Ruthenium-Catalyzed C-H Bond Activation/Arylation Accelerated by Biomass-Derived Ligands

Article abstract of DOI:10.1002/ejic.201900218

A variety of ligands are being explored extensively to achieve enhanced performance for ligand assisted C-H bond activation/functionalization reactions. We explored here several readily available biomass-derived ligands as effective additives to significantly enhance the catalytic activity of arene-Ru(II) dimer for ortho C-H bond arylation in a water-based catalytic reaction. We achieved almost 7-fold enhancement in the catalytic activity with [(η⁶-p-cymene)RuCl₂]₂ catalyst in the presence of levulinic acid ligand at 80 °C. Mass investigations revealed the in-situ formation of a ruthenium-levulinate complex, which presumably plays a crucial role in the formation of the important cycloruthenated intermediate by facilitating the initial activation of ortho C-H bond of 2-phenylpyridine. Density functional theoretical studies also inferred that the ligand assisted route is energetically more favorable, where the acetyl group is found to be involved in the deprotonation step.

Full text of DOI:10.1002/ejic.201900218

A Journal of
Accepted Article
Title: Biomass Derived Ligands Accelerated Ruthenium-Catalyzed C-H
Bond Activation/ Arylation
Authors: Chinky Binnani, Shyama Charan Mandal, Biswarup Pathak,
and Sanjay Kumar Singh
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To be cited as: Eur. J. Inorg. Chem. 10.1002/ejic.201900218
Link to VoR: http://dx.doi.org/10.1002/ejic.201900218

10.1002/ejic.201900218
European Journal of Inorganic Chemistry
Biomass Derived Ligands Accelerated Ruthenium-Catalyzed C-H
Bond Activation/ Arylation
Chinky Binnani,[a] Shyama Charan Mandal,[b] Dr. Biswarup Pathak[b] and Dr. Sanjay K.
Singh*[a]
[a] Catalysis Group, [b] Computational Materials Designing Group, Discipline of Chemistry, Indian
Institute of Technology Indore, Simrol, Indore 453552, Madhya Pradesh, India
E-mail: sksingh@iiti.ac.in (SKS)
Webpage: http://people.iiti.ac.in/~sksingh/
Abstract
A variety of ligands are being explored extensively to achieve enhanced performance for ligand
assisted C-H bond activation/functionalization reactions. We explored here, several readily
available biomass-derived ligands as effective additives to significantly enhance the catalytic
activity of arene-Ru(II) dimer for ortho C-H bond arylation in a water-based catalytic reaction.
We achieved almost 7-fold enhancement in the catalytic activity with [(η6-p-cymene)RuCl2]2
catalyst in the presence of levulinic acid ligand at 80 ℃. Mass investigations revealed the in-
situ formation of a ruthenium-levulinate complex, which presumably plays a crucial role in the
formation of the important cycloruthenated intermediate by facilitating the initial activation of
ortho C-H bond of 2-phenylpyridine. Density functional theoretical studies also inferred that
the ligand assisted route is energetically more favorable, where acetyl group is found to be
involved in the deprotonation step.
Keywords: C-H activation; biomass; platform chemicals; ligand tuned activity; DFT studies
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Introduction
Metal catalyzed C-H bond activation and functionalization methodologies are of significant
importance in the field of synthetic organic transformations.[1] It is evident that several metal
catalysts based on Rh,[2] Pd,[3] Ir,[4] and Ru[5] have been extensively explored for C-H bond
functionalization reactions. With further advancement in the field, the earth abundant 3d
transition metals (Mn, Co, Fe) are also seeking attention as active catalysts for C-H bond
activation and functionalization reactions in a very efficient, selective and cost-effective
manner.[6] Among the various metals explored for C-H activation/functionalization reactions,
the ruthenium-based catalysts, particularly arene-Ru(II) complexes have shown several
advantages over others due to its non-toxic nature, stability in air and water, high aqueous
solubility and therefore these catalysts are considered as one of the most promising catalytic
system for C-H activation/functionalization reactions. Among several strategies, designing and
utilizing efficient ligand to induce accelerated C-H bond activation reactions has contributed
remarkably to enhance the practical usability of C-H activation/functionalization reactions. In
this context, a variety of ligands such as carboxylates,[7] phosphorus-based ligands[8] and
several N,O/ O,O donor ligands,[9] either as additives or pre-coordinated with the metal center,
have been extensively studied to achieve enhanced catalytic activity. In general, carboxylate
additives facilitate the initial deprotonation of ortho C-H bond while phosphine-based ligands
play crucial role in stabilizing the active catalytic species.
