David
Stíbal
abc,
Jacinto
Sá
*b and
Jeroen A. van
Bokhoven
ab
aInstitute for Chemical and Bioengineering ETH Zurich, Wolfgang-Pauli Strasse, CH-8093 Zurich, Switzerland
bPaul Scherrer Institute (PSI), CH-5232 Villigen, Switzerland. E-mail: jacinto.sa@psi.ch; Tel: +41 56 310 29 10
cInstitute of Chemical Technology, Technická 5, Prague, 160 00, Czech Republic
First published on 25th September 2012
We report the photo-catalytic N-alkylation of aniline by Au–TiO2. We successfully alkylate aniline with several primary alcohols. The combined selectivities of mono- and di-alkylated products were always in excess of 70% and dependent on the alkylating alcohol used. A one-pot reaction from nitrobenzene was found to be possible with several substrates. Preliminary experiments showed that this approach could be adopted for the production of lactams using terminal amino-alcohols.
The most attractive method to prepare amine derivatives is the direct reductive amination of aldehydes and ketones. The carbonyl compound and the amine condense to form an imine that can be hydrogenated to the alkylated product by an appropriate reducing agent in a one-pot reaction.3 However the current methods have some drawbacks, such as lengthy reaction times, high reaction temperatures, reaction must be carried out under inert conditions and reaction often requires harmful reagents and often forms toxic products. Byun et al.4 synthesized N-alkylated amine from anilines and nitroarenes in one-pot using aldehydes and a Pd/C catalyst in aqueous alcoholic solvents with ammonium formate as the in situ source of hydrogen. Despite the high yields and the claim of green process, the reaction produces NH4+ and CO2 as by-products.
Heterogeneous photocatalysis was almost exclusively used in the degradation of unwanted molecules such as pollutants, however recently this technology was adopted for synthetic purposes. Kagiya and co-workers reported the photo-alkylation of linear amines for the first time.5 They reported a 33% yield in the alkylation of ethylamine to diethylamine over Pt–TiO2. They proposed a mechanism based on the condensation of amine and aldehyde leading to the formation of an imine, which was subsequently hydrogenated to the target product by H2 photo-generated in situ. The photo-catalyst was found later to be able to perform N-alkylation of aromatic amines by Matsushita et al.6
Herein, we report an efficient, facile and environmentally benign one-pot reductive N-alkylation of aniline and nitroarenes with linear alcohols, acting both as solvent and reagent, by photo-catalysis with Au–TiO2. To our knowledge, this is the first time that Au–TiO2 is proposed for N-alkylation of aniline and nitroarenes.7 Furthermore the strategy herein proposed can be used for the cyclization of linear amino-alcohols to form industrially relevant lactams.
The transmission electron microscopy (TEM) samples were prepared by dispersing the catalyst in ethanol, which was subsequently loaded in a copper grid. TEM measurements were performed on a HD2700CS (Hitachi, aberration-corrected dedicated STEM, cold FEG, 200 kV) and a Tecnai F30 ST (FEI, FEG, 300 kV).
Fig. 1 Schematic representation of the photo-reactor. |
Scheme 1 shows the photo-catalytic N-alkylation of aniline with a terminal alcohol over Au–TiO2. The catalytic performance after 4 h on stream is summarized in Table 1. Values close to 100% conversion were measured with all the alcohols after 4 h of reaction, except for 1-hexanol. The selectivity to alkylated products was found to be higher than 70%, which translates to high yield of the desired products. When the reactions were carried out for 24 h, the combined yield of alkylated products was higher than 95%. The yields are comparable to the ones reported by Byun et al.4 however it must be emphasized that they used an aldehyde as the starting reagent and hydrogen was formed from dissociation of ammonium formate, which herein was formed photocatalytically from the alcohol. The reaction was carried out at 50 °C and no irradiation did not yield significant amounts of alkylated products.
