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Polysilane-Immobilized Rh-Pt Bimetallic Nanoparticles as Powerful Arene Hydrogenation Catalysts: Synthesis, Reactions under Batch and Flow Conditions, and Reaction Mechanism Hiroyuki Miyamura, Aya Suzuki, Tomohiro Yasukawa, and Shu Kobayashi J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b06015 • Publication Date (Web): 06 Aug 2018 Downloaded from http://pubs.acs.org on August 7, 2018
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Journal of the American Chemical Society
Polysilane-Immobilized Rh-Pt Bimetallic Nanoparticles as Powerful Arene Hydrogenation Catalysts: Synthesis, Reactions under Batch and Flow Conditions, and Reaction Mechanism Hiroyuki Miyamura, Aya Suzuki, Tomohiro Yasukawa and Shū Kobayashi* Department of Chemistry, School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. *Corresponding author. E-mail:
[email protected] Arene hydrogenation, Heterogeneous catalyst, Flow reaction, Drug synthesis, Selective hydrogenation ABSTRACT: Hydrogenation of arenes is an important reaction not only for hydrogen storage and transport but also for the synthesis of functional molecules such as pharmaceuticals and biologically active compounds. Here, we describe the development of heterogeneous Rh-Pt bimetallic nanoparticle catalysts for the hydrogenation of arenes with inexpensive polysilane as support. The catalysts could be used in both batch and continuous-flow systems with high performance under mild conditions and showed wide substrate generality. In the continuous-flow system, the product could be obtained by simply passing the substrate and 1 atm H2 through a column packed with the catalyst. Remarkably, much higher catalytic performance was observed in the flow system than in the batch system, and extremely strong durability under continuousflow conditions was demonstrated (>50 days continuous run; turnover number >106). Furthermore, details of the reaction mechanisms and the origin of different kinetics in batch and flow were studied, and the obtained knowledge was applied to develop completely selective arene hydrogenation of compounds containing two aromatic rings toward the synthesis of an active pharmaceutical ingredient.
almost no reports on a general theory for selective arene hydrogenation of more complex compounds that contain more than two aromatic moieties in different chemical Hydrogenation of arenes and heteroarenes is an environments. If this kind of selective hydrogenation is important reaction in a variety of fields such as organic feasible and the selectivity is predictable, it would be synthesis, including drug and natural product synthesis,1 possible to introduce a new synthetic strategy in which and petroleum chemistry,2 as well as for the transition to a 3 selective arene hydrogenation could be conducted at a final hydrogen-based society. In addition, selective stage of synthesis of a complex compound, so-called latehydrogenation of arene and heteroarene moieties in more stage selective arene hydrogenation. Moreover, an ideal complex compounds bearing various functionalities is a catalytic arene hydrogenation system would function in challenge necessary for the synthesis of biologically active continuous-flow under atmospheric and mild conditions, compounds such as active pharmaceutical ingredients 1c, 4 since continuous-flow synthesis is in great demand in the (APIs). However, functional groups that are found in such field of hydrogen storage and the synthesis of APIs. Although compounds include highly polar and coordinative several arene hydrogenation protocols are applied in flow functionalities, such as pyridine, amide, ester, carboxylic systems,1c, 4, 7b, 8 there are no reports that evaluate and acid, amine, and alcohol, and these substrates and the compare catalytic performances directly and quantitatively corresponding products obtained after hydrogenation might between continuous-flow and batch systems in terms of strongly interact and poison the catalysts. Although durability of catalyst and catalytic turnover number (TON) hydrogenation of simple alkylarenes, especially benzene and 5 and turnover frequency (TOF). toluene, has been developed through the use of transition Here, we describe the development of high-performance metals, including bimetallic catalysts in both heterogeneous polysilane-immobilized Rh-Pt bimetallic nanoparticle and homogeneous systems,6 heterogeneous catalysts that catalysts that perform in both continuous-flow and batch can be useful for hydrogenation of highly functionalized systems for arene hydrogenation under mild conditions. arenes are very limited compared with those of simple alkyl1c, 4, 7 These catalysts showed not only very high catalytic activity substituted arenes. Furthermore, these catalysts and robustness but also high tolerance for various require very harsh conditions and show limited catalytic functionalities to realize broad substrate scope, including turnover, and catalyst deactivation and leaching of metals highly functionalized arenes, for the synthesis of are also sometimes problematic. In addition, there are ACS Paragon Plus Environment
Introduction
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pharmaceuticals and biologically active compounds. In addition, remarkably high catalytic TOFs were demonstrated in flow processes compared with batch systems, especially for arenes containing polar and coordinative functionalities that usually act as catalyst poisons. Moreover, the predictable selective arene hydrogenation of complex compounds that contain more than two aromatic moieties based on mechanistic studies is demonstrated.