The other set of ligands, which are rather weakly coordinating, also found to
significantly tune the catalytic activity in C-H bond functionalization reactions. For instance,
Yu et al. employed bulky pyridine ligands for the challenging C-H activation of electron
deficient arenes catalyzed on Pd catalyst.[10] They showed that sterically bulky 2,6-
dialkylpyridines induced a significant enhancement in the catalytic activity, which was
attributed to the facile replacement of bulky pyridine by reactant. We also observed an
2
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10.1002/ejic.201900218
European Journal of Inorganic Chemistry
accelerated Ru(II) catalyzed C-H bond arylation in the presence of weakly coordinating
electron deficient aniline ligands.[11] Apart from several monodentate ligands, various bidentate
ligands have also been explored to achieve enhance catalytic activity. For instance, Pd(II)
catalyzed ortho C-H bond alkylation was accelerated by N-protected amino acid ligands, where
it was proposed that the coordination/de-coordination mode of one of the coordinating group
of these ligands presumably tune the catalytic activity.[12] However, no direct role of these
ligands in deprotonation step was observed. The designing and development of various chiral
ligands for enantioselective Pd(II) catalyzed C-H bond activation/functionalization has also
revolutionized the synthesis of several chiral organic compounds with excellent
enantioselectivity.[13] Furthermore, accelerated Ru(II) catalyzed C-H bond arylation has also
been achieved in the presence of acetamide ligand where the pendent acyl group of Ru-
coordinated acetamide facilitated the deprotonation of C-H bond.[14] In a recent report, we have
also explored several pyridine based bidentate ligands and observed that 2-acetylpyridine
ligand greatly enhanced the catalytic activity for C-H bond arylation reaction.[15] The observed
ligand-induced enhancement in the catalytic activity was attributed to the involvement of acetyl
group in the deprotonation step due to its close proximity to the ortho C-H bond of 2-
phenylpyridine (Scheme 1).
Envisioned by the recent advancement and our continuous efforts towards ligand
assisted C-H bond activation reaction, herein we investigated in detail a wide range of ligands,
which can be readily derived from biomass, for arene-Ru(II) catalyzed C-H bond arylation in
water-based reaction condition (Scheme 1). As these ligands such as levulinic acid (L1), 2,5-
hexanedione and other furan-based ligands, contain acetyl, formyl or carboxylate groups, these
groups may play an important role in accelerating the catalytic activity for C-H bond arylation
of 2-phenylpyridine with several aryl chlorides over arene-Ru(II) catalyst. We also probed
mass investigations to elucidate the involvement of these ligands in the C-H bond activation
3
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10.1002/ejic.201900218
European Journal of Inorganic Chemistry
reactions by identifying reaction intermediates such as ligand coordinated Ru species and
cyclometalated species under the catalytic and controlled reaction conditions. Density
functional theoretical (DFT) calculations provided substantial support to our experimental
findings and the active role of the studied ligands in accelerating the catalytic activity for C-H
activation reactions.
Scheme 1. Various ligands explored for C-H bond activation reactions.
