One-pot amination of aldehydes and ketones over heterogeneous catalysts for production of secondary amines

ABSTRACT This review summarizes the recent studies on the synthesis of secondary amines by one-pot amination of aldehydes and ketones over heterogeneous catalysts. Amines are widely applied as the key intermediates in chemical industry for the synthesis of various commodities such as agrochemicals, drugs, detergents, lubricants, food-additives and polymers. Direct catalytic reductive amination of carbonyl compounds was considered which generally includes two steps: (i) formation of imines by interactions of aldehydes or ketones with amines, and (ii) subsequent hydrogenation of imines. Synthesis of secondary amines from carbonyl compounds and amines generated in situ under reaction conditions from their progenitors, e.g., respectively, alcohols or nitro-compounds, is also discussed in detail. Recent progress in application of hydrogen sources alternative to gaseous H2, such as formic acid, NaBH4, CO and water, favored development of metal-free catalysts including solid acid catalysts. The review addresses the scope of the amination reaction with aldehydes/ketones and nitro/amine compounds of different structure, the effect of the solvent, reaction conditions and catalyst properties. In addition, catalyst regeneration and reuse, kinetic regularities and kinetic modeling with an emphasis on the continuous mode of one-pot amination have been systematically summarized and discussed. It is suggested that the future work should focus on revealing the role of the catalytically active sites addressing their acid–base properties and the correlation between catalyst properties and the reaction performance, elucidating kinetic parameters and designing feasible reactor system for further industrial implementation.


Introduction
Efficient preparation of functionalized amines is of significant interest for synthesis of fine chemicals. Direct reductive amination of carbonyl compounds is in this context a promising method for preparation of amine derivatives, comprising first formation of imines by a reaction of aldehydes or ketones with amines and their subsequent hydrogenation. As with other one-pot processes such methodology brings clear ecological and economic benefits compared with the stepwise processes. [1,2] One-pot reductive amination of carbonyl compounds to produce secondary amines is an important research field, because these products are used as intermediates for synthesis of drugs, [3] such as, for example, 4-benzyl morpholine intermediate utilized in synthesis of drugs against lung cancer [4] or N-benzylaniline applied for synthesis of dibenzazepines [5] and neurogenic agents, [6] as well as preparation of 2,5-dideoxy-2,5-imino-D-altritol (DIA), an inhibitor of α-galactosidase A and a valuable compound in the Fabry disease treatment. [7] Pharmaceutical activity of N-substituted 5-(hydroxymethyl)-2-furfuryl amines as for example muscarinic agonists or cholinergic agents, has been also reported. [8,9] One-pot synthesis is highly desirable making the process more economically feasible avoiding separation of the intermediate, purification steps and consuming less energy. [1,2] Synthesis of secondary amines from aldehydes and ketones has been intensively studied using amines as a nitrogen source and as an example reaction scheme for reductive amination of cyclohexanone with benzylamine is depicted ( Figure 1). [2,[10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] Synthesis of secondary am ines can be realized via the one-pot synthesis where carbonyl compounds as well as amines are generated in situ under reaction conditions from their progenitors, e.g. alcohols or nitro-compounds, respectively. In that case, aldehydes or ketones with nitro-compounds are introduced into a reactor where the latter reagents are rapidly converted under a reductive atmosphere forming in situ amines, which in turn react with a carbonyl group forming the corresponding imines. Similarly, in situ dehydrogenation of alcohols gives carbonyl compounds, which in the presence of amines result in targeted imines. In the second step, the formed imines are hydrogenated to the desired secondary amines, for example amination of nitrobenzene with benzaldehyde ( Figure 2). [28][29][30] The latter reaction corresponds to a so-called hydrogen borrowing reaction described in detail in the Figure 1. Reductive amination of cyclohexanone with benzylamine. Adapted fromRef. [10] Open access.
Monometallic commercial catalysts, such as Pd/C and Ru/C, displayed low selectivity in one-pot amination of benzaldehyde with aniline. [11] Similarly, Ru/C and Rh/C catalysts in the amination of 4-fluorobenzaldehyde with 4-methoxyaniline [75] as well as Cu/Al 2 O 3 in the amination of 4-methoxyacetophenone [69] were not selective clearly showing a need for bifunctional catalysts in amination of carbonyl compounds. [61] Small Pd particles supported on NiO, [15] bimetallic Fe@Pd/C, [11] ligand attached Pd particles supported on a polymer, [17] Pd-Cu-β-cyclodextrin, [66] Pd/C covered by carbonaceous particles [67] and UiO-67-para-phenylenediamine-Pd [68] have been very efficient catalysts for amination of aldehydes with amines ( Table 1, entries 1-3, 5-9, 11-13 and Table 2, entries 1-6). It should be pointed out here that aldehydes are typically easier to be transformed to secondary amines in comparison with ketones as will be discussed further. When comparing properties of these catalysts, it was observed that the hydrogenation activity of Pd was suppressed by embedding it into a polymeric support, [17] cyclodextrin matrix, [66] carbonaceous support [67] or by using for example Fe@Pd/C catalyst with a lower hydrogenation ability. The latter catalyst contains iron atoms partially substituted with Pd. In addition ionic Pd 2+ species coordinated to a nitrogen containing polymer are also present. [68] It is also interesting to compare amine structure in reductive amination of benzaldehyde. For example, Pd/NiO with rather small Pd particles (5 nm) (Table S2, entry 1) was an efficient catalyst in reductive amination of benzaldehyde with cyclohexylamine under mild conditions (Table 1, entry 1), however, its amination with aniline resulted in a slightly lower yield of the secondary amine (Table 1, entry 6) under comparative conditions. [15] It was furthermore stated that even a reversible dehydrogenation reaction of the N-benzylaniline can occur, thus lowering its yield after prolonged reaction times. [15] In Ref. [15], the reactions were performed in a reaction tube, however, not clearly specifying if there was any stirring and what was the catalyst particle size. Thus, these results might have been obtained under diffusional limitations. As a comparison, a two-step process was proposed in Ref. [71], in which benzaldehyde reacted with aniline in the absence of a catalyst in methanol forming an imine, which in the second step was hydrogenated at 120°C under 20 bar H 2 in a flow reactor giving a high yield of benzyl aniline (Table 1, entry 4). [71] A constant yield of N-benzylamine was obtained during 6 h time-on-stream. Overall, reductive amination of benzaldehyde and its para-substituted derivatives has resulted in high yields of secondary amines. The reported literature suffers, however, from incomplete data, as for example, in reductive amination of benzaldehyde with 4-chloroaniline only the yield of amine was given (Table 1, entry 7). [17] Polystyrene embedded N-heterocyclic carbine-linked Pd was also an efficient catalyst in furfural amination with aniline (Table 1, entry 12) analogously to benzaldehyde. [17] Even Pd/C with the palladium particle size of 2.7 nm (Table S1, entry 5) was very efficient giving only amine as the product (  [17] 3  [15] (Continued)  [15] (Continued)  [67] (Continued)  [24] (Continued)  [25] (Continued)  [21] (Continued)  [27] a Catalyst properties are described in Table S1. b 1-(4-fluorophenyl)ethan-1-amine. entry 13), while Pd/Al 2 O 3 resulted in only 80% yield of the amine at 100°C under 3 bar hydrogen. [67] The reason for this were strong interactions of furfural with Pd(111) on Al 2 O 3 confirmed by DRIFTs measurements, while Pd/C contains less Pd(111) sites. In furfural amination, the furan ring was hydrogenated over Pd/Al 2 O 3 . In reductive amination of furfural gold, platinum, and iridium colloids supported on sulfonic acid-functionalized silica have been utilized (Table 1, entries 14-17 and Table S1, entries [13][14][15][16][17]. [26] Such colloids were uniformly dispersed across the support. Interactions of sulfonic acid groups and metal sites confirmed by XPS are favorable for the imine formation and subsequent hydrogenation. Activity of Pt and It in reductive amination of furfural was similar exceeding that of gold, which can be associated with a limited ability of gold to catalyze the hydrogenation step. It was reported that selectivity to the amine was independent on the metal nature as not affected by the metal type, further side reactions were prevented because of the interactions of sulfonic groups with the metal. [26] Similar amine yields of ca. 8% were obtained on Pt on SiO 2 prepared by the colloidal method or by impregnation, while introduction of sulfonic groups elevated the amine yield to 23% over Pt/SiO 2 -SO 3 H illustrating the role of acidic sites in reductive amination of aldehydes with amines. [26] Reductive amination of HMF and its derivatives has been intensively investigated (Table 1, entries [18][19][20][21][22][23][24][25][26][27][28][29][30]. [24,66,67] 1 wt% Pd/C with small Pd particles (2.7 nm) (Table S1, entry 5) gave only the desired amine as a product in HMF amination (Table 1, entry 19), while over 1 wt% Pd supported on Al 2 O 3 95% yield of the amine together with the over-hydrogenated [5-(anilinomethyl)-oxolan-2-yl]methanol was obtained. On the other hand, interactions of the furan ring with Al 2 O 3 in furfural were more prominent than in case of HMF, and it was confirmed by infrared spectroscopy that in reductive amination of HMF interactions of the furan ring with Pd(111) surface were suppressed due to presence of a hydroxyl group in HMF when compared to furfural amination. [66] In the amination of AMF, over Pt/Al 2 O 3 in methanol only 81% yield of the secondary amine was obtained due to formation of the corresponding alcohol (10%) and imine (9%) ( Table 1, entry 28). [24] On the other hand, when using 2-propanol as a solvent the main product was alcohol, 68%, and only 20% of the secondary amine was formed together with 12% imine (Table 1, entry 29). [24] Ketone aminations have also been largely investigated (Table 1, entries [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45]. Even amination of cyclohexanone with ammonia was reviewed because of its prominent solvent effect (see Section 2.1.3). [25] Reductive amination of cyclohexanone for production of secondary amines was performed over monometallic Pd [17] and bimetallic Pd-Fe catalysts [11] as well as over Au/TiO 2 . [10] High yields can also be obtained in amination of ketones, for example 91% yield of the desired amine was reported in in amination of cyclohexanone with aniline over polystyrene embedded N-heterocyclic carbene-linked (NHC) Pd particles. [17] In several studies, relatively high pressures and temperatures were used [10,11,17] in comparison to aldehyde amination. In amination of cyclohexanone with benzylamine, Au/TiO 2 with gold particles of ca. 3 nm size was producing 72% yield of the desired amine at 100°C under 30 bar hydrogen in cyclohexane as a solvent (Table 1, entry 35, Table S1, entry 7). [10] On the other hand, acetophenone with electron donating methoxy-and electron-withdrawing fluoro groups at para position could be rather selectively transformed to the corresponding amines in the reaction with benzylamine at 100°C under 1 bar hydrogen [69] and at 90°C under 10 bar hydrogen, [61] yielding 86% and 90%, amine, respectively (Table 1, entries 41 and 42). In the former case, the other products were imine (Y = 2%) and 1-phenylethanol (Y = 6%) formed by hydrogenation of the carbonyl bond.
When a sterically more hindered ketone, e.g. propiophenone, was used as a reactant, the best result was obtained over Au/TiO 2 with 2.9 nm Au particles with only 11% yield of the desired amine under the same reaction conditions when propiophenone conversion was only 20% (Table 1, entry 44). [10] Similar results were obtained in propiophenone amination with R-1-phenyl ethaneamine over Pd supported on polyethyleneimine exhibiting 2 nm Pd particles giving only 12% amine yield at 50°C under 3 bar hydrogen in 21 h (Table 1, entry 43). [21] The main product in Ref. [21] was imine indicating that electronic effects of the substrate are highly important in reductive amination of ketones. [21] Formation of N-alkylated α-methyltryptamine derivatives with 0-78% yield depending on the carbonyl structure was reported in reductive amination of αmethyltryptamine derivative ( Figure 4, Table 1, entry 45) with different aldehydes and ketones under 3 bar of hydrogen pressure using 10% Pd/C catalyst in methanol (Table 3). [27]

