Synthesis and catalytic activity of histidine-based NHC ruthenium complexes

Article abstract of DOI:10.1039/c0dt01768j

Main-chain C,N-protected histidine has been successfully alkylated at both side-chain nitrogens. The corresponding histidinium salt was metallated with ruthenium(ii) by a transmetalation procedure, thus providing histidine-derived NHC ruthenium complexes. These bio-inspired complexes show appreciable activity in the catalytic transfer hydrogenation of ketones. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c0dt01768j

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Dalton
Transactions
Cite this: Dalton Trans., 2011, 40, 2716
www.rsc.org/dalton
COMMUNICATION
Synthesis and catalytic activity of histidine-based NHC ruthenium complexes†
Ange`le Monney,a,b Galmari Venkatachalamb and Martin Albrecht*a,b
Received 15th December 2010, Accepted 2nd February 2011
DOI: 10.1039/c0dt01768j
Main-chain C,N-protected histidine has been successfully
alkylated at both side-chain nitrogens. The corresponding
histidinium salt was metallated with ruthenium(II) by a
transmetalation procedure, thus providing histidine-derived
NHC ruthenium complexes. These bio-inspired comsxsxs-
plexes show appreciable activity in the catalytic transfer
hydrogenation of ketones.
The synthesis of the histidine-derived carbene ligand precursors
started with the protection of the amine and the acid group
of native histidine (Scheme 1). An acetyl unit was chosen as
the amine protecting group because of its facile introduction
and high chemical stability. Acetyl histidine 2 was obtained
according to known procedures13 and subsequently esterified at
the C-terminus.14 The corresponding methyl ester 3a was only
soluble in highly polar solvents, which hampered the subsequent
transformations considerably. Therefore, the corresponding butyl
ester 3b, comprising a longer alkyl chain, was prepared by
esterification in n-BuOH. While the yields were high, racemisation
at the a-carbon occurred during the work-up, as demonstrated
by the loss of any optical rotation of 3 at the sodium D-line.
Attempts to avoid the racemisation, by using milder bases or a
phosphate buffer (pH = 7.2) for the neutralisation, have not been
successful thus far. Optical instability of the N-acetyl protected
amino acids is well-established15 and often an undesired process.
In our case, it may provide straightforward access to both L- and D-
histidine-derived ligand precursors, which may be easily resolved
when coordinated to a metal centre through the formation of
diastereomeric complexes. Hence, racemisation is not necessarily
disadvantageous and it has been claimed to be suppressed when
using different protecting groups.12a
Functionalisation of the racemic N,C-protected histidine 3b
included the alkylation of the side chain by deprotonation, using
NaH in DMF followed by the addition of 2-iodopropane. Selective
Ne-alkylation and the exclusive formation of the regioisomer 4
was confirmed by NMR spectroscopy, which showed a single
set of signals and a NOE cross-correlation of Cd H and the i-
Pr protons. This alkylation method allows, thus, two different
wingtip groups to be selectively introduced on the imidazole ring.
Quaternisation at Nd , by refluxing 4 and MeI in toluene, afforded
the histidinium salt 5a as a hygroscopic white solid. Introduction of
two identical wingtip groups at the imidazole ring was performed
in a single step by refluxing 3b in the presence of excess alkyl
halide and NaHCO3 as proton scavenger, thus yielding the Nd ,Ne-
dimethylated histidinium salt 5b. Apart from saving one synthetic
step, this route also uses milder reaction conditions, which might
be beneficial when enantiomerically pure ligands are sought.