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European Journal of Inorganic Chemistry
Results and discussion
At an outset, we evaluated the ligands L1-L7 (2 mol%) for C-H arylation of 2-phenylpyridine
(1a) with 4-chloroanisole (2a), as model substrates, catalyzed by [(η6-p-cymene)RuCl2]2 (1
mol%) catalyst at 80℃ in water-ethanol (9:1 v/v) solution. After evaluating various biomass-
derived ligands (L1-L7), we found that levulinic acid (L1), greatly accelerated the catalytic
activity with 70% yield of monoarylated product (3a) in 4 h (3a/4a selectivity = 93/7) (Table
1, entry 2). Yield for 3a was further improved to 87% by extending the reaction for 8 h under
analogous reaction condition. The remarkable activity shown by Ru(II) catalyst in the presence
of the acyclic ligand L1, can be attributed to the conformational freedom of L1 which further
facilitated its orientation to promote the deprotonation of ortho C-H bond of 2-phenylpyridine.
In contrary to the excellent activity achieved in the presence of levulinic acid (L1)
ligand, other furan-based ligands (L2-L7) showed relatively lower activity for the product 3a
(35-75% conv.) (Table 1). After levulinic acid (L1), 2-acetylfuran (L2) showed the highest
yield (65%) for 3a, (Table 1, entry 3) while furfural (L3), 5-HMF (L4), 5-methylfurfural (L5),
furfuryl alcohol (L6) and furan-2-carboxylic acid (L7) could not efficiently accelerated the
catalytic activity of ruthenium catalyzed C-H arylation reaction (Table 1, entries 4-8). It is
noteworthy to mention here that comparatively lower temperature, shorter reaction duration or
using aryl halide as a limiting agent may favor higher selectivity for monoarylation over
biarylation of 2-phenylpyridine.[7g][8g][16] It is also evident from the previous reports that using
excess of aryl halide (>2 equiv.) resulted in the higher selectivity of biarylated product.[8c]
Hence we optimized the reactions with slight excess of 2-phenylpyridine (1.1 equiv.) at 80 ℃
for 4 h to achieve higher selectively for the monoarylated product. As a result, high selectivity
for monoarylated product (3a) over biarylated product (4a) was maintained for all the
conducted reactions. The lower activity for ruthenium catalyzed C-H bond arylation of 1a in
the presence of furan-based ligands can be attributed to the tendency of these ligands to
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10.1002/ejic.201900218
European Journal of Inorganic Chemistry
polymerize in aqueous solvent.[17] Reports also revealed that the polymerization of 5-HMF
(L4) is lower than the furfuryl alcohol (L6), which is in line with the lower yield for 3a
observed with L6 (38%) as compared to the moderate yield (53%) achieved with L4. It is
evident from the results that O,O donor furan-based ligands having neutral oxygen donor
groups (L2-L6) outperformed over furan-2-carboxylic acid (L7) with anionic oxygen donor
(Table 1). These findings can be attributed to the strong coordination behavior of L7 with the
Ru(II) metal center. Previous studies also demonstrated enhanced catalytic activity for C-H
bond arylation reaction over 2-acetylpyridine ligated Ru(II) complex as compared to 2-
picolinate ligated Ru(II) complex.[15] Notably, carboxylate additives, such as acetates and
pivalates are well explored for the Ru(II) catalyzed C-H bond activation reactions,[7][18] where
these carboxylates facilitated the deprotonation of C-H bond by coordinating with the Ru
center.
Table 1. Catalytic ortho C-H bond arylation of 2-phenylpyridine (1a) with 4-chloroanisole
(2a) over [(η6-p-cymene)RuCl2]2 catalyst in the presence of various biomass-derived
ligands[a]
Sel. (%)
(3a/4a)
Yield[c] (%)
(3a)
Entry
Ligand
Conv. (%)
1
ligand free
12%
93/7
n.d.
83%
93/7
70%
2
3
>99%[b]
90/10[b]
87%[b]
(L1)
(L2)
75%
94/6
65%
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4
70%
65%
52%
91/9
94/6
93/7
58%
53%
42%
(L3)
5
(L4)
6
(L5)
7
44%
35%
96/7
38%
27%
(L6)
8
90/10
(L7)
[a] Reaction Condition: [(η6-p-cymene)RuCl2]2 (1 mol%), L1-L7 (2 mol %.), K2CO3 (3
equiv.), 2-phenylpyridine (1a) (0.6 mmol), 4-chloroanisole (2a) (0.5 mmol), water-ethanol
(9:1 v/v, 2 mL), 80 ºC, 4 h, N2 atmosphere, [b] time = 8 h, [c] isolated yield, conversion and
selectivity were determined by 1H NMR, n.d. = not determined.