Effect of catalyst properties in reductive amination of aldehydes and ketones
Metal loading and structure sensitivity are also important parameters in reductive amination of carbonyl compounds with amines. [61,67] For example, amination of 4-fluoroacetophenone with benzylamine was studied over different Pd-MIL-101(Cr) catalysts exhibiting the same metal particle size. [61] Figure 4. Reductive amination of α-methyltryptamine derivative into N,N-dialkyl-αmethyltryptamine derivative adapted from. [27] Copyright permission from Elsevier Ltd. Due to different Pd loading, the only difference in these catalysts is the ratio between Pd and Lewis acid sites, which are present in MIL-101 support. The results revealed that the selectivity to the desired amine increased with decreasing the metal loading. In addition, Pd loading on carbon was systematically studied in reductive amination of HMF with aniline in trifluorotoluene (TFT) as a solvent at 100°C under 3 bar hydrogen. [67] The results showed that with larger Pd particles both activity and selectivity of the catalysts decreased.
Highly dispersed Pd particles in Pd/C were the most efficient for amination of HMF with aniline, while for larger Pd particles complete imine conversion was not obtained. [67] Effect of the support has been investigated in comparative experiments using Pd/C and Pd/Al 2 O 3 with the same metal particle size illustrating that Pd/C was more selective. The reason for this was explained by CO adsorption experiments revealing that a larger amount of Pd(111) facilitates stronger interactions of the furan ring in Pd/Al 2 O 3 in comparison to Pd/ C. [67] Acidity of the support has been investigated in Ref. [61,69], when Cu was supported on alumina, silica, SiO 2 -TiO 2 and SiO 2 -Al 2 O 3 in amination of 4-methoxyacetophenone with aniline at 100°C under 1 bar hydrogen in toluene. The highest yields of the desired amine were obtained with SiO 2 -TiO 2 and SiO 2 -Al 2 O 3 as supports being 97% and 96%, respectively. In addition, an acidic MIL-101 was used as a support for Pd in the amination of 4-fluoroacetophenone to produce nearly 90% yield of the corresponding secondary amine under 10 bar hydrogen at 90°C (Table 1, entry 42, Table  S1, entry 12). [61] However, MIL-101 containing Cr 3+ ions with only Lewis acid sites, confirmed by ammonia TPD, [65] was able to only catalyze formation of imine, while activation of ketone was not efficient. [61] Furthermore, under comparative conditions, i.e. 90°C under 10 bar hydrogen, the yields of the desired amine were 90% and 28% for 0.2 wt% Pd-MIL -101 and 5 wt% Pd/C, respectively, while a large amount of hydrogenated 1-(4ʹ-fluorophenyl)ethanol was formed also over 5 wt% Pd/C demonstrating that the metal loading and the support are crucial for selective amination of this ketone. [61] It was also observed that the unwanted hydrogenolysis of the formed desired amine is promoted with a high Pd loading especially at a high temperature. [61]

Effect of reaction temperature.
Optimization of the reaction temperature and hydrogen pressure in reductive amination of aldehydes and ketones has been scarcely studied. [11,15,61] The highest yield of N-benzylcyclohexanamine, 94%, was obtained over Fe@Pd/C catalyst in 8 h (Table 1, entry 3, Table S1, entry 3) and this catalyst was active and selective at the highest studied temperature 80°C and the highest pressure 30 bar. The yields of products under different reaction conditions were not reported. In addition, several mono-or bimetallic Pd catalysts supported on NiO, [15] polymer-N-containing heterocyclic carbene (NHC) [17] and β-cyclodextrin [66] gave more than 90% yield at 50°C, 80°C and 180°C, respectively. Especially, Pd/NiO was very active and selective even at 25°C under atmospheric hydrogen pressure in transforming benzaldehyde with cyclohexylamine (Table 1,  entry 1, Table S1, entry 1). [15] As a comparison, the effect of temperature on the amine yield was studied in benzaldehyde amination with aniline in water under 30 bar hydrogen over Fe-Pd core shell structured catalyst on active carbon (denoted as Fe@Pd/C) [11] and over Pd/NiO at 1 bar hydrogen in ethanol. [15] In the latter case, the amine yield decreased at a higher temperature due to hydrogenation of benzaldehyde to toluene, [15] while the amine yield increased over Fe@Pd/C [11] at a higher temperature. It should, however, be pointed out here that in water a very high pressure was applied as hydrogen solubility in water is low. [76] High temperature also promoted decomposition of the desired secondary amine in the amination of 4-fluoroacetophenone with benzylamine to toluene and 4-fluoro-(1-acetophenone) over Pd-MIL-101 catalyst at 90°C under 10 bar hydrogen, while 50°C was the optimal temperature giving ca. 91% yield of the desired amine. [61] Furfural amination could be selectively performed over supported Pd catalysts in the temperature range of 80−100°C under 3-35 bar hydrogen (Table 1, entries 12, 13) [17,67] and over Me/SiO 2 -SO 3 H (Me = Au, Pt, Ir) at 90°C under 50 bar hydrogen (Table 1, entries 14-17, Table S1, entries [13][14][15]. [26] Especially, in ethyl acetate as a solvent high yields of imine were obtained over gold, iridium and platinum supported on SiO 2 -SO 3 H support lowering the yield of the amine (Table 1, entry 14). [26] It should be pointed out that hydrogen solubility in solvents has not been addressed when different solvents were tested. [17,26] Furthermore, reductive amination of 5-acetoxymethylfurfural with primary amines (e.g. aniline) in methanol could be efficiently carried out at low temperatures, i.e. 10-25°C and 5 bar of hydrogen pressure providing 99% and 86% yield of the secondary amine over Pt/Al 2 O 3 or Pd/Al 2 O 3 as well as Pd/C catalysts, correspondingly. [24] Ketone amination with amine has also been successfully performed over various supported metal catalysts under varying reaction conditions. [10,17,21,61,69] Note that in these studies pressure and temperature have not been typically optimized. [10,17,21] The results demonstrated that ketone amination can be performed in the temperature and pressure range of 50-100°C and 1-30 bar hydrogen, respectively (Table 1, entries [35][36][37][38][39][40][41][42][43][44][45]. A rather long reaction time has also been often needed (Table 1, entries 39-43).