Scheme 1 Photo-alkylation of aniline over Au–TiO2. |
Alcohol R–CH2OH | Conversiona (%) | Yield of Ar–NHR′a (%) | Yield of Ar–NR2′a (%) |
---|---|---|---|
a Calculated after 4 h on stream. b Reaction rate in mmol (min gcat)−1 calculated after 30 min of reaction; R′ = –CH2–R. | |||
CH3OH | 100.0 (0.17)b | 5.5 | 60.7 |
CH3CH2OH | 100.0 (0.15)b | 74.4 | 8.9 |
CH3(CH2)2OH | 99.7 (0.08)b | 89.1 | 2.4 |
CH3(CH2)3OH | 99.6 (0.06)b | 87.8 | 0.0 |
CH3(CH2)5OH | 74.0 (0.04)b | 52.5 | 0.0 |
The proposed reaction mechanism is illustrated in Fig. 2. The process is initiated by the oxidation of the terminal alcohol to its corresponding aldehyde via an alkoxy radical intermediate by the photo-generated holes in TiO2 upon absorption of a photon with enough energy to overcome the semiconductor band gap. Alcohol oxidation can occur via direct interaction with semiconductor surface holes or indirectly via a radical reaction, such as OH˙, formed by the reaction of OH− with the surface holes. The results presented within do not allow discrimination of the individual paths. The photo-generated electrons reduce the resultant protons to molecular hydrogen. The proposed active sites for the formation of hydrogen are the larger gold ensembles (5–15 nm) that act as an electron sink slowing down the rate of charge-pair recombination.8
Fig. 2 Proposed reaction mechanism for the photo-alkylation of aniline over Au–TiO2. |
Small nanoparticles of Au (1–3 nm) are expected to be bad electron reservoirs because they have less metallic character,9 essential for efficient charge transfer. Fig. 3 shows the particle size distribution of the gold catalyst after synthesis and after reduction, which was carried out before the reaction. The reduction sinters some of the Au nano-particles leading to a broadening of the particle size distribution. The catalyst in its state before catalysis is composed roughly by 40% of small gold nano-particles (<4 nm) and the remaining 60% are larger particles with sizes comprised between 5 and 13 nm.
Fig. 3 TEM analysis of the catalyst before and after reduction pre-treatment. (top) TEM images; (bottom) histogram of particle size distribution. |
After the formation of the aldehyde, an imine is formed from the condensation of the aldehyde and amine. This step is not catalytic and it is observed also with bare TiO2, however with a slightly lower rate. The next step is the hydrogenation of the imine double bond to form the corresponding aniline derivative. This crucial step is carried out on small gold ensembles, which activate the photo-generated molecular hydrogen. In the case of bare TiO2 the process ceases after the imine formation step since the bare support is not able to activate hydrogen. Selvam and Swaminathan10 reported the photo-formation of quinaldines from nitroarenes using Au–TiO2 as the photo-catalyst. In their proposed reaction mechanism, imines are reaction intermediates. However, their photo-catalyst is unable to hydrogenate the imine to the N-alkylated product. The disparity in the result can be easily rationalized if one takes a closer look at the particle size. Their catalyst had no particles smaller than 5 nm, which is fundamental to hydrogenate the photo-formed imines, i.e. split hydrogen. Therefore, the presence of small and large particles in our catalyst confers the essential dual function of gold, namely large gold particles for the photo-formation of hydrogen and gold particles below 5 nm to hydrogenate the imine.
The overall process is governed by the availability of protons, which is governed by the pKa of the alcohol. Methanol is from the alcohols tested the one with the lowest pKa, which increases with the increase of the carbon chain length.10 Therefore, the activity or the reaction rate should decrease with the increase of the carbon chain length, which was the case. Combination of low pKa and low kinetic stability of the methoxy radical promotes alkylation resulting in the appearance of the di-alkylated product. The di-alkylated product is produced at the expense of the mono-alkylated, which can be easily deduced from Fig. 4.
Fig. 4 Catalytic performance of Au–TiO2 as a function of time in the photocatalytic alkylation of aniline. Alkylating alcohol: (a) methanol and (b) butanol. () aniline conversion, () selectivity to N-monoalkylated product and (▲) selectivity to N,N-dialkylated product. |
The aforementioned results confirm that photo-catalytic N-alkylation of aniline with alcohols is possible, however to confer any high degree of flexibility to the methodology, photo-alkylation should be able to start from nitroarenes, which are the typical aniline precursors. The outcomes of the experiments in which nitroarenes were used as starting substrate are summarized in Table 2. The yields are smaller than the ones reported by Byun et al.,4 however they used up to 20 equivalents of ammonium formate to achieve the reported yields. Furthermore, the reaction was only carried out for 4 h in order to compare the effect of the substituent. When some of the reactions were allowed to proceed for 24 h, yields higher than 70% were obtained.