Based on the above findings, levulinic acid (L1) was identified as the best performing
ligand to induce 7-fold enhancement in the catalytic activity of [(η6-p-cymene)RuCl2]2 catalyst.
Notably, in the absence of the ligand, [(η6-p-cymene)RuCl2]2 displayed only poor catalytic
conversion under analogous reaction condition (Table 1, entry 1). Further, optimization of
reaction condition inferred that performing the catalytic reaction with lower amount of K2CO3
base (3 equiv.) significantly deteriorated the conversion. Moreover, reaction could not proceed
in the absence of base or performing the catalytic reaction at lower temperature (Table S1).
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100
80
60
40
20
0
Levulinic Acid (L1)
Without Ligand
60
30
150
90
0
120
Time (h)
Figure 1. Time dependent reaction profile for C-H arylation of 2-phenylpyridine (1a) with 4-
chloroanisole (2a) over [(η6-p-cymene)RuCl2]2 catalyst in ligand-free condition and in the
presence of ligand L1 under the optimized reaction condition.
As evident from the time dependent reaction profile (Figure 1), when reaction was
performed in the absence of any ligand, very slow reaction rate (4.89 × 10-4 sec-1) was observed.
Contrary to the base-free condition, significantly increased kinetics with relatively very high
rate constant (1.02 × 102 sec-1) was observed in the presence of levulinic acid (L1) (Figure 1
and Figure S1), suggesting that the enhancement in the catalytic reaction was probably due to
the involvement of levulinic acid (L1) in the C-H bond cleavage step. To further support this
hypothesis, we probed mass investigations, under the catalytic and controlled reaction
condition, to identify possible reaction intermediates for the Ru(II) catalyzed ortho C-H bond
arylation of 1a with 2a in the presence of the ligand L1 (Figure 2). Notably, levulinate
coordinated arene-Ru species ([Ru]-A, m/z = 351, [M]-Cl) was observed upon the treatment
of [(η6-p-cymene)RuCl2]2 with levulinic acid (Ru:L1 = 1:1) in water-ethanol (9:1 v/v) in the
presence of K2CO3 at 80 ºC for 1.5 h (Figure S2). Further, upon addition of 2-phenylpyridine
(1a) (Ru:1a = 1:5), mass peak corresponding to the crucial cyclometalated species [Ru(η6-p-
cymene)(κ2-C,N-2-phenylpyridine)Cl]([Ru]-B, m/z = 390, [M]-Cl) was appeared as prominent
peak (Figure S3). The ligand coordinated arene-Ru species [Ru]-A, was also observed under
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European Journal of Inorganic Chemistry
the base free condition, which was possibly formed via an initial aqua-coordinated arene-Ru
species ([(η6-p-cymene)Ru(OH2)Cl2] (m/z = 288, [M]-Cl) (Figure S4). Notably, presence of
the prominent mass peak at m/z 390 corresponding to the cyclometalated species [Ru-B] under
base free condition upon the treatment of [(η6-p-cymene)RuCl2]2 with 2-phenylpyridine (Ru:1a
= 1:5) in the presence of levulinic acid (L1) at 80 ºC, substantiate the crucial role of levulinic
acid (L1) in achieving high catalytic activity. Earlier reports also inferred the presence of
analogous cyclometalated species [Ru-B] as one of the key intermediate in several Ru(II)
catalyzed C-H bond activation reactions.[19] Further to investigate the role of acetyl and
carboxylate groups, we performed the catalytic reaction by replacing levulinic acid (L1) with
dicarbonyl compounds (2,5-hexanedione (L8) and 2,3-butanedione (L9)) and aliphatic
carboxylic acids (1-butanoic acid (L10), 1-hexanoic acid (L11), 1,6-hexanedioic acid (L12))
(Scheme S1). Results inferred that the dicarbonyl ligands (L8 and L9) could not enhance the
catalytic performance, attributed to their poor coordination with the metal center and hence
could not efficiently participated in the ligand assisted deprotonation step. Moreover,
controlled experiments performed using aliphatic carboxylic acid (L10 ‒ L12) also inferred no
significant enhancement in the catalytic reaction, presumably due to the strong coordination
behavior of these ligands with the metal center.