Metallation of the histidine-derived imidazolium salts was ac-
complished by using a transmetallation procedure.16 Accordingly,
Ag2O-mediated proton abstraction and subsequent transruthen-
ation with [Ru(cym)Cl2]2 afforded the two ruthenium complexes
6a and 6b.‡ Both complexes are air and moisture stable and were
purified by flash chromatography on silica gel, using a mixture
The use of naturally abundant products as versatile starting
materials for ligand development is an appealing concept in
homogeneous catalysis and is an increasingly popular strand
of bioinorganic and bioorganometallic chemistry.1 A variety
of biologically relevant classes of compounds have been func-
tionalised for transition metal coordination, including DNA,2
carbohydrates,3 steroids,4 alkaloids5 and vitamins such as biotin.6
Proteins constitute a particularly attractive platform for ligand
synthesis, partly because of the diversity of the functional groups
in the amino acid side chains.7 Both covalent and supramolecular
anchoring of complexes onto peptidic scaffolds has successfully
been demonstrated.8 Covalent linkers may be established, for
example, via side chain functionalisation of the amino acids.9
Histidine is remarkable in this respect, since imidazole has been
widely employed as a precursor for N-heterocyclic carbenes,10
which are probably the most popular class of ligands during the
last decade.11
Alkylation of the histidine side chain and the subsequent
metallation of the histidinium salt hence constitutes an attractive
approach to bioorganometallic chemistry.12 This provides poten-
tial catalyst precursors with activity and selectivity properties that
may be tailored by biochemical principles inherent to enzymes,
such as second coordination sphere modification or side-chain-
directed substrate recognition. Towards this end, we report here a
straightforward synthesis of catalytically active ruthenium centres
anchored covalently to a histidine side chain through a histidine-
derived NHC spectator ligand.
aSchool of Chemistry and Chemical Biology, University College Dublin,
Belfield, Dublin 4, Ireland. E-mail: martin.albrecht@ucd.ie; Fax: (+)353-
17162501
bDepartment of Chemistry, University of Fribourg, Chemin du Muse´e 9,
CH-1700 Fribourg, Switzerland
† Electronic supplementary information (ESI) available: Experimental
and analytical details. CCDC reference number 804412. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c0dt01768j
2716 | Dalton Trans., 2011, 40, 2716–2719
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Scheme 1 Synthesis of the histidine-based ligand precursors 5.
of acetonitrile and water (9 : 1). The disappearance of the signal
1
due to the Ce-bound proton in the H NMR spectrum, as well
as the downfield carbene signal in the 13C NMR spectrum (dC
=
173.6 and 172.9 ppm for 6a and 6b, respectively), supported the
formation of complexes 6. Notably, the NMR spectra in CDCl3 are
broad at room temperature, presumably due to rotation about the
Ru–Ccarbene and the Ru-cymene bonds, which causes epimerisation
at Ru. The resonances are markedly better resolved upon moder-
ate warming. Variable temperature NMR spectroscopy revealed
(de)coalescence of the wingtip groups, which allows for estimating
the energy barrier for rotation about the Ru–Ccarbene bond. From
these measurements, a distinct influence of the amino acid residue
was noted as the activation barrier DG = 65( 2) kJ mol-1 for
6a was higher than that determined for the model complex 7a
(DG = 60( 2) kJ mol-1). This significant difference suggests that
functionalisation at the imidazole C4 position (i.e. Cg in Scheme 2)
has a marked influence on the Ru–C bond, despite being remote.
Fig. 1 ORTEP plot of complex 6a (50% probability, hydrogen atoms
◦
˚
omitted for clarity). Selected bond lengths (A) and angles ( ): Ru1–C1
2.067(10), Ru1–Cl1 2.407(3), Ru1–Cl2 2.430(3), Ru1–Ccentroid 1.691(5),
C1–Ru1–Cl1 88.4(3), C1–Ru1–Cl2 89.1(3), Cl1–Ru1–Cl2 84.0(1).
˚
ment. The Ru1–C1 bond length is 2.067(10) A and hence is within
the typical observed range.17
Complexes 6 were evaluated as catalyst precursors for the
transfer hydrogenation of ketones. Benzophenone was used as
substrate and i-PrOH as hydrogen donor (Table 1). The known
unfunctionalised analogues of complexes 6, i.e. complexes 7
(cf Scheme 2),18 were included as a reference. Under standard
conditions, i.e. using KOH as a co-catalyst in refluxing i-PrOH
(substrate/base/catalyst 100 : 10 : 1), the reference complexes 7
showed generally higher catalytic activity than the corresponding
histidine-based complexes 6 (Table 1, entries 1–4). While these
activity differences were observed in most runs, it should be noted
that the catalytic performance of these monodentate carbene
complexes showed very poor reproducibility in our hands.19
For example, in some runs the catalytic activity of complex 7a
ceased after 5 min at conversion below 5%, while in other runs
Scheme 2 Synthesis of the histidine-based ruthenium carbene complexes
and model complexes.