Substrate | Conv.a (%) | Initial rateb | Yield of Ar–NH2a (%) | Yield of Ar–NR2′a (%) |
---|---|---|---|---|
a Conversion and yield after 4 h on stream. b Reaction rate in mmol (min gcat)−1 calculated after 30 min of reaction. c Reaction rate of bare TiO2; R′ = –CH2–R | ||||
99.4 | 0.034 (0.090)c | 18.5 | 50.0 | |
86.8 | 0.060 (0.059)c | 45.2 | 24.1 | |
97.4 | 0.040 (0.057)c | 12.7 | 5.6 | |
98.0 | 0.032 (0.071)c | 60.2 | 3.9 | |
100 | 0.090 (0.048)c | 76.5 | 0.0 | |
99.8 | 0.071 (0.042)c | 52.8 | 24.2 | |
94.2 | 0.051 (0.028)c | 52.1 | 21.3 | |
99.5 | 0.073 (0.057)c | 9.2 | 56.9 | |
84.4 | 0.002 (0.055)c | 30.6 | 32.8 | |
100 | 0.009 (0.073)c | 23.7 | 7.6 | |
100 | 0.043 (0.075)c | 9.5 | 0.6 | |
100 | 0.039 (0.030)c | 27.7 | 20.3 | |
54.8 | 0.027 (0.015)c | 5.9 | 10.9 | |
99.4 | 0.034 (0.090)c | 18.5 | 50.0 |
Two possible reaction mechanisms can be postulated for the reduction of the nitroarenes to the corresponding aniline. The first is the hydrogenation of the nitro-group over nano-size gold, as previously reported.11 Normally hydrogenation reactions are carried out with 10 bar of hydrogen and at a temperature exceeding 60 °C,11d to ensure meaningful catalytic conversions. Furthermore, the catalytic activity of the bare support is often very low and the overall catalytic performance is not strongly affected by the presence of substituents.12
The other possible mechanism is the photo-reduction of nitroarene. Nitroarene reduction was proposed by Mahdavi et al.,13 who demonstrated that TiO2 under UV light could efficiently reduce nitroarenes to corresponding anilines. Addition of Ag to the catalyst formulation improved the catalytic performance,14 which they attributed to a decrease of charge-recombination, suggesting that nitro reduction occurs primarily on TiO2. Furthermore, the activity was found to be dependent on the nitroarene substituent identity and position with respect to the nitro group,15 which is precisely what the results summarized in Table 2 show. Therefore we assume that conversion of nitro to amine occurs photo-catalytically on TiO2. After the formation of aniline, the reaction proceeds as previously mentioned.
The reported yields are not satisfactory for all nitroarenes, which has to do with the nitroarene reaction rate to aniline. A plethora of species were measured, however it should be pointed out that they were all intermediate species of either aniline formation (slower reaction rates in the nitroarene reduction) or N-alkylation, possibly caused by the competition for the active site, i.e., products related to other reactions were not detected. When some of the reactions were allowed to proceed for 24 h, yields of 70% or better were measured, suggesting that the low yields are related primarily to the short time on stream. However for comparison purposes the reactions were carried out for the same time as that of the alkylation of aniline.
N-heterocycles are important scaffolds for many drugs and natural products.16 As a proof of concept, we tested our catalyst in the photo-cyclization of amino-alcohols for the production of commercially valuable lactams and heterocycle amines, as depicted in Scheme 2 and shown in Table 3.
Scheme 2 Photo-cyclization of 5-aminopentanol over Au–TiO2. |
Reaction time/h | Conversion (%) | Yield of δ-valerolactam (%) | Yield of piperidine (%) |
---|---|---|---|
4 | 74.0 | 16.3 | 4.8 |
17 | 98.5 | 32.5 | 0.3 |
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