The above findings inferred that the facile coordination of the ligand L1 in a bidentate
manner with the ruthenium center via acetyl and carboxylate-O- groups, as also evidenced by
the presence of levulinate coordinated arene-Ru species ([Ru]-A) (m/z = 351, [M]-Cl) during
mass studies, is presumably responsible for the observed accelerated catalytic activity. In this
context, previous studies also revealed that analogous bis-chelating ligands may display
coordination/de-coordination behavior during the catalytic reaction and hence significantly
tune the catalytic reactivity (Scheme S2).[14][15][20] It is also evident from the literature that the
enhanced catalytic activity in Ru-picolinate systems was due to the involvement of acetyl group
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in C-H deprotonation, while remain coordinated with metal center with strongly coordinating
pyridine.[15]
Figure 2. Mass spectral identification of several intermediate species formed during the ortho
C-H bond activation/ arylation of 1a over Ru catalyst under stoichiometric reaction conditions
in the presence of levulinic acid (L1). Step I: water-ethanol (9:1 v/v), 80 ℃, 1.5 h, N2
atmosphere. Step II: K2CO3, water-ethanol (9:1 v/v), 80 ℃, 1.5 h, N2 atmosphere.
To further support our experimental findings, we performed DFT calculations
(computational details given in supporting information)[21] for C-H bond activation/arylation
of 2-phenylpyridine(1a) and calculated reaction free energies (ΔG) for the formation of the
crucial cycloruthenated species [Ru(η6-p-cymene)(κ2-C,N-2-phenylpyridine)(H2O)]+ (5),in the
presence and absence of ligand L1. As mass studies evidenced the presence of a water
coordinated ruthenium species [(η6-p-cymene)RuCl2(OH2)] (m/z 288, [M]-Cl) in the absence
of ligand, we considered this as active catalytic species for DFT calculations under ligand-free
condition. The reaction free energy profile, Figure 3, suggested that the formation of the crucial
cycloruthenated species (5) is energetically favorable (ΔG = 14.0 kcal/mol) in the presence of
the ligand L1 compared to that for ligand-free condition (ΔG = 22.9 kcal/mol). These results
further evidenced the crucial role of the ligand L1 in the C-H activation of 2-phenylpyridine.
Further, it was also evident from the DFT calculations that the species 2A-I having acetyl group
in the close proximity of ortho proton of 2-phenylpyridine was stable by 2.7 kcal/mol than the
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species 2A-II having carboxylate group in that place. These results are in concurrence with
earlier reports,[14][15][20] suggesting that presumably the acetyl group was involved in the C-H
bond activation of 2-phenylpyridine (Figure S5). Further, upon replacing the ligand L1 with
2,5-hexanedione (L8), free energy calculations revealed that the C-H activation reaction was
highly unfavorable in the presence of L8 (ΔG = 30.7 kcal/mol) (Table S2). These results
inferred that presumably the anionic carboxylate ensured the strong anchoring of ligand with
the metal center, while the acetyl group facilitated C-H deprotonation via a facile coordination-
decoordination inter-conversion pathway (Figure 3). Therefore, based on the above findings,
we anticipated that the significantly enhanced catalytic activity of [(η6-p-cymene)RuCl2]2 in
the presence of levulinic acid (L1) for C-H bond arylation of 1a is presumably due to the
involvement of acetyl group of L1 in C-H bond deprotonation.
3B
+30.7
2B
+14.0
3A
4A
2A
5 +L1
4B
1B
0.0
5 +L8
1A
5
Figure 3. Reaction free energy profile, as calculated by DFT, to study the role of ligands,
levulinic acid (L1) and 2,5-hexanedione (L8), in ruthenium catalyzed ortho C-H bond
activation/arylation of 2-phenylpyridine (1a).