Effect of hydrogen pressure.
The effect of hydrogen pressure on the amine yields has been also studied. [11,17,68] The results show that for benzaldehyde amination relatively high pressure promote amine formation (Table 1, entry 2 , 3, 8, 9). [11,17] At the same time, Pd/NiO was active and selective in benzaldehyde amination already at 25°C under 1 bar hydrogen ( Table 1, entry 1), [15] while higher reaction temperatures gave lower amine yields and more toluene was formed by hydrogenation of benzaldehyde. In Ref. [17], it was reported that the highest yields of the desired amine were obtained at high pressures, when the hydrogen pressure was varied in the range of 25-40 bar in amination of benzaldehyde with aniline at 80°C over PS-Pd-NHC in water. On the other hand, Pd supported on metal organic framework UiO modified with p-phenylenediamine was an efficient catalyst in this reaction in ethanol as a solvent at 50°C when more than 5 bar hydrogen was applied (Table 1, entry 20, Table S1 entry 6). [68] The highest applied hydrogen pressure, 30 bar was efficient for production of N-benzylaniline from benzaldehyde and aniline over Fe@Pd/C in water, [11] but no information about other products at lower pressures was given. Low hydrogen pressures were also applied to facilitate HMF amination with aniline over supported Pd catalysts giving high yields of the corresponding amine (Table 1, entry 19,20). [67,68] It should be pointed out that such aspect as low hydrogen solubility in water [76] has not been discussed at all indicating that more systematic physico-chemical approach is required in this research area.

Solvent effect.
Several studies are available addressing the solvent effect in the synthesis of secondary amines by reductive amination of carbonyl compounds. [15,17,25,26,65,67] Typically 2-propanol and ethanol gave the highest amine yields, [15] while rather comparative amine yields over Pd-βcyclodextrine catalyst were achieved in ethanol and water. [66] Water was reported as the best solvent for benzaldehyde amination with aniline . [17] No clear correlation of the amine yield and the solvent dielectric constant could be established, which in part can be related to not considering solvent dependent hydrogen solubility. It should be mentioned in Ref. [17] that a low yield of the desired amine (48%) in benzaldehyde amination with aniline over a Pd supported catalyst was reported without mentioning the yields of the side products.
Reductive amination of furfural with aniline was studied in methanol, water, ethyl acetate and THF over Pt/SiO 2 -SO 3 ( Table 1, entries 14-17) [26] indicating that the highest amine yield was obtained in ethyl acetate (Table 1, entry 14). [26] Lower amounts of side products in ethyl acetate is related to inhibition of the imine formation due to a decrease of aniline nucleophilic ability because of aniline. Alcoholic solvents exhibit more side reactions, in particular the reaction in methanol with furfural gave furfuryl acetal, competing with the imine formation. Reversibility of imine formation as well as generation of a hydroxylamine derivate is a feature of water as a solvent, which hinders utilization of the latter despite such positive characteristics as low costs, environmental friendless and safety. In THF there is no protonation of aniline which becomes available as a nucleophile. Subsequently, THF gave the highest imine yield despite condensation of the secondary amine (Table 4). [26] These results indicate that more systematic studies are required to unravel the effect of solvents on synthesis of secondary amines. For example, in amination of cyclohexanone with ammonia over Ru/C catalyst under hydrogen atmosphere [25] in different solvents condensation of cyclohexanone with cyclohexylamine resulted in imine formation in methanol with the highest rate. [25] The solvent effect in the synthesis of primary amine was studied in more detail considering formation of both imine and the Shiff base via interactions of synthesized primary amine again with the initial ketone. No clear correlations between the cyclohexylamine yield and the Hildebrand-Hansen and Kamlet-Taft parameters often used to explain the solvent effects were found. [77,78] Instead, the solvent has a profound influence on the catalyst reactivity and product distribution. Thus, in aprotic polar solvents, such as dioxane and THF, the main product was imine indicating inhibition of imine hydrogenation. Such inhibition effect in hydrogenation is plausibly due to the strong adsorption of the solvent on the catalysts blocking accessibility of the active sites. Solvent-catalyst interactions are weaker for protic and aprotic apolar solvents inhibiting hydrogenation. In protic solvents the reactions between the ketone and ammonia and the imine was more prominent than in aprotic apolar solvents. The lowest cyclohexylamine selectivity in water can be explained by instability of the imine and the Schiff base in water, and, faster C = O double bond hydrogenation. DFT calculations for C = O hydrogenation under basic conditions suggested involvement water in the reaction as a hydrogen donor. Not only on Ru but also over catalysts ( Figure 5), selectivity to cyclohexylamine in methanol was substantially higher than in water suggesting a general validity of the solvent effect. [25] Continuous synthesis of N-substituted 5-(acetoxymethyl)-2-furfuryl amines was also shown to be efficient in methanol, which is a suitable solvent for condensation of aromatic aldehydes with primary aromatic amines as well as for hydrogenation of imines. [71,79,80] Much lower yields of the imine in the first stage were observed in ethanol and isopropanol eventually retarding formation of the desired product (Table 1, entries 28, 29). Subsequently, 5-(acetoxymethyl)-2-furanmethanol was generated by hydrogenation of the initial aldehyde -5-acetoxymethylfurfural. [24] 2.1.3.3.1. Effect of reactant concentration. The effect of the initial reactant concentration has been very scarcely studied. [69] It has been already known for a long time that the production of secondary amines from carbonyl compounds can be facilitated with a large excess of amine. [81] The decreasing ratio of aniline/ketone in amination of 4-methoxyacetophenone with aniline over Cu/SiO 2 gave less alcohol as a side product. [69] At the same time,  The product yields were determined by 1 H NMR however, the yield of the desired amine decreased as well. Furthermore, it was stated in Ref. [69] that the excess of amine in comparison to ketone suppressed formation of the dialkylated product.

Catalyst recycling
Typically catalyst recycling has been very successful in reductive amination of carbonyl compounds with amines [11,67] as there was no metal leaching. [67] The yield of the desired amine decreased due to catalyst poisoning. [69] For example, in benzaldehyde amination with aniline over Pd supported on polystyrene embedded N-containing heterocyclic carbene in water at 80°C at 35 bar hydrogen the yield of amine 93-94% remained the same in four cycles. [17] Pd supported on active carbon has been ra ather promising catalyst in reductive amination of aldehydes most probably due to rather mild reaction conditions. [67,69] For example, Pd/C catalyst was also successfully recycled in HMF amination with aniline under 3 bar hydrogen at 100°C when it was washed and dried at 100°C between the cycles. [69] In addition, Pd/C catalyst was very active and selective in HMF amination with aniline at 100°C under 3 bar hydrogen giving 98% yield and only a minor decrease in the yield was observed in the third cycle. [67] In Ref. [67], the Pd/C catalyst was only filtrated and washed three times with ethanol after which it was reused without a separate reduction step prior to the second experiment. This result is very promising and most probably Pd remains stable due to rather mild reaction conditions. Furthermore, the filtrate test showed that the reaction was heterogeneously catalyzed.
On the other hand, degradation of the MOF support was observed in amination of HMF with aniline in ethanol at 50°C under 5 bar hydrogen. At the same time HMF conversion decreased by nearly 25% [68] when the catalyst was only washed with ethanol and dried. It was also stated that aggregation and Pd leaching were observed. Analogously, the yield of amine decreased from 93% to 86% in the fourth cycle in benzaldehyde amination with aniline in water over Fe@Pd/C catalyst at 80°C under 30 bar hydrogen. [11] Ru/C could be recycled after cyclohexanone reductive amination with ammonia in methanol resulting in a conversion decrease from ca. 95% to ca. 88% and indicating thus a reasonable catalyst stability. An increase of the imine yield was concomitant with lower yields of the Schiff base, cyclohexylamine and cyclohexanol. [25] In recycling Cu/SiO 2 catalyst in amination of 4-methoxy-acetophenone with aniline the yield of the product decreased from 86% to 71% during recycling, [69] although no Cu leaching occurred. The reason for the lower yield of amine was stated to be catalyst poisoning rather than coking.
The yield of aminomethylhydroxymethylfuran (99%) did not change within 2.5 h time-on-stream in the reductive amination of 5-acetoxymethylfurfural (AMF) with aniline on Pt/Al 2 O 3 , which did not display any visible changes. Nevertheless, ca. 4.5 wt% of hydrogen-enriched carbonaceous species were formed according to TG-DSC-MS [24] not affecting catalytic activity.