Results and Discussion Catalyst preparation and arene hydrogenation in a batch system We have developed polysilane-encapsulated Pd nanoparticle catalysts for the hydrogenation of C–C double bonds, triple bonds, and nitro groups in both batch and flow systems.9 Polysilane is a polymer with interesting electronic properties, derived from s-conjugaed electrons of the silicon backbone.10 s-Conjugated electrons show reduction ability to generate metal nanoparticles from metal salts and stabilize metal nanoparticles by multiple, weak interactions. Polysilane is also commercially available and inexpensive. In addition, polysilane is a highly stable and safe material that does not swell with organic solvents; the latter feature is highly beneficial for continuous-flow systems because almost no pressure increases or clogging occurs, especially under multi-phase flow conditions of gas and liquid.9, 11 Therefore, we chose polysilane as a support to generate heterogeneous metal catalysts for the hydrogenation of arenes. In this context, we first prepared single and bimetallic metal nanoparticle catalysts (Rh, Pt, Pd, and bi- and tri-metallic) using NaBH4 as an external reductant to facilitate the formation of metal(0) nanoparticles in the presence of two types of polysilane supports: dimethylpolysilane (DMPSi) and methylphenyl polysilane (MPPSi) (Table 1). Metal salts were dropwise into the mixture of polisilane and NaBH4 and metal nanoparticles were generated immediately under reductive conditions. The generated nanoparticles were deposited and stabilized by the polysilane through electronic interactions. Alumina was added as a second support to stabilize the catalyst structure in the following step. Methanol that is a poor solvent for polysilane was added to form polysilane encapsulated metal nanoparticles. The obtained mixture was heated under vacuum, and partial inter-crossliking of polysilane and alumina proceeded through oxygen bond because a part of Si-Si bond was converted to Si-O-Si bond during the reduction of the metal. This inter-crossliking between the primary support (polysilane) and the secondary support (alumina) is important for the stability of the catalyst and prevention of metal leaching.9b These catalysts were composed of metal nanoparticles with an average size of approximately 5–6 nm (SI Figures 3
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and 4). The alloyed structure of the Rh-Pt bimetallic nanoparticles was confirmed by scanning transmission electron microscopy (STEM) and energy–dispersive X-ray spectroscopy (EDS) line/mapping analyses. In addition, the EDS analysis clarified that polysilane and alumina formed composite supports but nanoparticles located mostly at the silicon part (SI Figures 5 and 6).9d H2 pulse chemisorption analysis revealed that the active site (total mol of adsorbed hydrogen in unit gram of catalyst) in Rh-Pt/(DMPSi-Al2O3) was calculated as 0.0155 mmol/g. We evaluated the performance of the prepared catalysts in the hydrogenation of toluene to afford methylcyclohexane (MCH) in atmospheric hydrogen under neat conditions and at ambient reaction