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Based on our experimental findings and DFT calculations, a plausible reaction
mechanism for biomass derived ligand accelerated ortho C-H bond activation/arylation of 2-
phenylpyridine is depicted in Scheme 2. In the first step, the precatalyst [(η6-p-cymene)RuCl2]2
generates the active catalytic species 1A by the direct coordination of ligand L1 either to the
precatalyst or via a water coordinated species 1C. Subsequently, upon coordination of 2-
phenylpyridine, species 2A was generated. Further, the species 2A was transformed to a
cyclometalated species 5 via a ligand (L1)-accelerated concerted metalation deprotonation
(CMD) step, and the ligand L1 was released. Finally, the oxidative addition of arylhalide over
the species 5, and subsequently the release of the monoarylated product (3a) via reductive
elimination step (6→1A) generated the active catalytic species 1A.
Scheme 2. The plausible reaction pathway for the ruthenium catalyzed ortho C-H
activation/arylation of 2-phenylpyridine in the presence of biomass-derived ligand L1.
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After establishing that the ligand levulinic acid (L1) substantially accelerated the
activity of ruthenium catalyzed C-H bond activation/arylation of 2-phenylpyridine (1a) with 4-
chloroanisole (2a), C-H arylation of 2-phenylpyridine (1a) with other arylating agents was
further explored under the optimized reaction conditions. As summarized in Table 2, a wide
range of aryl chlorides (2a-2h) as coupling partners of 2-phenylpyridine (1a) delivered high
yields for the monoarylated products (3a-3h), while biarylated products (4a-4h) were formed
as minor products. C-H arylation of 2-phenypyridine (1a) with 4-chloroanisole (2a) afforded
monoarylated product 3a with 93% selectivity and 87% isolated yield (Table 2, entry, 1). The
unsubstituted aryl halide, chlorobenzene (2b) showed >99% conversion with 85% yield for 3b
(Table 2, entry, 2). Electron rich (2a, 2c-2e) and electron deficient (2f) aryl chlorides both
exhibited high yield for the corresponding monoarylated products (3a, 3c-3f) of 2-
phenylpyridine (1a). 4-chlorotoluene (2c) also afforded high conversion of 2-phenylpyridine
(1a) to the corresponding monoarylated product (3c) with high selectivity (3c:4c = 96:4) and
89% yield (Table 2, entry 3). 4-Chlorostyrene (2d) and 4-chlorobenzhydrol (2e) also afforded
appreciably very high selectivity (99:1) for the corresponding monoarylated products (3d and
3e, Table 2, entries 4-5). Further, the electron deficient 4-chloromethylbenzoate (2f) also
exhibited high selectivity (88%) and yield (65%) for 3f (Table 2, entry, 6). Notably, the sulphur
containing (hetero)aryl halides, 2-chlorothiophene (2g) and 5-methyl-2-chlorothiophene (2h)
also resulted in remarkably high conversion with high yields for the corresponding
monoarylated products 3g (90%) and 3h (83%) (Table 2, entries 7-8). In contrary to 2-
chlorothiophene (2g), reaction with nitrogen containing heterocycle, 2-bromopyridine (2i) was
found to be quite sluggish and only 20% conversion was observed in 4 h and 52% conversion,
even after 24 h, with poor yield for the monoarylated product (3i) (Table 2, entry 9).