Kinetics and modeling in amination of carbonyl compounds with amines using molecular hydrogen
Reaction kinetics was investigated in HMF amination with aniline over Pd supported on UiO-67 in the presence of polymer (poly-para-phenylenediamine, PpDA) UiO-67/PpPDA/Pd at 50°C under 5 bar hydrogen. [68] The results showed that the main product was imine, while also amine was already formed after first 5 min ( Figure 6). Then the maximum concentration of imine was reached already after 15 min and thereafter it reacted completely further to amine in 2 h. [68] Modeling of the reaction kinetics in amination of 4-fluoroacetophenone with benzylamine was demonstrated. [61] The reaction network contained as the first step imine formation followed by its hydrogenation. In addition, decomposition of the formed amine was also observed under the applied reaction conditions. Furthermore, it is known that the imine formation over Lewis acidic sites is a reversible reaction, which was also included in the reaction scheme: in which A, B and U denote ketone, amine and the undesired amine, while I and D are imine and the secondary amine. Both hydrogenation and hydrolysis occurring on Pd are modeled with the first order reactions. It was observed that k 2 and k 3 were correlating with Pd loading.

Continuous amination of carbonyl compounds with amines over heterogeneous catalysts with molecular hydrogen
Reductive amination of aldehydes and ketones with amines has been demonstrated over Pd and Ni supported on a static mixer [20] and over Ni supported on different supports. [74] A comparative study of continuous amination of several amines with aldehydes and ketones was performed over Ni supported on NaX zeolite, carbon and magnesium oxide in the temperature range of 60-240°C under atmospheric pressure. [74] Synthesis of several secondary amines was successfully demonstrated over these catalysts, however, time-on-stream behavior was not reported. [74] Interestingly even dehydroaromatization of cyclohexylamine occurred over Ni/MgO in its amination with butylamine forming N-butylaniline instead of N-butylcyclohexylamine. [74] Continuous reductive amination in a tubular reactor containing a static mixer printed with Ni or Pd was demonstrated. [20] The metals were loaded either via cold spraying (Ni) or electroplating (Pd). In Ref. [20], amination of benzaldehyde with butylamine was optimized revealing that the reaction was efficient under 24 bar hydrogen pressure giving at 120°C in ethyl acetate as a solvent 77% yield of the desired amine over Ni supported on 3D printed catalytic static mixer (CSM) with a long residence time. After lowering the hydrogen pressure to 20 bar and increasing the liquid flow rate twofold, the main product was imine with 53% yield with the amine being the rest. As a part of scaling up a larger solution volume (1 L) was analyzed indicating only minor leaching of the metals (at ppb level). For Pd-CMS maximally 93% yield of N-benzylbutylamine was obtained under optimized conditions, 20 bar hydrogen at 120°C. In addition to benzaldehyde also other aldehydes and ketones were used as reactants including HMF, 5-methylfurfural, cinnamaldehyde, vanillin, 2-heptanone as well as nitrogen sources (4-anisaldehyde, αmethylbenzylamine, piperidine, morpholine). Catalyst fouling and humins formation was confirmed in the spent catalyst after using 5-methylfurfural and 5-(chloromethyl)furfural as reactants. Time-on-stream behavior was, however, not described.
Continuous mode reductive amination of 5-acetoxymethylfurfural (AMF) or HMF with aniline was performed in methanol as a solvent over packed bed catalysts including platinum, palladium and gold supported on carbon and alumina. [24] The process includes non-catalytic condensation of AMF (or HMF as the initial aldehyde) with primary amines giving an imine and subsequent hydrogenation of the latter. Platinum catalysts afforded high yields of different N-substituted 5-(acetoxymethyl)-2-furfuryl amines at 25-55•C and 5 bar H 2 , while low selectivity was seen on Pd and Au supported on γalumina and carbon (Table 1, entries [21][22][23][24][25][26][27][28][29][30]. The effect of the primary amine structure on formation of aminomethylhydroxymethylfuran (AMHMF) derivatives was studied using the reaction between AMF and different aromatic and aliphatic amines over Pt/Al 2 O 3 catalyst according to Figure 7 (Table 4).
High yields of secondary amines up to 99% were obtained [24] with AMF and aromatic amines containing electron-donating substituents (i.e. methyl and methoxy-) in m-and p-positions (Table 4, (Table 4, entries 7 − 13) resulted in weaker nucleophilic properties of the corresponding aromatic amines in comparison, thereby giving lower imine yields at the first stage. [24] The order of the nucleophilicity decrease was in line with the desired product yield. The yield of aminomethyl hydroxymethylfuran (AMHMF) derivatives yield in the reaction between AMF and chloroaniline isomers was dependent on the position of an electron-withdrawing substituent in the aromatic amine (Table 4, entries 8, 14 − 16). Steric hindrance created by Cl substituent influences also hydrogenation of the imine, namely imines formed from m-chloroaniline and o-chloroaniline are less reactive than the imine obtained from p-chloroaniline (Table 4, entries 8, 14, 16). [24] Significantly lower yields of AMHMF derivatives were observed for aliphatic amines (n-hexylamine, cyclohexylamine and n-dodecylamine) than for aniline ( Table 4, entries 17 − 21) due to hydrogenation of the acetyl group in the desired products.

Mechanism
Mechanistic aspects of one-pot reductive amination of carbonyl compounds with amines under molecular hydrogen have been scarcely studied. [15,67,69,82] In one-pot synthesis of secondary amines from aldehydes and amines the corresponding imine is formed in situ and then reduced to amine. [67] In this reaction the acid sites are required for the amine adsorption providing imine formation while hydrogenation of the latter to amine requires the metal sites. Several studies concluded that the Lewis acid sites catalyze imine formation. [61,68] In addition to formation of a secondary amine, several side reactions can also occur, for example furan ring hydrogenation and opening, [67] hydrogenation of aldehyde or ketone. [15,69] It has also been observed that the formed imine from the reaction between 4-fluoroacetophenone and benzylamine can decompose to toluene and 4-methoxy-ethyl -2-amine. [61] In the reductive amination of a carbonyl compound with a primary amine the first step, imine formation is also crucial (Figure 8). The forthcoming hydrogenation of an imine requires a suitable metal, a support and temperature, which were discussed in previous Sections. The role of solvent in selective imine formation was recently emphasized. [82] In the first step Figure 7. Scheme of reductive amination of AMF with different aromatic and aliphatic amines adapted from. [24] Copyright permission from Elsevier Ltd. a carbinol amine is formed after a nucleophilic attack of an amine group on carbon in the C = O bond. [83] Subsequent water elimination, required to form an imine, is dependent on the solvent polarity. Because aldehyde condensation, for example with aniline is an equilibrium reaction, several parameters promote imine formation including low pH, high temperature and the use of polar solvents.