temperature (Table 2). When singlemetal nanoparticle catalysts of Rh, Pt, or Pd immobilized on DMPSi were used, the Rh catalyst showed moderate activity, whereas the Pt and Pd catalysts showed almost no activity (entries 1–3). Interestingly, when a bimetallic catalyst of Rh and Pt (Rh-Pt/(DMPSi-Al2O3)) was used, a significant increase in activity was observed; MCH was obtained in 76% yield with only 0.025 mol% Rh (entry 4). This result might be explained by a synergistic effect of the two metals on the surface of the alloyed nanoparticles. Indeed, we previously demonstrated a number of unique effects in bimetallic systems that were absent from their monometallic counterparts.12 The use of Rh-Pt/(MPPSi-Al2O3) also led to comparable results under the same reaction conditions (entry 5). We then raised the reaction temperature from 30 to 50 °C in an attempt to increase the reactivity. We compared the activities of bi- and tri-metallic catalysts. RhPt/(DMPSi-Al2O3) showed higher activity than RhPd/(DMPSi-Al2O3) and Rh-Pt-Pd/(DMPSi-Al2O3) (eintries 68). We were pleased to find that the use of Rh-Pt/(DMPSiAl2O3) under these conditions gave an excellent yield of MCH (entry 9). However, such high performance was not realized by the use of Rh-Pt/(MPPSi-Al2O3) (entry 10). The catalyst loading of Rh-Pt/(DMPSi-Al2O3) was then reduced to 0.00625 mol% in an attempt to achieve higher catalytic turnover. This led to almost full conversion with RhPt/(DMPSi-Al2O3) at 50 °C for 60 h; TON of 16,000 (198,193 per active site) (entry 11). Table 1. Preparation of catalysts NaBH4 (x equiv.) metals /diglyme (1 equiv. each) Me Si THF, 0 ºC, 1 h R n
dry
neat, 100 ºC 5 h, in vacuo
MeOH 1) filtration 2) wash (acetone, H2O)
2h
R = Me: M/(DMPSi-Al2O3) 1) filtration 2) wash R = Ph: M/(MPPSi-Al2O3) (H2O, THF, CH2Cl2)
Metal 1 / Metal 2 / x (Metal 3)
M
R
Rh
Me Rh(OAc)2
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Al2O3
6
Metal 2/(3) (mmol/g) (mmol/g) Metal 1
0.011
–
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Journal of the American Chemical Society
Pt
Me Na2PtCl6
12 0.061
–
Pd
Me Pd(OAc)2
6
0.067
–
Rh-Pt
Me Rh(OAc)2/Na2PtCl6
18
0.080– 0.096
0.025– 0.031
Rh-Pt
Ph
18 0.100
Rh-Pd
Me Rh(OAc)2/Pd(OAc)2 18 0.074
Rh(OAc)2/Na2PtCl6
0.036
Rh(OAc)2/Na2PtCl6/ Rh-Pt-Pd Me 18 0.068 Pd(OAc)2
0.025/0.0 42
Table 2. Optimization of reaction in the batch system M/(DMPSi-Al2O3) or M/(MPPSi-Al2O3) (x mol%) T ºC, H2 (1 atm), 20 h, neat
Entr y
Catalyst (M; R)
Rh (M) (x, mol%)
Tem p (°C)
Yield TON[d] (%)[a]
1
Rh; Me
0.025
30
40
1,600
2
Pt; Me
0.025
30
2
64 (/Pt)
3
Pd; Me
0.025
30
0
0
4
Rh-Pt; Me
0.025 (0.008 Pt) 30
76
3,020
5
Rh-Pt; Ph
0.025 (0.008 Pt) 30
72
2,880
6[c]
Rh-Pt; Me
0.1 (0.033 Pt)
50
>99
1,000
7[c]
Rh-Pd; Me
0.1 (0.05 Pd)
50
65
650
8[c]
Rh-Pt-Pd; Me
0.1 (0.037 Pt) 50 (0.062 Pd)
53
530
9
Rh-Pt; Me
0.025 (0.008 Pt) 50
99
3,960
10
Rh-Pt; Ph
0.025 (0.008 Pt) 50
77
3,080
0.00625 (0.0021Pt)
>99
16,000 (198,193) [e]
11[c] Rh-Pt; Me
50
[a] Determined by GC. [b] Reaction time 24 h. [c] Reaction time 60 h. [d] Defined as moles of reacted toluene per mole of Rh. [e] Defined as moles of reacted H2 per mole of active site of catalyst.
