cc36927c
www.rsc.org/chemcomm
The ligand 6,60-dihydroxy terpyridine (dhtp) is presented as a bifunc- promotes directed interactions between the secondary coordi-
tional ligand capable of directing proton transfer events with metal- nation sphere environment and metal-bound substrates.
coordinated substrates. Solid-state analysis of a Ru(II)-dhtp complex
The ligand, 6,60-dihydroxy terpyridine was selected as a
reveals directed hydrogen-bonding interactions of the hydroxyl groups rigid, pincer-based framework that enforces interactions of
of dhtp with a Ru-bound chloride ligand. The utility of dhtp was the ligand hydroxyl groups with metal-bound substrates, and
demonstrated by chemoselective transfer hydrogenation of ketones.
is capable of promoting bifunctional catalysis.7
The tautomerism of 6,60-dihydroxy terpyridine(dhtp) provides
Metal–ligand cooperativity is a key aspect of H2 activation/transfer accessible proton donors and acceptors in the secondary coordina-
by bifunctional catalysts. These systems exploit intramolecular tion sphere of the metal center, when maintaining a meridonal
proton transfer as a means to (a) store proton equivalents in the N,N,N-coordination mode. The ligand binding modes of the two
ligand periphery and/or (b) utilize the protonation/deprotonation tautomeric forms of dhtp also present drastically different ligand
event to modulate the structural and electronic properties of the fields; the hydroxy-tautomer serving as an L3-type ligand, while the
ligand.1 Biological systems similarly engage metal–ligand coop- deprotonated pyridone tautomer (dhtp0) acting as an LX2-type
erativity to mediate multi-electron redox events, proton-coupled ligand (Fig. 1). Such proton-responsive ligand-field dependence is
electron-transfer reactions, and substrate activation.2 A biologically- a common feature of catalysis involving proton-transfer events.1c,d,8
relevant M–L platform for bifunctional activation was recently
We targeted a straightforward synthesis of dhtp, amenable to
visualized following the discovery of a 2-hydroxypyridine-derived gram quantity scalability. Because this compound was previously
cofactor in the active site of the hydrogenase metalloenzyme, [Fe]- synthesized using F2-derived reagents9 and multi-step ring-closing
hmd,3 and subsequently, synthetic transition-metal complexes metathesis routes,10 we devised an alternative two-step route
supported by 2-hydroxypyridine (2-HP)-derived ligands have been that proceeds from the commercially-available 6,60-dibromo
demonstrated to promote (de)hydrogenation catalysis.4 While the terpyridine (Scheme S1, ESI†). Palladium(II)-catalyzed coupling
intimate details of the role of the 2-HP unit in [Fe]-hmd are still of 6,60-dibromo terpyridine with sodium tert-butoxide afforded
under investigation, the tautomeric pair 2-HP and 2-pyridone likely 6,60-di-tert-butoxy terpyridine in 81% yield. Conveniently,
function to facilitate H2 cleavage and transfer.3b,5
hydrolysis of the tert-butoxide groups proceeds within minutes
Approaches to synthetic systems that seek to emulate a coopera- at room temperature upon addition of formic acid, and cleanly
tive H2 activation pathway, reminiscent of [Fe]-hmd, have targeted provides dhtp in 80% yield as a microcrystalline powder; the
bidentate ligand frameworks, such as bipyridine and bipyrimidine, preparation can be scaled to gram quantities.
that incorporate 2-HP units.6 Piano-stool type complexes containing
The ability of metal-dhtp adducts to promote hydrogen-
such appended 2-HP structural units have shown promising hydro- transfer reactivity was probed by examining Ru(II) complexes
genation activity; however, the orientation of the appended OH containing PPh3 as an auxiliary ligand. Reaction of equimolar
groups with respect to the metal-bound substrate limits their utility
as efficient hydrogenation catalysts due to a necessary reorganiza-
tion required for H2 heterolysis. Accordingly, we targeted
hydrogen-transfer reactivity using a ligand framework that
Department of Chemistry, University of Michigan, 930 N. University, Ann Arbor, MI,
USA. E-mail: nszym@umich.edu
† Electronic supplementary information (ESI) available: Detailed synthetic and experi-
mental procedures as well as 1H and 31P NMR spectra of 1. CCDC 902601. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c2cc36927c
Fig. 1 Dhtp as a proton-responsive ligand.