Amination of carbonyl compounds with amines using various hydrogen sources generated in-situ
Several hydrogen sources other than molecular hydrogen have been used including in-situ generated hydrogen from the water-gas shift reaction, [54,75,84] decomposition of formic acid [13,14,65] or NaBH 4 (Table 5), [12,16,19] and dimethylformamide over ZrO 2 [85] as well as using iron powder in CO 2 /H 2 O. [2] The main drawback in the use of NaBH 4 is that it is expensive and forms toxic waste NaBO 2 in water according to the following reaction: Under excess of water even NaBO 2 .xH 2 O can be formed. [86] Recycling of the waste is also challenging. NaBH 4 assisted amination of aldehydes and ketones Figure 8. Reaction mechanism for formation of an imine from a carbonyl compound and an amine. [82] [13] 4 Pd-Cu supported on βcyclo-dextrin 100°C, FA-microwave, 15 bar N 2 , ethanol Y AM = 37 [66] (Continued)  [12] (Continued)  [2] (Continued)  [2] (Continued)  [85] has been demonstrated in literature. [16,19] Typically, the reaction proceeds under mild conditions over solid acids [12,16,19] giving high yields of the desired amine. Even solvent free amination of benzaldehyde with aniline was demonstrated at 25°C in the presence of an equimolar amount of NaBH 4 in comparison to ketone giving 95% amine yield over carbon based solid acid (Table 5, entry 9). [12,87] This catalyst, prepared by heating naphthalene with sulfuric acid, and subsequent carbonization, has a surface area of 24 m 2 /g cat and strong acidity, which was 5.3 fold that of Nafion. The CSBA was claimed to be very stable and non-corrosive. [88] Amination of a large variety of aldehydes and ketones with different amines was successfully tested giving mostly very high amine yields under mild conditions in a short reaction time. [12] An alternative to sodium borohydride is formic acid, an inexpensive reducing agent, [13] which has also been used together with trimethylamine, forming an azeotropic mixture with the latter ( Table 5, entry 5). [14] During decomposition of formic acid CO 2 is predominantly produced, while over some catalysts CO can be also released along with water. Hydrogen can be also generated from the water gas shift reaction involving CO and water. [75] Despite CO toxicity, this option has some benefits in comparison to utilization of molecular hydrogen, as CO is less flammable. [75] Carbon monoxide assisted reductive amination of carbonyl compounds occurred at different pressures and temperatures, which were varied in the range of 5-50 bar and 60-160°C, respectively (Table 5, entries [6][7][8]. [54,75,84] Reaction times have been changed from 2.5 to 20 h. Amination of HMF with aniline using CO in the presence of Au/TiO 2 where the support had the rutile phase [84] gave more than 99% yield of the desired product ( Table 5, entry 8). In this process, hydrogen was generated in-situ because of the water gas shift reaction. The highest amounts of hydrogen confirmed by CO/H 2 O temperature programmed surface reaction techniques were produced over Au/TiO 2 catalyst in comparison with Au/CeO 2 , Au/ZrO 2 , Au/Al 2 O 3 and Au/SiO 2 exhibiting the same gold particle size.
Au/TiO 2 catalyst exhibiting gold particles of the size of 2 nm was very active in HMF amination with aniline at 60°C under 20 bar CO ( Table 5, entry 8). [84] Recyclability of Au/TiO 2 was also demonstrated in six consecutive experiments for which the catalyst was washed with acetone and dried under vacuum prior to the next experiment. A very high yield of amine was obtained after the sixth experiment without any leaching of Au. [84] Concentration profiles of imine, amine and the corresponding alcohol, 2,5-bis-(hydroxymethyl)furan are presented in Figure 9.
The undesired alcohol yield was ca. 12%. Furthermore, it was confirmed that under an inert atmosphere, HMF reacted very fast with aniline to form the imine, while in the presence of CO/water the rate limiting step is imine hydrogenation to amine. In Ref. [84], the scale up experiment was also made for amination of HMF with aniline over Au/TiO 2 under 20 bar CO at 60°C for 15 h giving 98% yield of amine (Table 5, entry 8). The reaction mechanism was proposed including adsorption of CO on metallic gold. Subsequently, CO reacts with water via the water gas shift reaction forming hydrogen and CO 2 . HMF forms imine by condensation with aniline followed by the formed imine hydrogenation on the gold surface.
In the amination of 4-fluoroacetophenone with p-anisidine high CO pressure of 50 bar was applied at 160°C over different Rh catalysts in THF, which was found to be the best solvent (Table 5, entry 7). [75] The highest yield of the desired amine, 82% was obtained over commercial Rh on a carbon matrix with the highest catalyst loading (1 mol%) after 20 h. This method was also successfully demonstrated for different substrates. [75] Reductive amination of benzaldehyde, 2-pyridinecarboxaldehyde with different substituted aromatic amines mediated by CO 2 /water/Fe mixture + Pd/C was reported by Ma et al. (Table 5, entries [14][15][16][17][18][19][20][21][22]. [2] Two sequential paths for the hydrogen transfer from water to the imine intermediate were proposed. The first step implies a hydrogen transfer from water to Pd(0), leading to formation of highly active Pd hydrides. Then, the generated Pd hydrides are able to hydrogenate the imine intermediate to the amine product, accompanied by regeneration of Pd(0) catalyst ( Figure 10). Isotope-labeling experiments using D 2 O confirmed that water acts not only as a solvent, but also as a hydrogen source ( Figure 11). [2] Yields ranging from 11% to 82% for various amines and aniline derivatives were obtained ( Table 5). The highest yields were seen for aldehydes with methyl-and methoxy-groups at the para-position (Table 5, entries 15,16). [2,47] Reductive amination with aniline or p-anisidine giving heteroaromatic aldehydes was also reasonably efficient (Table 5, entry 17,18,19). Similar yields were seen for aniline with an electron-donating group ( Table 5, entry 17) and reductive amination of benzaldehyde with m-toluidine (Table 5, entry 20). Much worse results were noticed for 1-naphthylamine at an elevated temperature (Table 5, entry 21), while the steric hindrance in 2,6-dimethylaniline was a reason for an even lower yield of 11% yield of the (Table 5, entry 22). Nevertheless, the method utilizing CO 2 as a reaction medium and promoter has a good potential for further industrial exploitation.
A slight decrease in the amine product yield was observed with the SILP catalyst after three consecutive cycles, which can be related to the ionic liquid leaching.

Comparison of different methods to synthesize secondary amines
It is instructive to compare different methods for production of secondary amines. For example, N-benzylcyclohexylamine, which is an intermediate for synthesis of pharmaceuticals, [89] can be prepared via reductive amination of cyclohexanone with benzylamine in hydrogen, [10] or alternatively using NaBH 4 as a reductant over solid carbon catalyst (Table 6). [12] The third method is to use formic acid as a reducing agent together with Au/TiO 2 , [13] acidic ionic liquid supported on silica [14] or sulfonic acid supported on hydroxyapatite encapsulated γ-Fe 2 O 3 [γ-Fe 2 O 3 @HAP-SO 3 H]. [19] Furthermore, N-benzylcyclohexylamine can be prepared by amination of benzaldehyde with cyclohexylamine. [19] These comparative studies are Figure 12. Reductive amination of 4-methylfurfural with nitrocyclohexane over Au/TiO 2 adapted from Ref. [94] Copyright permission from Elsevier Ltd. collected in Table 6. The results demonstrate that chemical reducing agents require low temperatures and that especially NaBH 4 was very active already within 10 min. [12] Higher temperatures and relatively high hydrogen pressures were required for transforming cyclohexanone and benzaldehyde to the corresponding amine, [10,17] mild reaction conditions and a non-metallic catalyst can be used with formic acid.
This catalyst was selective in amination due to a lower hydrogenation activity of Ag in comparison with Pd. Moreover, presence of Ag also diminished aggregation of Pd nanoparticles. [93] Some magnetic heterogeneous catalysts, facilitating easy catalyst separation, were found to be active in amination of aldehydes. [23,52,60] In [52] Pd supported on magnetic composite Fe 3 O 4 @SiO 2 /EDAC prepared via formation of covalent bonds between ethylene diamine functionalized cellulose (EDAC) and silica coated Fe 3 O 4 was shown to be a very efficient catalyst in transformation of benzaldehyde and its derivatives to secondary amines under mild conditions at 25°C and 1 bar hydrogen in a ethanol-water mixture (Table 7, entry 5, Table S2 entry 5). [52] The reaction time was also quite short over Pd-Fe 3 O 4 /SiO 2 (ethylene diamine), 2.5 h [52] in comparison to Pd/Fe 3 O 4 /C for which 8 h was required (Table 7, entry 10, Table S2, entry 10). [90] Moreover, separation and recycle was reported to be facile. Analogously Pd/Fe 3 O 4 -NH 2 /starch (Pd@Fe 3 O 4 -NH 2 -starch) catalyst with the average diameter of Pd particles of 8.4 nm was efficient in benzaldehyde amination with nitrobenzene giving 93% yield at 25°C in the ethanol-water mixture under hydrogen atmosphere already after 2 h (Table 7, entry 9, Table S2, entry 9). [60] This catalyst was prepared by contacting iron chloride hexahydrate in sodium acetate and 1,6-hexanamine in ethylene glycol as a solvent to form magnetic Fe 2 O 3 -NH 2 nanoparticles, which were further functionalized with starch chloride in the presence of trimethylamine in chloroform. Such method facilitated formation of metallic Pd particles inside starch-amine coated magnetic Fe 2 O 3 . [60] Magnetic hollow mesoporous spheres composed of Fe 3 O 4 modified polystyrene, after calcination were transformed to hollow spheres followed by loading with Pd. The catalyst prepared in this way was active giving 94.2% yield of benzylaniline at 8 h under hydrogen atmosphere at 25°C (Table 7, entry 11,  Table S2, entry 11). [23] The role of Ag in Pd-Ag alloys in amination of benzaldehyde with nitrobenzene is to decrease the hydrogenation ability of Pd and to suppress the alcohol formation, while MIL-101 metal organic framework provides the Lewis acidity (Table 4, entry 6). Amination of a ketone, cyclohexanone, with nitrobenzene was also successful giving 83% yield at 25°C under 1 bar hydrogen over the same Pd@Fe 3 O 4 -NH 2 -starch catalyst mentioned above which exhibited 8.4 nm Pd particles (Table 7, entry 24, Table S2, entry 9). [60] Interestingly nitrone was the main product in reductive amination of 4-methylfurfural with nitrocyclohexane over Au/TiO 2 in ethanol at 60°C under 10 bar hydrogen. [94] Only 3% of N-[(5-methylfuran-2-yl)methyl]cyclohexamine was formed after 14 h apparently because dehydration of nitrone formed in the reaction between N-hydroxyaniline (hydroxylamine) and benzaldehyde was retarded ( Figure 12).