Table 3. Recovery and reuse of the catalyst Rh-Pt/(DMPSi-Al 2O3) (0.025 mol% as Rh) 50 ºC, H 2 (1 atm), 24 h, neat
Run
1
Yield (%)[a]
2
3
4
5[b] 6[b] 7[b] 8[b] 9[b] 10[b]
99 99 97 88 96 97 97 98 97 96
[a] Yield determined by GC analysis. [b] After the fourth run, the
catalyst was heated under Ar before use at 100 °C for 7 h.
Recovery and reuse of Rh-Pt/(DMPSi-Al2O3) were then investigated (Table 3). Rh-Pt/(DMPSi-Al2O3) was recovered by simple filtration of the reaction mixture and drying in vacuo at room temperature. High yields were maintained for the initial three runs; however, the catalytic activity decreased slightly in the fourth run. Catalytic activity was regenerated in the fifth run after reviving the catalyst by heating under an Ar atmosphere. Recycling and regeneration of the catalyst by heating after each run was continued, and almost full conversion was maintained until the tenth run.
Poisoning of the catalyst, either by a small amount of impurity or by solvent molecules that are adsorbed on metal nanoparticles during the work-up process, may account for the slight loss of catalytic activity. These molecules would be removed by heating the catalyst to revive the catalytic activity. We thus demonstrated the robustness of the Rh-Pt nanoparticle catalyst during this reuse investigation; a total TON of 42,480 was achieved. We also confirmed, by ICP analysis of the reaction mixture, that no measurable leaching of either of the metals (Rh or Pt) occurred during the recovery and reuse investigation. STEM analysis revealed that the size of the nanoparticles remained small during recovery and reuse, even after the regeneration process under heating (SI Figures 11-14). We then investigated the scope of the reaction in the batch system with respect to the substrate (Figure 1 and Table 4). Arenes with less bulky substituents, such as toluene (1a), benzene (1b), and ethyl benzene (1c), were fully hydrogenated under the optimized conditions (entries 1–3). Cumene (1d) and tert-butyl benzene (1e), which have bulky substituents, required 40 h (entries 4 and 5). Arene with a long alkyl chain (1f) afforded the desired product quantitatively, even with 0.1 mol% catalyst loading in 64 h (entry 6). The p-, m-, and o-xylenes 1g, 1h, and 1i required longer reaction times; full conversions were obtained with enriched cis configurations, albeit with slightly different diastereoselectivities (entries 7–9). The tendency to form the cis isomer has been noted previously for arene hydrogenation when using metal nanoparticles.6b, 6d, 6f, 6i, 6l, 6n, 6q, 6t, 6x This might be caused by steric repulsion between the surface of the nanoparticles and the methyl groups in the partially reduced intermediates. The presence of the trans isomers in these three cases suggests that partially reduced intermediates might disaggregate from the surface of the nanoparticles at least once before complete hydrogenation. For mesitylene (1j), moderate yield was observed, probably because of its high steric bulk (entry 10). Tetrahydronaphthalene (1k) was hydrogenated to decaline under relatively harsh conditions (entry 11). We then investigated the electronic effects of directly connected substituents on the aromatic ring. Aromatic compound 1l, with a strong electron-withdrawing trifluoromethyl