c
400 Chem. Commun., 2013, 49, 400--402
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Table 1 Scope of transfer hydrogenation catalyzed by 1 and KOtBua
Entry
1
Substrate
Yieldb (%)
98
TOFc (hꢁ1
)
82
Fig. 2 Solid-state structure of 1 (30% thermal ellipsoids: hydrogen atoms not
involved in hydrogen bonds, phenyl rings on PPh3 ligands and PFꢁ anion omitted
for clarity).‡ Selected bond distances (Å) and angles (1): Ru1-N1 1.974(3), Ru1-N2
2.129(3), Ru1-N3 2.116(3), Ru1-Cl1 2.4926(8), Ru-P1 2.4403(9), Ru1-P2 2.415(1),
N2-Ru1-N3 158.05(12), N1-Ru1-Cl1 177.29(8), P1-Ru1-P2 178.31(3).
2
3
100
92
100
42
quantities of RuCl2(PPh3)3 and dhtp in refluxing methanol under
an inert atmosphere provided trans-RuCl(dhtp)(PPh3)2PF6 (1) after
anion metathesis with [NH4][PF6]. The solid state structure of 1
(Fig. 2) reveals octahedral coordination around ruthenium(II), with
mutually trans PPh3 ligands. Notably, both of the pendant hydroxyl
groups engage in close-contact interactions to the Ru-bound
chloride (O1-Cl1 and O2-Cl of 3.017(3) and 2.966(3) Å, respectively);
consistent with intramolecular hydrogen-bonding interactions.
Additionally the solid-state structure of 1 reveals C–O distances
of the terpyridine fragment (1.336(5) and 1.335(5) Å) consistent
with C–O single bonds and a neutral ligand scaffold.11
4
5
100
78
64
66
6
7
17
0
10
0
The orientations of the hydroxyl groups in 1 with respect to the
Ru-bound chloride can be used to approximate subsequent
M-substrate interactions. For a relevant comparison, Ru-based
piano-stool complexes featuring 6,60-dihydroxy bipyridine (dhbp),
8d
79
26
[(Z6-arene)Ru(dhbp)Cl]+,6d were selected. In 1, the torsion angles 9d
between the Ru–Cl and C–O bond vectors are 2.931 and 4.221 (avg.
57e,f
n.d.
10d
66e
95e
n.d.
n.d.
3.581), which demonstrates that the two bond vectors lie nearly
co-planar. In contrast, the torsion angles are significantly greater
in the case of the dhbp adduct: 65.451 and 62.441 (arene = C6Me6,
avg. 63.951), and 82.711 and 82.311 (arene = p-cymene, avg. 82.511).
The OHꢀꢀꢀCl interaction was further investigated by comparison
of the average distances between the hydroxyl groups and the Cl
atom between 1 and the [(Z6-arene)Ru(dhbp)Cl]+ complexes; 3.007 Å
for 1, 3.489 Å (arene = C6Me6) and 3.773 Å (arene = p-cymene), the
former is consistent with an intramolecular hydrogen-bonding
interaction. The differences in distances, as well as geometry,
11d
a
General conditions: 0.05 mmol ketone, 0.00025 mmol 1, 0.005 mmol
KOtBu, 0.500 mL PrOH, 0.029 mmol PhTMS, 80 1C, 12 h. NMR yield
i
b
c
calculated against PhTMS internal standard. TOF calculated after 2 h,
d
TOF = 0.5 ꢂ [(mmol ketone)o – (mmol ketone)t=2]/(mmol 1). Reaction
e
time 24 h. Yield determined by GC/MS; yield of carbonyl hydrogenation
f
product. Note other products are observed, see text. 1 mol% PPh3 added.
between hydroxyl groups and the ruthenium-bound chloride atom tolerates heteroaromatics such as 2-acetylpyridine, which can
(a surrogate for a metal-bound hydride) suggest that the ligand be reduced to the corresponding alcohol in good yield (79%) over
geometry imposed by 1 is predisposed to offer a strongly coupled 24 h (entry 8). This finding is noteworthy because the product,
hydride/hydroxyl system for hydride and proton transfer.