Effect of reaction conditions in amination of aldehyde and ketones with nitroarenes over heterogeneous catalysts and catalyst recycling
Noble metal catalysts have been very active in reductive amination of aldehydes with nitro-compounds already at relatively low temperatures. [59,63] For example, an optimum reaction temperature, 60°C was obtained in amination of n-heptaldehyde with 3-nitrostyrene over Au/Al 2 O 3 catalyst in a flow reactor under 50 bar hydrogen for production of the corresponding unsaturated amine giving 74% yield of the desired amine, N-(3-vinylbenzyl)-amine, [63] while at a higher temperature the C = C double bond in the side chain was also hydrogenated. Under optimum conditions the amount of the hydrogenated side chain product was 8.5%. [63] Benzaldehyde amination with nitrobenzene was successfully performed at 25°C giving 92% amine yield [59] in ethanol over Pd nanoparticles supported in Cherry tree gum in 20 min (Table 7, entry 8). At higher temperatures, the yield of amine was reported to decrease. [59] Interestingly, this catalyst was inactive for amination of acetophenone with nitrobenzene under mild conditions, i.e. at 25°C under 1 bar hydrogen ( Table 7, entry 22), [59] while Pd@MIL-101 [30] and Pd 2 Ag 1 alloy supported on metal organic framework MIL-101 [65] worked well at 110°C under 5 bar hydrogen (Table 7, entry 25,26). This result indicates that reductive amination of ketones requires more harsh conditions than aldehyde amination.
Over transition metal catalysts, higher reaction temperatures have been applied even for amination of aldehydes [28,61] in comparison to noble metal catalysts. The highest studied temperature, 150°C, was found to be the best one for amination of benzaldehyde with nitrobenzene over Co supported on nitrogen doped carbon catalyst under 10 bar hydrogen in ethanol ( Figure 13). [62] Analogously, the highest studied temperature, 150°C was the best one in the same reaction over Fe 2 O 3 supported on nitrogen doped graphite under 50 bar hydrogen giving 46% yield of N-benzylaniline in 30 h ( Figure 13). [28] It can also be noted that hydrogenation of imine proceeds more slowly at lower temperatures. For amination of ketones very harsh conditions, 160°C and 50 bar were required for Co 3 O 4 nitrogen doped graphitic carbon (denoted as NGr@C) (Table S2 entry 11). [29] 3.1.2.1. Effect of hydrogen pressure. Low hydrogen pressure has been applied in reductive amination of aldehydes with nitrocompounds over Pd supported catalysts (Table 7, entries 3-11), [23,46,47,51,52,56,59,60,65] whereas transition metal catalysts operated under harsher conditions (Table 7, entries [12][13][14]28). [28,29,62] Higher hydrogen pressures are beneficial for hydrogenation of the formed imine in amination of aldehydes with nitro-compounds over Cu/Al 2 O 3 and Co supported on nitrogen doped carbon, [29,62] while a low hydrogen pressure retarded imine hydrogenation over Co supported on mesoporous N-doped carbon (denoted as Co/m-CN) in the amination of benzaldehyde with nitrobenzene. [62] This catalyst was prepared in one-pot synthesis pyrolyzing cobalt nitrate hexahydrate, melamine and polyacrylonitrile under inert atmosphere. [62] Higher hydrogen pressure, 70 bar, promoted amine formation in the same reaction at 160°C over Fe 2 O 3 supported on nitrogen doped graphite (NGr) in THF water mixture. [28] It was also observed  Figure 13. Effect of temperature in reductive amination of benzaldehyde with nitrobenzene over Co supported on mesoporous nitrogen doped carbon (square) adapted from Ref. [62] and over Fe 2 O 3 supported on nitrogen doped graphitic carbon (circle) adapted from Ref. [28] Notation: open symbol imine, solid symbol amine. Copyright permissions from John Wiley & Sons and from Elsevier Ltd.
that with a lower hydrogen pressure the formed aniline in n-heptanal amination with p-nitrotoluene over Cu/Al 2 O 3 was not reacting further and 50 bar at 115°C was required to maximize the amine yield of the desired amine over this catalyst. [72] The yield of amine with 9 wt% Cu/Al 2 O 3 was 85% and 15% n-heptanol was also formed. [72] In amination of ketones even over Pd catalysts in some cases higher than atmospheric pressure was required (Table 7, entries 23, 26). [30,65]

Effect of solvent.
The effect of solvents has been intensively studied in amination of carbonyl compounds with nitro compounds. [28,29,51,[59][60][61] Relatively polar solvents gave high yields of secondary amines in aldehyde amination with nitro compounds. For example, the best solvent in the amination of benzaldehyde with nitrobenzene was a mixture of ethanol-water (3:1) over inorganic/organic Pd loaded amine functionalized composite catalyst denoted as Pd-Fe 3 O 4 -SiO 2 -EDAC. [52] This catalyst was prepared via coprecipitation FeCl 2 and FeCl 3 to form Fe 3 O 4 nanoparticles followed by formation of silica layer on the surface of Fe 3 O 4 using a sol-gel process. Thereafter, cellulose modified by 1,2-ethylene diamine was covalently bonded with silica coated Fe 3 O 4 particles. The highest yield of N-benzylaniline (above 99%) was obtained in ethanol over Co supported on nitrogen doped carbon (denoted as CoCN) catalysts under 10 bar hydrogen at 150°C, [62] while at 130°C more imine was also observed (6%). Furthermore, a THF-water mixture was a suitable solvent for production of N-benzylaniline over Co 3 O 4 supported on nitrogen modified graphite (NGr) catalyst at 110°C under 50 bar hydrogen in 24 h giving 95% amine yield. [29] It was also observed that the presence of more water in the dioxane-water solvent mixture in the amination of benzaldehyde with nitrobenzene lowered the yield of the desired amine by inhibiting the further imine hydrogenation over Co 3 O 4 /NGr catalyst at 110°C under 50 bar hydrogen. [29] It was stated that catalyst poisoning can also be inhibited via applying more hydrophobic solvents. Triethylamine and water were not appropriate solvents over Co supported on nitrogen doped mesoporous carbon (mCN-900, pyrolyzed at 900°C) giving large amounts of unreacted imine and aniline as products in reductive amination of benzaldehyde with nitrobenzene. [62]

Molar feed ratio.
Changes in the molar ratio between the reactants, i.e. nitroarene/aldehyde, have been scarcely studied. [28][29][30]51] Typically a slight excess of nitroarene was used in amination of benzaldehyde. [51] It was observed in Ref. [28] that an excess of benzaldehyde in its amination with nitrobenzene causes a slower reaction rate as well as formation of a higher amount of benzylalcohol over Fe 2 O 3 supported on nitrogen modified graphite (NGr) catalyst [28] and over Co 3 O 4 supported on nitrogen doped graphitic carbon (NGr@C). [29] In addition with a three-fold excess of nitrobenzene N, N-dibenzylaniline (see Figure 1) was formed over Pd-MIL-101 catalyst. [30] 3.1.2.4. Catalyst recyclability. Several catalysts exhibited very good recyclability in amination of benzaldehyde with nitrobenzene such as Pd/polymer, [46] PdCu supported on β-cyclodextrin, [66] Pd/Fe 3 O 4 , [51] Pd supported on Fe 3 O 4 carbon composite catalyst, [90] Pd@MIL-101, [30] Pd 2 Ag 1 @MIL-101, [65] Pd/Fe 2 O 3 @C, [90] Fe 2 O 3 supported on nitrogen doped graphitic carbon composite catalyst (NGr@C). [28] Metal leaching can be a problem in the liquid phase reductive aminations, for example in HMF amination in ethanol over Pd/C, 76% of Pd was leached out from the commercial catalyst after 6 h. [67] In addition, Pd leaching occurred during HMF amination also from Pd/UiO-67 (ca. 65% of Pd was leached). [68] On the other hand, no metal leaching was reported from ironfenantroline complex immobilized on a carbon support, [28] from a polymer supported Pd catalyst, [46] and from Pd supported on Fe 3 O 4 -carbon composite, [90] However, the presence of polymer retarded catalyst deactivation of Pd supported polyparaphenylene diamine modified metal organic framework UiO-67 in HMF amination with aniline in ethanol, at 50°C under 5 bar hydrogen [68] and ca. 95% of Pd remaining in the catalyst.
In general, aggregation of metal particles can be one of reasons for the activity decline. [30] Under mild conditions, no aggregation of Pd supported on gum acacia occurred. This catalyst exhibited the same metal particle size of ca. 9 nm after the fifth reaction cycle in amination of benzaldehyde with nitrobenzene at 25°C under 1 bar hydrogen. [47] The yield of N-benzylaniline, however, decreased slightly from the fresh catalyst giving 88% to 85% in the fifth cycle. On the other hand, a minor increase of the Pd particle size was observed in Pd@MIL-101 when it was used in benzaldehyde amination with nitrobenzene at 110°C under 5 bar hydrogen. [30] A very promising catalyst exhibiting excellent recyclability in reductive amination of benzaldehyde with nitrobenzene was Pd/Fe 3 O 4 @C [90] prepared by solvothermal synthesis (Table S2, entry 10). The yield of secondary amine decreased only form 92% in the first cycle to 88% in the sixth cycle while no Pd leaching was observed. Furthermore, it was stated that the catalyst synthesis is simple and convenient. In addition, this solvothermal method to synthesize catalyst is attractive for large-scale industrial synthesis. On the other hand, it was shown in several studies [28,29,51] that the yield of N-benzylaniline is decreasing during recycling. Thus, the yield of benzylaniline decreased from 92% to 87% in the fourth cycle with Pd/Fe 3 O 4 catalyst in amination of benzaldehyde with nitrobenzene under hydrogen atmosphere in ethanol at 25°C [51] when the catalyst was washed with ethanol between experiments. For Fe 2 O 3 supported on nitrogen modified graphitic carbon the yield of N-benzylaniline decreased from 63% to 55% from the first to the fifth cycle at 170°C under 50 bar hydrogen during 30 h. [28] Analogously for Co 3 O 4 supported on nitrogen modified graphite -carbon composite (NGr@C) catalyst used in amination of benzaldehyde with nitrobenzene the yield of the desired amine decreased after the first use from 95% to 60% for the sixth recycle, [29] even if no leaching neither catalyst structural changes were detected. The reason for catalyst deactivation might be accumulation of carbonaceous species on the catalyst surface.