group, gave an excellent yield (Table 4, entry 12). Free carboxylic acid derivatives 1m and 1n afforded excellent yields in cyclopentyl methyl ether (CPME) and moderate diastereoselectivity was observed for 1n (entries 13 and 14). Ethyl benzoate (1o) and benzamide (1p) were hydrogenated quantitatively while preserving the functionalities (entries 15 and 16). We then investigated the compatibility of the reaction conditions towards functional groups. Arenes with carboxylic acid, hydroxyl, primary amine, and N-Boc-protected amine groups (1q, 1r, 1s, 1t) were reduced to the corresponding cyclohexyl compounds
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with retention of these functionalities (entries 17–20). NBoc-protected phenyl glycine (1u) and its methyl ester (1v) were reduced to the corresponding cyclohexane derivative while maintaining the optical purity and preserving the Bocprotecting group (entry 21 and 22). N-Boc-protected anthranilic acid (1w) was hydrogenated smoothly, retaining the functionalities (entry 23). Phenol (1x) was smoothly reduced to cyclohexanol without formation of either cyclohexanone or cyclohexenone (entry 24). Hydroquinone (1y) was fully hydrogenated in isopropanol to afford 1,4dihydroxy cyclohexane with almost 1:1 ratio of cis-trans isomers. The low diastereoselectivity can be explained by the formation of a stable intermediate involving a ketone moiety that can be easily detached from the catalyst surface before the next hydrogenation (entry 25). Anisole (1z), nbutyl phenyl ether (1æ), and isopropyl phenyl ether (1aa) were fully reduced to the corresponding cyclohexyl ethers, quantitatively without cleavage of the ether bond (entries 26–28). On the other hand, cyclopentyl phenyl ether (1ab) afforded not only cyclohexyl cyclopentyl ether but also cyclohexanol (21%) and cyclopentanol (24%) (see SI, Table 6). Interestingly, a slight increase in hydrogen pressure (3.9 atm) prevented ether cleavage; cyclohexyl cyclopentyl ether was obtained as the sole product (entry 29). Diphenyl ether (1ac) afforded dicyclohexyl ether in 76% yield under slightly pressurized conditions, accompanied by the formation of cyclohexanol (entry 30). Primary, secondary, and tertiary aniline derivatives were also investigated. Aniline (1ad) was fully hydrogenated; however, cyclohexylamine was obtained in moderate yield because of the formation of dicyclohexylamine (41%) (entry 31). On the other hand, methylaniline (1ae) was smoothly reduced to the corresponding cyclohexylamine derivative under pressurized conditions (entry 32). Dimethylaniline (1af) required harsher reaction conditions (20 atm H2, 120 °C) for full reduction, probably because the catalytic activity was diminished by the strong coordinating nature of tertiary amines (entry 33). Protected anilines, acetanilide (1ag) and N-boc aniline (1ah), were converted into the corresponding cyclohexylamine derivatives in excellent yields while maintaining the protecting group (entries 34 and 35). The protection of amine group may mitigate its coordinating ability on the nanoparticle surface, thereby allowing milder reaction conditions compared with those required for alkylated aniline derivatives. Heteroaromatic compounds such as furan (1ai) and dimethyl furan (1aj) were smoothly reduced to the corresponding tetrahydrofuran derivatives under mild conditions, and the latter gave the cis isomer as the major product (entries 36 and 37). Although pyridine (1al) could be reduced under atmospheric conditions (entry 39), pyrrole (1ak) required 10 atm of hydrogen (entry 38). Hydrogenation of substituted pyridines, especially those containing an ester group at the meta-position, attracts