1-(2-pyridinyl)ethanol, is a strongly chelating bidentate ligand,14
To confirm the utility of the favorable orientations of the which could coordinate an active hydrogenation catalyst that
hydroxyl groups in 1, we examined transfer hydrogenation reacti- contains more than one accessible coordination site.
vity of acetophenone using complex 1 as a catalyst. Using 0.5 mol%
Given that one of the hallmarks of outer-sphere hydrogena-
1 and 10 mol% KOtBu in neat 2-propanol, acetophenone is tion catalysts is the ability to perform chemoselective hydroge-
reduced to 1-phenylethanol in nearly quantitative (98%) yield over nations, we examined the transfer hydrogenation of unsaturated
the course of 12 hours at 80 1C (Table 1, entry 1).12,13 Substitution ketone substrates by 1 and KOtBu. Using our general conditions
of the 4-position with electron donating groups (entry 3) was found for transfer hydrogenation, 5-hexen-2-one is converted to a
to slightly decrease hydrogenation, while electron withdrawing mixture of hydrogenation products with high conversion (95%)
groups (entry 2) slightly promoted hydrogenation. Aliphatic over 24 h; the ratio of 1 : 0.55 : 0.71 obtained for 5-hexen-2-ol,
ketones were hydrogenated with yields highly sensitive to the 2-heptanone and 2-hexanol, respectively, with a 42% yield of
ketone steric environment (entries 4–6). Additionally, when 5-hexen-2-ol. We hypothesized that this low observed selectivity
benzophenone is used as a substrate no hydrogenation product may be due to a competitive inner-sphere hydrogenation pathway
is observed (entry 7). The catalytic system of 1 and KOtBu which could be suppressed using PPh3. In support, addition of
c
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1 mol% PPh3 provided an increase in selectivity for the carbonyl Notes and references
hydrogenation product, giving a ratio of the aforementioned
‡ Crystal data for 1ꢀEt2O: C55H51ClF6N3O3P3Ru, Mw = 1145.42, Triclinic;
%
products of 1 : 0.16 : 0.30 after 24 h, with 57% yield of 5-hexen-
2-ol (Table 1, entry 9).15 This finding is consistent with suppression
of an alternative, non-selective hydrogenation mechanism, how-
ever further studies are merited to elucidate the intimate details.
Based on our results illustrating a high steric dependence on
hydrogenation, we hypothesized that the chemoselectivity of
transfer hydrogenation by 1/KOtBu could be further increased by
introducing steric differentiation between the carbonyl and
olefin groups. We tested this by performing the transfer hydro-
genation of 5-methyl-5-hexen-2-one (entry 10). Transfer hydro-
genation of this substrate proceeds to 81% conversion after
24 h to afford a mixture of 5-methyl-5-hexen-2-ol, 5-methyl-5-
hexen-2-one and 5-methyl-5-hexen-2-ol in a 1 : 0.09 : 0.13 ratio,
respectively, with a 66% yield of 5-methyl-5-hexen-2-ol. Further
increasing the steric environment around the olefin provides high
chemoselectivity. Transfer hydrogenation of 6-methyl-5-hexen-2-
one provides 6-methyl-5-hexen-2-ol as the exclusive transfer hydro-
genation product in 95% yield (entry 11). This highlights the
ability of the catalytic system 1/KOtBu to differentiate between
steric environments and double bonds, and consistent with prior
reports of metal-mediated bifunctional catalysis.1b,e
Ligand dissociation is a common initiation step for most
Ru-based inner-sphere hydrogenation catalysts.16 Thus, we examined
whether exogenous PPh3 hindered catalytic transfer hydrogenation
mediated by 1. We hypothesized that, for an outer sphere mecha-
nism, conditions suited to suppress the loss of PPh3 would not
inhibit catalysis. Indeed, when an excess of PPh3 (2–8 eq.) is added
to the reaction mixture, the rate of transfer hydrogenation cata-
lyzed by the 1/KOtBu system is not significantly affected (Fig. S7,
ESI†). This result suggests that PPh3 dissociation is not involved in
the rate-limiting step of transfer hydrogenation, and is consistent
with a catalytically-active species that retains both PPh3 ligands.17
The stoichiometry of transfer hydrogenation was also examined by
quantifying the formation of acetone, relative to 1-phenylethanol,
during the reduction of acetophenone, which revealed that equi-
molar quantities of acetone and 1-phenylethanol are produced
concomitantly during the transfer hydrogenation.