Both complexes are stable as solids at ambient conditions, but
decompose within minutes in DMSO and within a few days in most
common organic solvents (e.g. MeCN, toluene, CH2Cl2, CHCl3).
A single crystal of complex 6a, obtained by layering a concentrated
CHCl3 solution with pentane, was analysed by single-crystal X-
ray diffraction. The complex crystallised in a centrosymmetric
space group (P21/c), implying the co-crystallisation of both the R
and the S stereoisomers, as a racemate. The molecular structure
(Fig. 1) features a ruthenium centre in a piano-stool-type arrange-
This journal is
The Royal Society of Chemistry 2011
Dalton Trans., 2011, 40, 2716–2719 | 2717
©

View Article Online
Table 1 Transfer hydrogenation using Ru-carbene complexes 6 and 7a
We thank A. Neels, Y. Ortin and F. Nydegger for analytical
measurements. This work was financially supported by the Swiss
National Science Foundation, COST D40 and the European Re-
search Council through a Starting Grant. M.A. also acknowledges
the Alfred Werner Foundation for an Assistant Professorship.
entry
catalyst
additive
conversion
0.5 h
10–16%b
31–47%b
21%
20%
39%
56%
87%
17%
39%
2 h
—
—
56%
60%
88%
93%
99%
50%
85%
1
2
3
4
5
6
7
8
9
7a
7b
6a
6b
7a
7a
7b
6a
6b
—
—
—
—
Notes and references
‡ Typical procedure: A mixture of 5a (500 mg, 1.14 mmol) and Ag2O
(265 mg, 1.14 mmol) in dry CH2Cl2 (25 mL) was stirred at reflux for
15 h in the dark. After filtration of the cold mixture through Celite, solid
[Ru(cym)Cl2]2 (350 mg, 0.57 mmol) was added to the filtrate and stirring
in the absence of light was continued for 2.5 h. The reaction mixture was
subsequently filtered through Celite and the volatiles were removed under
reduced pressure. The residue was purified by flash chromatography (SiO2,
MeCN–H2O 9 : 1), thus affording pure 6a as a brown-orange solid (353
mg, 50% yield).
PPh3
P(n-Bu)3
P(n-Bu)3
P(n-Bu)3
P(n-Bu)3
a General conditions: benzophenone (1 mmol), KOH (100 mmol), catalyst
(10 mmol), and where indicated, additive (10 mmol) in refluxing i-PrOH (5
mL); b After 10 min with limited reproducibility, see text for details.
1H NMR (500 MHz, CDCl3, 50 ◦C) d 6.92 (br, 1H, CdH), 5.39–5.49 (m,
3
3
2H, CcymH), 5.22 (septet, JHH = 6.7 Hz, 1H, NCHMe2), 5.09 (d, JHH
=
5.7 Hz, 2H, CcymH), 4.78 (br, 1H, CaH), 4.09–4.18 (m, 2H, COOCH2),
3
3.87 (br, 3H, NCH3), 3.07–3.10 (m, 1H, CbH2), 2.96 (septet, JHH = 7.0
Hz, 1H, CcymCHMe2), 2.79 (br, 1H, CbH2), 2.05 (s, 3H, CcymCH3), 1.96
(br, 3H, CH3CO), 1.60–1.64 (m, 2H, CH2CH2CH3), 1.35–1.40 (m, 2H,
3
3
CH2CH3), 1.37 (d, JHH = 6.7 Hz, 6H, NCH(CH3)2), 1.29 (d, JHH
=
under seemingly identical reaction conditions, 97% conversions
were reached after identical periods, which would place these
ruthenium complexes amongst the most active transfer hydro-
genation catalysts known to date (TOF50 ~ 105 h-1).20 Possibly, the
heterogeneisation of the catalyst precursor to catalytically active
ruthenium nanoparticles may occur.21
3
7.0 Hz, 6H, CcymCH(CH3)2), 0.93 (t, JHH = 7.3 Hz, 3H, CH2CH3), NH
not resolved; 13C{ H}NMR (125 MHz, CDCl3, 50 ◦C) d 173.6 (Ccarbene),
1
171.1 (C O), 170.3 (C O), 131.5 (Cg ), 117.4 (CdH), 108.8 (Ccym), 98.4