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much attention because the hydrogenated products can be easily converted into valuable pharmaceuticals. Of these processes, full hydrogenation of ethyl 3-nicotinate (1am) is one of the most challenging tasks. In earlier studies,1c, 4 very harsh conditions (100 atm H2) were typically required. Interestingly, Rh-Pt/(DMPSi-Al2O3) was found to be a highly active catalyst for this transformation; quantitative conversion into ethyl nipecotinate (2am) was achieved with partially reduced product 3am under 10 atm H2 at 100 °C in hexane (entry 40). A pyridine derivative with a dimethyl acetal moiety (1an) was successfully reduced to the corresponding piperidine derivative in excellent yield with retention of the acetal moiety (entry 41). Ethyl 4-nicotinate (1ao) was also hydrogenated smoothly under mild conditions to afford the fully reduced product in excellent isolated yield (entry 42). Quinoline (1ap) and isoquinoline (1aq) afforded tetrahydroquinoline almost quantitatively at 80 °C under pressurized conditions without formation of full hydrogenated compounds (entries 43 and 44). Difficulty in full hydrogenation of these bicyclic structure might be caused by the steric repulsion of initially hydrogenated cycle, as 1k also required harsh conditions. Me
R
R=M 1a
Me
Me
1d
iPr
1e H 1b Et 1c n-Octyl 1f Me tBu
Me
Me
Me
1g
Me
CF3
COOH
COOH
Me
1j
1i
1h
1k
O
COOEt
COOH
NH2
1l
1m
1s
1r OH
COOH O N H
O HOOC N OtBu H 1t
NH2
OH
HO
O
1x
O
1v
1u
1ab
Me Me
Me
N
1ad
N H 1ak
1ae
N
H N
O
OMe
1am
OEt
OMe N 1an
N
1ao
OH
1ap
N
2ap
N H
1aq
OH
H H
N
NH
H H
H
HO
H
HO
1ar
2aq
OtBu
O 1ah
O
1af
O
OEt
N 1al
1aa
H N
1ag
1ac
O 1aj
HN
O
nBu
1æ
1z O
OtBu O
1y
NH2
H N
OtBu MeOOC
O
1w
1ai
H N
1q
OMe
OH
OtBu
O
1p
1o
1n
2ar
Figure 1. List of substrates. Table 4. Substrate scope in the batch system aromatic compounds
Rh-Pt/(DMPSi-Al 2O3) (x mol% as Rh) T °C, H 2 (P atm), t h, neat or solvent
saturated compounds
Entry Substrate x P T t Solvent Yield (mol%) (atm) (°C) (h) (%)[a] 1
1a
0.1
1
50
24
neat
>99[b]
2
1b
0.1
1
50
24
neat
>99[b]
3
1c
0.1
1
50
24
neat
>99[b]
4
1d
0.1
1
50
40
neat
94[c]
5
1e
0.1
1
50
40
neat
94
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6
Journal of the American Chemical Society 1f
0.1
1
50
64
neat
99
7
1g
0.1
1
50
48
neat
>99[b,
8
1h
0.1
1
50
48
neat
>99[b, e]
9
1i
0.1
1
50
144 neat
>99[b, f]
10
1j
0.1
1
50
24
neat
45[c, g]
11
1k
0.1
10
80
24
neat
85
12
1l
0.03
1
50
64
neat
94
13
1m
0.1
1
50
24
CPME
98
14
1n
0.1
10
80
36
CPME
87[h]
15
1o
0.1
1
50
24
neat
99
16
1p
0.1
10
80
24
EtOH
>99
17
1q
0.3
1
50
24
CPME
>99
18
1r
0.1
10
80
24
neat
52[c]
19
1s
0.1
10
80
24
neat
54[c]
d]
20
1t
0.3
1
50
24
CPME
99
21
1u
1.7
10
80
48
EtOAc
81
22
1v
1.7
1
50
48
EtOAc
99
23
1w
1.7
10
80
24
EtOAc
93[i]
24
1x
0.03
10
80
26
neat
81
25
1y
0.1
1
50
24
i-PrOH 85[j]
26
1z
0.1
1
50
24
neat
99
27
1æ
0.1
1
50
120 neat
74
28
1aa
0.1
1
50
24
neat
76
29
1ab
0.1
3.9