Space group P1; a = 9.8116(2), b = 13.4845(3), c = 20.0259(14) Å, a =
107.241(7)1, b = 95.644(7)1, g = 94.671(7)1; V = 2501.09(19) Å3; Z = 2;
r
calcd = 1.521 Mg mꢁ3; F(000) 1172; Crystal size 0.13 ꢂ 0.02 ꢂ 0.02 mm3,
reflections collected: 69 525; independent reflections: 9002 [R(int)
=
0.1001]; y range 2.33 to 68.251; goodness-of-fit on F2 1.152; final R
indices [I > 2s(I)]: R1 = 0.0521, wR2 = 0.1406; R indices (all data): R1
0.0546, wR2 = 0.1434.
=
¨
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ligand in transition-metal complexes (see ref. 9 and 10).
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In conclusion, we have presented dhtp as a rigid bifunctional
ligand that promotes directed interactions with metal-bound
substrates, such as chloride (a surrogate for hydride). The
ruthenium(II) complex 1 efficiently catalyzes the transfer hydro-
genation of a variety of ketones in the presence of KOtBu in
2-propanol. High chemoselectivity was realized in the presence
of substituted alkenes, and 1 selectively catalyzes the reduction
of carbonyl groups in the presence of non-polar olefins. A
potential catalytic cycle for this transformation may involve an
outer sphere transfer of hydride/proton equivalents from the
metal and ligand backbone (respectively) to a ketone substrate.
Further experiments to isolate potential catalytic intermediates,
as well as detailed mechanistic analyses, are currently underway.
We thank the University of Michigan for financial support, and
NSF grant CHE-0840456 for X-ray diffraction instrumentation.
C.M.M. thanks the NSF-GRFP and the University of Michigan
Rackham Graduate School for predoctoral fellowships. Jeff W.
Kampf is acknowledged for crystallographic assistance.
12 In the absence of base, we observe no reduction of acetophenone. When
the amount of base is decreased to 5 mol%, the rate of acetophenone
redution is nearly unaffected, however the time required to reach the
maximum rate is significantly longer (>200 min vs. o30 min). When
1 mol% base is used, no reduction of acetophenone is observed. These
findings are consistent with base-dependent activation of the pre-
catalyst: see ref. 1g and A. Mikhailine, A. J. Lough and R. H. Morris,
J. Am. Chem. Soc., 2009, 131, 1394–1395.
13 The maximum TOF for acetophenone reduction catalyzed by
1/KOtBu (82 hꢁ1) surpasses that observed for the [(Z6-arene)Ru(dhbp)Cl]+
system (7.33 hꢁ1), however the electronic dissimilarity between
the two catalysts limits the applicability of comparison based on
geometry alone (see ref. 6d).
14 S. G. Telfer, N. D. Parker, R. Kuroda, T. Harada, J. Lefebvre and
D. B. Leznoff, Inorg. Chem., 2008, 47, 209–218.
15 See ESI†.
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2004, 248, 2201–2237.
17 The addition of Hg0 (ca. 1.4 ꢂ 104 eq.) during transfer hydrogenation
has no effect on the reaction profile. The mercury poisoning experiment,
as well as the highly reproducible reaction kinetics (see SI) provide
evidence consistent with a homogeneous ruthenium catalyst: see J. A.
Widegren and R. G. Finke, J. Mol. Catal. A: Chem., 2003, 198, 317–341.
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402 Chem. Commun., 2013, 49, 400--402
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