(Ccym), 86.5 (CcymH), 85.3 (CcymH), 82.4 (br, 2 ¥ CcymH), 65.9 (COOCH2),
52.4 (NCHMe2), 50.6 (CaH), 36.8 (NCH3), 31.0 (CcymCHMe2), 30.7
(CH2CH2CH3), 28.3 (CbH2), 24.9 (2 ¥ NCH(CH3)2), 23.4 (CcymCH(CH3)2),
23.1 (CH3CO), 21.9 (CcymCH(CH3)2), 19.2 (CH2CH3), 18.9 (CcymCH3),
13.7 (CH2CH3); Elem. anal. calcd for C26H41N3O3Cl2Ru (615.60): C 50.73,
H 6.71, N 6.83; found: C 50.50, H 6.50, N 6.77.
Stabilisation of the catalytic intermediate was sought by using
phosphines as additives.22 In the presence of PPh3 (1 : 1 ratio
of Ru and PR3), the transfer hydrogenation activity of complex
7a was slightly lower (Table 1, entry 5), yet the reproducibility
was significantly better. Addition of P(n-Bu)3 improved both
catalytic activity and reproducibility. The effect was particularly
pronounced for the catalytic performance of complexes 6b and
7b, containing two methyl wingtip groups (entries 7 and 9). In
contrast, complexes 6a and 7a, comprising an isopropyl wingtip
group, were slightly less active (entries 6 and 8), presumably due
to steric congestion at the ruthenium centre. As a general trend,
the histidine-derived carbene ruthenium complexes displayed a
lower catalytic activity than the model complexes prepared from
simple imidazolium salts. Since the first coordination sphere
of the metal centre is identical in both the histidine-derived
complexes 6 and their model complexes 7, these activity differences
suggest that the remote amino acid residue has an impact on
the (catalytic) properties of the metal centre, thus corroborating
NMR spectroscopic analyses. Such remote tunability may provide
interesting opportunities for catalyst optimisation through bio-
inspired concepts.
In summary, histidine was successfully used as a starting
material for two new NHC ruthenium complexes. The histidine-
derived complexes were readily accessible in five to six steps
using a final transmetallation procedure and, depending on the
wingtip substitution pattern, they exhibit moderate to good
catalytic performance in transfer hydrogenation. An attractive
feature of these complexes is based on the fact that the catalytic
activity differs from that of simple imidazol-2-ylidene ruthenium
complexes, thus allowing the activity to be tailored both via
wingtip group modification and via remote substitution at the
amino acid moiety of the complex. Work along these lines is
currently in progress.
Crystal data for 6a: yellow rod, C26H41Cl2N3O3Ru, Mr = 615.59, mono-
˚
clinic, a = 11.1246(13), b = 10.9646(9), c = 24.403(3) A, a = 90.00, b =
3
˚
˚
92.472(10), g = 90.00 A, V = 2973.8(6) A , T = 173(2) K, space group
P21/c, Z = 4, 19 658 measured reflections, 5293 unique reflections (Rint
0.2063), R1 = 0.0679, wR2 = 0.1384 for I > 2s(I).
=
1 (a) G. Jaouen, A. Vessieres and I. S. Butler, Acc. Chem. Res., 1993, 26,
361–369; (b) K. Severin, R. Bergs and W. Beck, Angew. Chem., Int. Ed.,
1998, 37, 1635–1654; (c) R. H. Fish and G. Jaouen, Organometallics,
2003, 22, 2166–2177; (d) T. Moriuchi and T. Hirao, Acc. Chem. Res.,
2010, 43, 1040–1051; (e) C. G. Riordan, Dalton Trans., 2009, 4273
(themed issue).