80
24
neat
86
The utility of arene hydrogenation catalyzed by RhPt/(DMPSi-Al2O3) is highlighted in the synthesis of intermediates of drugs and biologically active compounds (Scheme 1). Cyclohexane carboxylic acid derivative 2n was obtained from commercially available benzoic acid derivative 1n in 87% yield, and 2n can be converted into nateglinide by using a reported method (Scheme 1 (a)). NBoc-protected phenyl glycine was hydrogenated quantitatively, and the resulting product can be converted into melagatran by following the reported procedure (Scheme 1 (b)). As noted above, ethyl 3-nipecotinate (2am) is an intermediate for several pharmaceuticals, such as tiagabine (Scheme 1 (c)). Pyridine derivative 1ao could be hydrogenated to the corresponding piperidine derivative, which is an intermediate for the synthesis of donepezil, in excellent yield (Scheme 1 (d)). Scheme 1. Application to the preparation of intermediates for drug synthesis (cat. = Rh-Pt/(DMPSi-Al2O3)) (a) 1n
H N
cat. (0.1 mol%) H2 (10 atm), 80 ºC CPME, 24 h, 87%
2n
CO2Me
O Ph Nateglinide
R. Yahalomi, et al. European Patent, EP1487782 (A1) (2002) O
(b) cat. (1.7 mol%) 1u
H2 (10 atm), 80 ºC EtOAc, 48 h, 99%
2u
N H
H 2N
O
H N
N
CO2H
NH Melagatran L.A. Sobrera, et al. Drugs Future 2002, 27, 201. O
(c) 1am
cat. (0.1 mol%) H2 (10 atm), 100 ºC hexane, 24 h, 99%
N
S
2am
S
OH
(R)-Tiagabine
Knutsen, L. J. S. et al., J. Med. Chem. 1993, 36, 1716. (d)
OMe
cat. (3 mol%) 1ao
2ao
Ph
N
O
OMe
30
1ac
0.1
3.9
80
24
neat
76[c]
31
1ad
0.1
10
80
24
neat
59[c]
32
1ae
0.1
10
80
24
neat
91
33
1af
0.1
20
120 48
neat
83
Arene hydrogenation in a continuous-flow system
34
1ag
0.13
1
50
46
CPME
95
35
1ah
0.27
1
50
46
CPME
95
36
1ai
0.1
1
50
24
neat
99[b]
37
1aj
0.1
1
50
24
neat
81[k]
38
1ak
0.1
10
80
24
neat
83
39
1al
0.1
1
50
37
neat
93
40
1am
0.1
10
100 24
hexane 99
41
1an
2.6
10
80
48
neat
97
42
1ao
1
1
50
36
neat
90
43
1ap
0.1
10
80
24
neat
96
44
1aq
0.1
20
120 24
neat
76
We applied Rh-Pt/(DMPSi-Al2O3) to continuous-flow hydrogenation systems (Figure 2, SI Figure 15). Toluene and hydrogen, as liquid and gas substrates, respectively, were simultaneously passed through a column containing RhPt/(DMPSi-Al2O3) without a backpressure controller at the outlet (i.e., open to the atmosphere). The inlet of the column was constructed as a double-layered structure with a metallic mesh through which both the liquid and gas components pass and intermix well before entering the catalyst-packed region (SI Figure 17). Using Rh-Pt/(DMPSiAl2O3) as catalyst, reaction conditions were optimized under the multiphase continuous-flow conditions, changing parameters of substrate and hydrogen flow rates, and column heating temperature (SI Table 2). When the liquid substrate was delivered with a flow rate of 0.05 mL/min together with 63 mL/min hydrogen (corresponding to 1.86 equiv. of the amount theoretically required for quantitative conversion) through Rh-Pt/(DMPSi-Al2O3) (666 mg), packed
[a] Isolated yield. [b] Determined by GC analysis. [c] Determined by 1H NMR analysis. [d] cis/trans = 68:32 [e] cis/trans = 78:22 [f] cis/trans = 92:8 [g] all-cis/cis-cis-trans = 88:12 [h] cis/trans = 67:33 [i] cis/trans = 80:20 [j] cis/trans = 57:43 [k] cis/trans = 97:3
H2 (10 atm), 100 ºC hexane, 24 h, 99%
Donepezil A. Imai, A. et al. European Patent, EP1911745 (A1) (2008)