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Table 2. Catalytic ortho C-H bond arylation of 2-phenylpyridine (1a) with various
(hetero)arylhalides (2a-2i) over [(η6-p-cymene)RuCl2]2 catalyst in the presence of levulinic
acid (L1) ligand[a]
Entry
Substrate
2a
Conv. (%)
Sel. (%) Yield (%)[d]
1
83%
>99%[b] (8 h)
93/7
90/10[b]
(3a:4a)
3a (87%)[b]
2
3
4
>99%
>99%
90%
93/7
(3b:4b)
2b
2c
2d
3b (85%)
96/4
(3c:4c)
3c (89%)
99/1
(3d:4d)
3d (83%)
5
6
73%
80%
99/1
(3e:4e)
2e
2f
3e (67%)
88/12
(3f:4f)
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3f (65%)
7
>99%
>99%
93/7
(3g:4g)
2g
3g (90%)
3h (83%)
3i (32%)[c]
8
9
89/11
(3h:4h)
2h
20%
99/1
52%[c] (24 h)
80/20
(3i:4i)
2i
[a] Reaction Conditions: [(η6-p-cymene)RuCl2]2 (1 mol%), L1 (2 mol %.), K2CO3 (3 equiv.),
2-phenylpyridine (1a) (0.6 mmol), aryl halide (2a-2i) (0.5 mmol), water-ethanol (9:1 v/v, 2
mL), 80 ºC, 4 h, N2 atmosphere, [b] time = 8 h, [c] time = 24 h, [d] isolated yield. Conversion
and selectivity were determined by 1H NMR.
Conclusion
In summary, we investigated in detail the role of several biomass-derived ligands as active
additives for accelerated Ru(II) catalyzed C-H bond arylation reaction. Among the studied
ligands, levulinic acid (L1) ligand afforded an excellent enhancement in the catalytic activity
of [(η6-p-cymene)RuCl2]2 for C-H bond arylation of 2-phenylpyridine (1a) with 4-
chloroanisole (1b) in a water-based reaction condition. We achieved high compatibility of the
studied Ru(II)-levulinate catalytic system for C-H bond arylation of 2-phenylpyridine (1a) with
a wide range of electron rich and electron deficient aryl halides and heteroaryl halides. Kinetic
studies and mass spectral identification of ligand coordinated Ru(II) species ([Ru]-A) and the
crucial cyclometalated species ([Ru]-B) under the catalytic and controlled reaction condition
evidenced the possible crucial role of the ligand L1 in the observed accelerated catalytic
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activity. In concurrence with the experimental findings, DFT calculations also revealed that the
C-H bond activation of 2-phenylpyridine (1a) is energetically more favorable (by 8.9 kcal/mol)
in the presence of ligand L1 as compared to the ligand-free reaction. Our experimental findings
and DFT calculations evidenced the involvement of acetyl group of the ligand L1 in the
deprotonation step, and suggesting that the anionic carboxylate group facilitated the strong
anchoring of ligand to the metal center. Therefore, we believe that the present study utilizing
biomass-derived ligands to achieve remarkably 7-fold enhanced catalytic activity for C-H bond
activation/arylation over arene-Ru(II) catalyst is significant, and such systems will also help in
the development of other ligand-tuned highly active catalytic system. Further investigations in
this direction are underway in our laboratory.
Experimental section
Synthesis of 5-hydroxymethyl furfural (5-HMF) (L4). The biomass derived furan derivative 5-
hydroxymethyl furfural (5-HMF) was prepared by slight modification in the previously
reported method.[22] D-fructose (1 mmol, 0.180 g) was dissolved in 2 mL of 2-propanol
followed by the addition of 0.5 mmol (0.027 g) of NH4Cl. The reaction mixture was continued
to stir at 120 ºC for 12 h and the progress of the reaction was monitored by thin-layered
chromatography. After completion, 2-propanol was removed by evaporation under reduced
vacuum. Then, 5 mL water was added in the remaining fraction and extracted with diethyl ether
(3 × 10 mL) and dried over anhydrous Na2SO4. All the volatiles were removed under vacuum
to obtain the crude product. Product was purified by using column chromatography and
confirmed by 1H and 13C NMR.