2 (a) W. Beck and N. Kottmair, Chem. Ber., 1976, 109, 970–993; (b) A. J.
Boersma, R. P. Megens, B. L. Feringa and G. Roelfes, Chem. Soc. Rev.,
2010, 39, 2083–2092.
3 (a) M. Dieguez, O. Pamies and C. Claver, Chem. Rev. (Washington,
DC, U. S.), 2004, 104, 3189–3215; (b) S. Castillon, C. Claver and Y.
Diaz, Chem. Soc. Rev., 2005, 34, 702–713.
4 R. Gust, W. Beck, G. Jaouen and H. Schoenenberger, Coord. Chem.
Rev., 2009, 253, 2742–2759.
5 A. Kascatan-Nebioglu, M. J. Panzner, J. C. Garrison, C. A. Tessier and
W. J. Youngs, Organometallics, 2004, 23, 1928–1931.
6 G. Klein, N. Humbert, J. Gradinaru, A. Ivanova, F. Gilardoni, U. E.
Rusbandi and T. R. Ward, Angew. Chem., Int. Ed., 2005, 44, 7764–7767.
7 D.-H. Wang, K. M. Engle, B.-F. Shi and J.-Q. Yu, Science, 2010, 327,
315–319.
8 (a) M. E. Wilson and G. M. Whitesides, J. Am. Chem. Soc., 1978, 100,
306–307; (b) D. Qi, C.-M. Tann, D. Haring and M. D. Distefano, Chem.
Rev., 2001, 101, 3081–3111; (c) M. T. Reetz, M. Rentzsch, A. Pletsch,
M. Maywald, P. Maiwald, J. J. P. Peyralans, A. Maichele, Y. Fu, N.
Jiao, F. Hollmann, R. Mondiere and A. Taglieber, Tetrahedron, 2007,
63, 6404–6414; (d) C. M. Thomas and T. R. Ward, Chem. Soc. Rev.,
2005, 34, 337–346.
9 For selected examples, see: (a) E. T. Kaiser and D. S. Lawrence, Science,
1984, 226, 505–511; (b) I. M. Bell, M. L. Fisher, Z. P. Wu and D. Hilvert,
Biochemistry, 1993, 32, 3754–3762; (c) K. M. Nicholas, P. Wentworth,
Jr., C. W. Harwig, A. D. Wentworth, A. Shafton and K. D. Janda,
Proc. Natl. Acad. Sci. U. S. A., 2002, 99, 2648–2653; (d) M. T. Reetz,
Proc. Natl. Acad. Sci. U. S. A., 2004, 101, 5716–5722; (e) E. Weerapana,
C. Wang, G. M. Simon, F. Richter, S. Khare, M. B. D. Dillon, D. A.
2718 | Dalton Trans., 2011, 40, 2716–2719
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Bachovchin, K. Mowen, D. Baker and B. F. Cravatt, Nature, 2010, 468,
790–795.
5576; (d) Y. Cheng, H.-J. Xu, J.-F. Sun, Y.-Z. Li, X.-T. Chen and Z.-L.
Xue, Dalton Trans., 2009, 7132–7140; (e) C. Gandolfi, M. Heckenroth,
A. Neels, G. Laurenczy and M. Albrecht, Organometallics, 2009, 28,
10 A. J. Arduengo III, R. L. Harlow and M. Kline, J. Am. Chem. Soc.,
˚
1991, 113, 361–363.
5112–5121; (f) Ruthenium-carbene bonds shorter than 2 A are not
11 (a) D. Bourissou, O. Guerret, F. P. Gabbaie and G. Bertrand, Chem.
Rev., 2000, 100, 39–91; (b) F. E. Hahn and M. C. Jahnke, Angew. Chem.,
Int. Ed., 2008, 47, 3122–3172; (c) S. Diez-Gonzalez, N. Marion and S.
P. Nolan, Chem. Rev., 2009, 109, 3612–3676; (d) L. Mercs and M.
Albrecht, Chem. Soc. Rev., 2010, 39, 1903–1912.