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in a stainless column maintained at 70 °C, using an aluminum heating block, toluene was fully converted and analytically pure MCH was obtained quantitatively, without the requirement for purification. The reaction systems reached steady state very rapidly (within 10 min). We also monitored the pressure at the peristaltic pump and verified that almost no increase in pressure was observed (50 days); a total TON of 347,149 (99,815,534 reacted H2/active site) was achieved. Notably, no regeneration of the catalyst packed in the column was required during the long-period continuous-flow hydrogenation reaction, although catalyst regeneration was required in batch reactions for the recovery and reuse. mass flow controller
1 atm 63 mL/min
peristaltic pump 0.05 mL/min
neat
aluminium heating block at 70 ºC
H2
temperature controller Rh-Pt/(DMPSi-Al2O3) 666 mg in 5φ x 5 cm column >99% conversion was maintained for 1214 h (>50 days).
Figure 2. Schematic representation of the continuousflow reactor (hourly yield; SI Table 5) We also compared this flow system with the corresponding batch system using the same substrate/catalyst ratio for >50 days under the optimized reaction conditions of the batch system, except for the catalyst loading. Conversion of 99[b]
11
1l
>99
2
1b
>99[b]
12
1o
98[c]
3
1c
>99
13
1y
>99[i]
4
1d
>99[b]
14
1z
>99[c]
5
1e
>99
15
1æ
>99
6
1f
>99
16
1aj
>99[j]
7
1g
>99[b,e]
17
1ak
99
8
1h
>99[b,f]
18
1al
95
9
1i
>99[b,g]
19
1ao
>99[c]
10
1j
>99[h]
20
1am
98[k]
21
1ar
92[l]
[a] Isolated yield of fractions collected during steady state. [b] De-
termined by GC analysis. [c] In hexane (0.24 M) at 100 °C. [d] In iPrOH (0.1 M). [e] cis/trans = 64:36. [f] cis/trans = 77:23 [g] cis/trans = 89:11. [h] cis/trans = 75:25. [i] cis/trans = 61:39. [j] cis/trans = 91:9. [k] In hexane (0.24 M), H2 (10 atm), at 100 °C; for optimization detail of 1am, see SI Table 3. [l] In i-PrOH (0.03 M) at 50 ºC.
Comparison of reaction kinetics between batch and flow systems In the substrate scope study, it was established that reactivity is highly dependent on the functionality of the arenes. However, reactivity tendency was sometimes very different between the batch system and the flow system. We were initially interested in the origin of this difference and hence decided to observe the reaction kinetics in both batch and flow systems. In all kinetic experiments, 1 atm H2 was used. First, reaction profiles, using toluene as substrate in a batch system, were recorded; these followed zero-order kinetics with respect to the substrate (SI Figure 19).6z, 13 When 0.1–0.3 mol% of Rh-Pt/(DMPSi-Al2O3) as Rh loading was used, only a slight increase in the reaction rate was observed. When the catalyst loading was reduced to 0.025, 0.0125, and 0.00625 mol%, the reaction rate gradually decreased in proportion to the amount of Rh (SI Figure 20). From these results, it appears that, when the catalyst loading
was 0.1–0.3 mol%, the rate-limiting step is mainly the dissolving and diffusion of hydrogen from the gas to the liquid phase (Scheme 2, step A). The rate-limiting step then gradually shifted to the step of the hydrogen adsorption to the surface of the nanoparticles. The reaction kinetics were first-order in catalyst when