Continuous amination of carbonyl compounds with nitroarenes
Continuous amination of carbonyl compounds was demonstrated over Ag, Au and Cu catalysts, [63,72,92] which were relatively stable. [63,[71][72][73]92] The amine yield in the reaction between n-heptaldehyde and benzylamine at 80°C over Au/Al 2 O 3 decreased with time-on-stream from 95% to 90% in 140 min due to carbon deposition on the catalyst surface. It was, however, reported that the gold particle size remained the same. [63] Analogously a slight catalyst deactivation occurred in the amination of heptanal with nitrobenzene at 100°C under 30 bar hydrogen for Ag/Al 2 O 3 catalyst. In this case the carbonaceous species were removed by regenerating the catalyst in air at 330°C for 20 h almost restoring the catalyst activity. [92] The authors compared the space time yields of the amine obtained over Ag/Al 2 O 3 [92] and Au/Al 2 O 3 [63] and concluded that the gold catalyst was ca. twofold more efficient. The yield of the desired amine over Ag/Al 2 O 3 under 30 bar hydrogen at 100°C in toluene was 85% with the imine yield of 9%. [93] Continuous amination of n-heptanal with p-nitrotoluene was also successfully demonstrated over Cu/Al 2 O 3 catalyst under 50 bar hydrogen at 115°C in toluene as a solvent giving 82% yield of the desired amine and 18% aniline. [73] On the other hand, THF and isopropanol caused severe deactivation of Cu/Al 2 O 3 completely retarding the reaction. [73] The yield of amine decreased slightly with increasing time-on-stream due to deposition of carbonaceous products on the catalyst surface. The catalyst could, however, be regenerated after washing with toluene/2-propanol and treatment in air at 330°C for 2 h. [73] The use of methanol as a solvent produced more aniline as an intermediate over Au/Al 2 O 3 , moreover, as reported in Ref. [63], aldehydes are easily hydrogenated in alcohols. It was also pointed out that the space time yield of the desired amine was only 3.3 times lower over Cu/Al 2 O 3 in comparison with a more expensive Au/Al 2 O 3 in reductive amination of n-heptanal with nitrobenzene. [63,73]

Kinetics and modeling of amination of carbonyl compounds with nitroarenes
Kinetics of aldehydes and ketones amination with nitrocompounds has been very scarcely studied. [30,70] Concentration profiles as a function of time were shown, for example in, [70] for amination of benzaldehyde with nitrobenzene, which was performed over a Pt nanowire catalyst at 100°C under 1 bar hydrogen. Experimental data corresponded to a typical consecutive reaction. Already after 1 h the main product was N-benzylaniline. The second major product was N-benzylidineaniline, which reacted further after a prolonged reaction time. Over this catalyst also traces of benzyl alcohol were formed originating from benzaldehyde hydrogenation. A simple kinetic model was developed also for benzaldehyde amination with nitrobenzene over several catalysts, such as Au@TiO 2 , MIL-101-SI-Pt, MIL-101-SI-Pd modified with salicylaldehyde (SI) (preparation method for MIL-101-SI-Pt catalyst is given in Table S2, entry 2) as well as Pd loaded on molybdophoshoric acid modified SiO 2 at 110°C under 5 bar hydrogen. In Ref. [30], a consecutive reaction network involving nitrobenzene transformations to imine and further hydrogenation to amine was considered while nitrobenzene hydrogenation to aniline and its further reaction to imine were of minor importance because the aniline concentration in the reaction mixture was very low. The results revealed that the slowest reaction varied depending on the catalyst type. For the best catalyst MIL-101-SI-Pd such reaction was nitrobenzene hydrogenation, while for MIL-101-SI-Pt imine hydrogenation was slower. In addition, it was stated that the slowest process in one-pot amination of benzaldehyde with nitrobenzene is imine hydrogenation over Co 3 O 4 supported on nitrogen modified graphite (denoted as Co 3 O NGr@C) at 110°C under 50 bar hydrogen. [29] These results show [30,70] that there is a clear need to further study reaction kinetics in a systematic way considering a potential influence of hydrogen pressure, temperature and initial reactant concentration, as such data are largely missing.

Reaction mechanism for amination of carbonyl compounds with nitroarenes
The mechanism of carbonyl compounds amination has been quite intensively studied. [72,82] It was proposed in Ref. [72] that the nitro group is first adsorbed on the active metal sites followed by hydrogenation. Thereafter, the formed amine reacts with an aldehyde giving the imine, [72] which in turn was hydrogenated on the metal sites. It should, however, be pointed out that the amine can also react with aldehyde in the liquid phase in the absence of any catalyst. The major side reaction in reductive amination of carbonyl compounds is alcohol formation from aldehydes and ketones, [70] which is typically inhibited in the presence of large amounts of amine formed in the first step. [72] Mechanistic studies were performed for benzaldehyde amination with nitrobenzene. [70] The imine, N-benzylideneaniline, was used as a reactant in the presence of 1 bar hydrogen at 110°C over Pt nanowire, giving only ca. 5% yield of N-benzylaniline after 24 h. Furthermore, the authors using in-situ infrared spectroscopy demonstrated that nitrobenzene was reduced in the first step to nitrosobenzene, which in turn forms phenyl(phenylamino)methanol from the reaction between benzaldehyde giving a dihydroxy intermediate. This intermediate is dehydrated to N-benzylaniline. It was also confirmed that phenyl(phenylamino)methanol is easier to be dehydrated to N-benzylaniline than to N-benzylideneaniline. [70] According to DFT calculations, the bonding energy of N-H is higher than that for C-OH explaining why N-benzylaniline is formed easier than N-benzylideneaniline.
The reaction mechanism for one-pot reductive amination of a nitroarene under hydrogen atmosphere with an aldehyde was recently proposed in Ref. [82]. In the first step nitroarene is hydrogenated to the corresponding amine (intermediate I) followed by its condensation with an aldehyde to an imine (intermediate II) (Figure 14). The formed imine is subsequently hydrogenated giving a secondary amine. In addition, when using an excess of the aldehyde, the tertiary amine (by-product 3ʹ) can be formed. On the other hand, with an excess of amine the aminal byproduct (III) can be formed. Furthermore, hydrogenation of an aldehyde (reactant 2) can occur generating the corresponding alcohol (by-product 2ʹ). In addition even dehydration of the alcohol has been observed resulting in the corresponding hydrocarbon (by-product 2ʹ). Figure 14. Mechanism for one-pot reductive amination of nitroarenes with aldehydes. [82] .