Synthesis of furan-2-carboxylic acid (2-furoic acid) (L7). The biomass derived furan
derivative, furan-2-carboxylic acid (2-furoic acid) was prepared by following the reported
procedure using Ni0.90Pd0.10 nanoparticles as a catalyst.[23] A two-neck round-bottom flask was
charged with freshly prepared 5 mol % Ni0.90Pd0.10 nanoparticles followed by the addition of
16
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10.1002/ejic.201900218
European Journal of Inorganic Chemistry
furan 2-carboxyaldehyde (1 mmol, 82.8 µL). The reaction mixture was stirred at 80 ºC with a
continuous flow of air for 1 h. The progress of the reaction was monitored by thin-layered
chromatography. After the completion of the reaction, the catalyst was recovered from the
reaction mixture by centrifugation and brine solution (5 mL) was added with the 1.2 M HCl (3
mL). The crude reaction mixture was extracted by using diethyl ether (5 × 10 mL) and
combined organic layer was dried over anhydrous Na2SO4. Then all the volatiles were removed
under vacuum to obtain the crude product. Then the product was purified by using column
chromatography and confirmed by 1H and 13C NMR.
General procedure for the catalytic ortho C-H bond arylation of 2-phenylpyridine with
arylhalides. All the reactions were carried out under N2 atmosphere. Ortho C-H bond arylation
reactions of 2-phenylpyridine were performed in a two necked round bottom flask. Flask was
charged with ruthenium catalyst, [(η6-p-cymene)RuCl2]2 (1 mol %, 0.005 mmol, 0.00306 g),
ligand (2 equiv., 2 mol%) and K2CO3 (3 equiv., 1.5 mmol, 0.207 g) with water-ethanol (2 mL)
in 9:1 v/v ratio. Water-ethanol solvent medium was chosen in order to avoid
decomposition/polymerization of furan-based ligands. Solution was stirred for 15 minutes and
then 2-phenylpyridine (0.6 mmol, 86 µL) and arylhalide (0.5 mmol) was added. The reaction
was continued to stir at 80 ºC for 4 h under N2 atmosphere and then cooled down to room
temperature. Further, the reaction mixture was extracted with ethyl acetate (3×10 mL) and dried
over anhydrous Na2SO4. All the volatiles were removed under vacuum to obtain the crude
product. Conversion and selectivity of the mono and biarylated products were determined by
1H NMR. Products were purified and isolated from the crude reaction mixture by using column
chromatography on silica gel with ethyl acetate/n-hexane as eluents.
Mass spectrometric analysis for the identification of reactive intermediate species. Mass
studies were also carried out in a two necked reaction flask containing [(η6-p-cymene)RuCl2]2
(1 mol%, 0.005 mmol, 0.00306 g) in 2 mL water-ethanol [(9:1) v/v] with or without base. Then
17
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10.1002/ejic.201900218
European Journal of Inorganic Chemistry
ligand (2 mol%) and 2-phenylpyridine (0.025 mmol, 3.6 µL) was added for maintaining the
catalyst: ligand: substrate ratio i.e. C:L:S = 1:2:5. Reaction mixture was heated at 80 ºC under
nitrogen atmosphere for 1.5 h. 100 µL of aliquot from the reaction mixture was withdrawn at
different intervals of reaction time (0, 30, 60, 90 and 120 minutes) which was diluted with
methanol and ESI-MS was recorded in positive mode. Mass spectra were analyzed, and active
intermediates generated during the reaction have been identified.
Acknowledgements
Authors thank IIT Indore, CSIR, New Delhi (01(2885)/17/EMR-II) and SERB (DST), New
Delhi (EMR/2016/005783) for the financial support. Thanks to SIC, IIT Indore for the
instrumentation facility. C.B. thanks IIT Indore for her fellowship.
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(Table of content)
Readily available biomass-derived ligands significantly accelerated catalytic activity of [(η6-p-
cymene)RuCl2]2 for ortho C-H bond activation/ arylation of 2-phenylpyridine with a variety of
(hetero)aryl chlorides in a water-based reaction condition. Extensive mass studies, kinetic
experiments and DFT studies evidenced the crucial role of the ligand levulinic acid to achieve
7-fold enhancement in catalytic activity of [(η6-p-cymene)RuCl2]2, wherein the ligand assisted
route is energetically more favorable presumably due to the involvement of acetyl group in
facilitating the ruthenium catalyzed C-H deprotonation.
24
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