12 For related approaches, see: (a) F. Hannig, G. Kehr, R. Froehlich and G.
Erker, J. Organomet. Chem., 2005, 690, 5959–5972; (b) Y. N. Belokon,
A. V. Grachev, V. I. Maleev, V. N. Khrustalev, A. S. Peregudov and M.
North, Tetrahedron: Asymmetry, 2008, 19, 756–760; (c) A. Meyer, M.
A. Taige and T. Strassner, J. Organomet. Chem., 2009, 694, 1861–1868.
13 E. Pedoroso, A. Grandas, M. Dolors Ludevid and E. Giralt, J.
Heterocycl. Chem., 1986, 23, 921–924.
uncommon, see for example F. E. Hahn, A. R. Naziruddin, A. Hepp
and T. Pape, Organometallics, 2010, 29, 5283–5288; (g) O. Kaufhold,
F. E. Hahn, T. Pape and A. Hepp, J. Organomet. Chem., 2008, 693,
3435–3440.
18 (a) A. M. Voutchkova, L. N. Appelhans, A. R. Chianese and R.
H. Crabtree, J. Am. Chem. Soc., 2005, 127, 17624–17625; (b) G.
Venkatachalam, M. Heckenroth, A. Neels and M. Albrecht, Helv.
Chim. Acta, 2009, 92, 1034–1045; (c) A. Prades, M. Poyatos and E.
Peris, Adv. Synth. Catal., 2010, 352, 1155–1162.
19 (a) A. Prades, M. Viciano, M. Sanau and E. Peris, Organometallics,
2008, 27, 4254–4259; (b) Y. Zhang, C. Chen, S. C. Ghosh, Y. Li and S.
H. Hong, Organometallics, 2010, 29, 1374–1378.
14 J.-S. You, X.-Q. Yu, X.-Y. Su, T. Wang, Q.-X. Xiang, M. Yang and
R.-G. Xie, J. Mol. Catal. A: Chem., 2003, 202, 17–22.
15 (a) V. du Vigneaud and R. R. Sealock, J. Biol. Chem., 1932, 96, 511–517;
(b) R. W. Jackson and W. M. Cahill, J. Biol. Chem., 1938, 126, 37–41;
(c) W. M. Cahill and I. F. Burton, J. Biol. Chem., 1940, 132, 161–
169.
16 J. C. Y. Lin, R. T. W. Huang, C. S. Lee, A. Bhattacharyya, W. S. Hwang
and I. J. B. Lin, Chem. Rev., 2009, 109, 3561–3598.
17 See for examples: (a) J. Huang, E. D. Stevens, S. P. Nolan and J. L.
Petersen, J. Am. Chem. Soc., 1999, 121, 2674–2678; (b) M. Poyatos, E.
Mas-Marza, M. Sanau and E. Peris, Inorg. Chem., 2004, 43, 1793–1798;
(c) L. Mercs, A. Neels and M. Albrecht, Dalton Trans., 2008, 5570–
20 (a) H. Yang, M. Alvarez, N. Lugan and R. Mathieu, J. Chem. Soc.,
Chem. Commun., 1995, 1721–1722; (b) P. Dani, T. Karlen, R. A.
Gossage, S. Gladiali and G. Van Koten, Angew. Chem., Int. Ed., 2000,
39, 743–745; (c) M. Albrecht, J. R. Miecznikowski, A. Samuel, J.
W. Faller and R. H. Crabtree, Organometallics, 2002, 21, 3596–3604;
(d) C. Thoumazet, M. Melaimi, L. Ricard, F. Mathey and P. Le Floch,
Organometallics, 2003, 22, 1580–1581.
21 S. Jansat, D. Picurelli, K. Pelzer, K. Philippot, M. Gomez, G.
Muller, P. Lecante and B. Chaudret, New J. Chem., 2006, 30, 115–
122.
22 J. H. Dam, G. Osztrovszky, L. U. Nordstroem and R. Madsen, Chem.–
Eur. J., 2010, 16, 6820–6827.
This journal is
The Royal Society of Chemistry 2011
Dalton Trans., 2011, 40, 2716–2719 | 2719
©