Amination of aldehydes and ketones with nitroarenes over heterogeneous catalysts using alternative hydrogen sources
As alternative hydrogen sources NaBH 4 , [50] CO-H 2 O [54,95] and formic acid [49,55,56] have been used for amination of nitroarenes over heterogeneous catalysts. When formic acid is used as a hydrogen source, typically an excess of formic acid is required. [49] Benzaldehyde amination with nitrobenzene was demonstrated using 10 fold excess of formic acid giving 66% yield of the desired amine at 60°C in 6 h over Au/SiO 2 -NH 2 . [49] However, even a higher yield, 93% was obtained in THF using a quinuclidine base as an additive together with Au/SiO 2 -NH 2 at 80°C with 15 fold excess of formic acid in 8 h ( Table 8, entry 1). This catalyst was also very stable without any leaching. [49] It was stated that when amine is adsorbed on the gold surface, the energy barrier to hydrogen heterolytic dissociation decreased. [49] Application of NaBH 4 allowed to synthesize benzylamine over Ni/H-mZSM-5 catalyst with high 95% yield at room temperature. [50] Higher temperatures and longer reaction times were required for transition Co metal catalysts to transform benzaldehyde to N-benzylaniline (Table 8, entries 3-6, Figure 15). [53,54,56] CO/water assisted one-pot reductive amination by transfer hydrogenation was also  Figure 15. Effect of temperature in reductive amination of benzaldehyde with nitrobenzene over Co supported on nitrogen doped carbon (CN-600, pyrolyzed at 600°C) (ball) adapted from Ref. [53] and over Co supported on nitrogen doped carbon (CN-800, pyrolyzed at 800°C) (rectangular) adapted from Ref. [56] in the presence of formic acid. Notation: open symbol: imine, solid symbol: amine. Copyright permissions from Elsevier Ltd and from American Chemical Society. demonstrated over Co/N-C calcined at 600°C. [90] The highest yield of N-benzylideneaniline was ca. 90% at 170°C under 30 bar CO. In this system hydrogen is provided by the water gas shift reaction: CO+H 2 O ! CO 2 + H 2 .
The proposed reaction mechanism shown in Figure 16 illustrates formation of as-formed proton (N-H + ) and a hydride Co-H − , which are active species in hydrogenation of the nitro group. Furthermore, higher reaction temperatures favored imine hydrogenation to the corresponding amine as in the case of molecular hydrogen as a hydrogen source. An acid leached mesoporous Co catalyst supported on nitrogen doped carbon (Co@CN) ( Table 8 entry 3) was an active and selective catalyst in formic acid assisted amination of benzaldehyde [56] even in the absence of a base. Formic acid was used 4.5 fold excess in comparison to aldehyde at 150°C in THF over Co supported on nitrogen doped carbon. [56] The effect of the molar ratio of benzaldehyde to nitrobenzene was also studied in benzaldehyde amination in the presence of formic acid over Co supported on Figure 16. The reaction mechanism for one-pot reductive amination of nitrobenzene with benzaldehyde using the CO/H 2 O assisted system. [95] Copyright Elsevier Ltd.  [53] nitrogen doped carbon (CN-800, pyrolyzed at 800°C), [56] showing that the yield of the desired amine decreased with decreasing benzaldehyde to nitrobenzene ratio. A rather high reaction temperature, 190°C, was required, since at lower temperatures the imine was the main product indicating that hydrogenation of C = N requires a higher temperature than of the nitro group. [56] Nickel nanoparticles supported on the proton form of ZSM-5 zeolite (Ni/ H-mZSM-5) with a microporous/mesoporous hierarchical structure were used in one-pot reductive amination of aldehydes with nitroarenes comprising various electron-donating and electron-withdrawing groups in the presence of NaBH 4 as a mild reducing agent (Table 9). [50] Presence of an electron-withdrawing group in the nitro aromatic ring decreasing the electron density at the nitro group was beneficial from the kinetic viewpoint (Table 9, entry 6), whereas an opposite effect was seen for electron-donating groups ( Table 9, entries 7 and 8) which can be related to different ability of accepting the hydride ions. The latter increases at a lower electron density at the nitro groups. On the other hand, higher reaction rates were obtained for the compounds containing the electron-donating groups in the benzaldehyde ring (Table 9, entries 2-5). In fact, the electron-donating groups stabilize the protonated carbonyl bond intermediate, which is beneficial for reaction kinetics. A study of reusability of the Ni/H-mZSM-5 catalyst demonstrated very low Ni leaching (ca. 3%) and the preserving catalyst structure according to XRD. The recycled catalyst washed with water (10 mL) and ethanol (3 mL × 5 mL) could be reused six times. [50] Catalyst recycling was also investigated in formic acid assisted amination of benzaldehyde. [49,53] No gold leaching was observed from Au/SiO 2 -NH 2 and the hot filtration test indicated that the reaction occurred only over the heterogeneous catalyst. [49] The yield of the desired amine decreased only slightly due to a minor agglomeration of the gold particles. [49] Recycling of Co supported on nitrogen doped carbon (denoted as Co-CN-600-AT, which was acid leached and pyrolyzed at 600°C) was successfully demonstrated in benzaldehyde amination at 190°C under 10 bar nitrogen in the presence of three-fold excess of formic acid. [53] In Ref. [53], separation of Co-CN-600-AT with a magnet and the catalyst reuse after washing it with water and ethanol followed by vacuum drying at 60°C confirmed absence of the metal leaching and an activity decrease.
Kinetic analysis of the formic acid assisted amination of benzaldehyde with aniline at 150°C in THF showed consecutive formation of imine followed by its hydrogenation to the amine as expected (Figure 17). [56] In Co supported on nitrogen doped carbon catalyzed amination of benzaldehyde with aniline using six fold excess of formic acid with respect to benzaldehyde at a high temperature promoted formation of amine instead of the imine. [53] The authors [53] also observed that N-benzylidene aniline can be reversibly transformed to benzaldehyde and aniline in a mixture of formic acid-water and Turn-over number (mol product/mol Ni) and turn-over frequency (mol product/(mol Ni·h)). especially that the yield of benzyl aniline was suppressed at lower temperatures due to this reaction. The reaction mechanism for formic acid assisted transfer hydrogenation was also discussed. The first step is heterolytic splitting of formic acid to H + adsorbed on N and Co-HCOO − . Presence of nitrogen in the catalyst is beneficial for the interactions of formate anions with Co nanoparticles. It was confirmed by utilization of deuterated formic acid, DCOOD, that heterolytic cleavage of hydrogen is possible with D + and D − adsorbing respectively on N and Co. [56] Furthermore, it was stated that formation of Co-HCOO − species is the rate limiting step. In the recycling tests of Co supported on nitrogen modified carbon neither aggregation of the metal nor leaching were observed.
In CO-assisted reductive amination of benzaldehyde with nitrobenzene [95] and 4-methoxynitrobenzene, [54] the effect of CO pressure was also systematically studied ( Figure 18, Table 8, entries 4, 5) indicating that a higher CO pressure enhanced formation of amine, while in benzaldehyde amination with 4-methoxynitrobenzene the yield of the corresponding tertiary amine increased. In Ref. [54], the highest yield of the desired secondary amine was  obtained after 24 h reaction at 5 bar CO at 120°C. It was also confirmed that CO assisted reductive amination did not proceed in THF as the water gas shift reaction generating hydrogen requires water. Palladium-catalyzed chemoselective reduction and reductive amination of nitroarenes with water as a hydrogen source mediated by diboronic acid was reported in Ref. [48]. The authors proposed that interactions of Pd with diboronic acid B 2 (OH) 4 3 . This hydride complex (HO) 2 B-Pd-H in essence plays a role of the hydrogenating agent allowing, first, hydrogenation of a nitroaromatic compound into the corresponding primary amine, and, second, hydrogenation of the giving finally the desired secondary amine. The role of water and diboronic acid was reported to be in recovering palladium and provide formation of (HO) 2 B-Pd-H complex required for the catalytic cycle. [48] a) b)  Figure 18. Effect of CO pressure in reductive amination of benzaldehyde with a) nitrobenzene over Co supported on nitrogen modified carbon catalyst in water at 170°C after 10 h adapted from [95] notation: solid symbol -amine, open symbol -imine and b) 4-methoxynitrobenzene over Co 2 Rh 2 /C at 120°C after 12 h in THF and a small amount of water adapted from, [54] notation: solid symbol -amine, open symbol -tertiary amine, a and b denote the yield of secondary amine and tertiary amine, respectively after 24 h. Copyright permissions from Elsevier Ltd and from American Chemical Society.

Future outlook
Based on the literature analysis, it can be concluded that there is still a lack of experimental data preventing in depth understanding of the role of the active sites in the catalyst and correlation of the catalytic properties with its performance. In most of the papers, only the yield of the desired amine is given, [1,[11][12][13][14]17,46,47,51,52,66,68,75] and in several studies the catalyst reuse has been addressed. [11,17,24,28,30,51,[65][66][67]69,90] However, rather few papers have addressed formation of side products, [10,[24][25][26]61,68,84] the reaction mechanism, [82 , 95] presented kinetic analysis [56,62,68,84,95] or did kinetic modeling. [61] Such studies could, however, give valuable information for the development of reductive amination toward industrial applications. In addition, continuous mode of operation is an attractive option to elucidate catalyst stability and industrial feasibility of the process. [24,63,71,72,74,92] Typically rather diluted reaction mixtures have been used. Subsequently very seldom data are available on amination of more concentrated reaction mixtures [84] and the effect of the initial reactant concentration is addressed. [69] The nature of active sites in the catalyst for reductive amination of carbonyl compounds is typically not adequately addressed because catalyst acidity [10,65] or basicity [10] have been determined very seldom. Furthermore, a systematic physico-chemical approach has been very scarcely applied in reductive amination of carbonyl compounds. More research is required to systematically study the effect of the initial reactant concentrations [69] and pressure [11,17,68] and to reveal reaction orders with respect to the reactants as well as to determine activation energies for different reaction steps in reductive amination of carbonyl compounds.

Conclusions
One-pot reductive amination of aldehydes and ketones for synthesis of secondary amines, important intermediates for production of pharmaceuticals, has been reported for several different types of aldehyde and ketones with high yields obtained in many cases. The feedstock, aldehydes and ketones, are inexpensive and very abundant from biorefinery processes, while nitro compounds are obtained by nitration of benzene. Nitro compounds can also be reduced in situ to the corresponding amines, which then react with aldehydes or ketones in one-pot synthesis of secondary amines. The analysis of literature showed clearly that reductive amination over heterogeneous catalysts is a promising method giving more than 90% yields of secondary amines. For example, in reductive amination of benzaldehyde with cyclohexylamine 94% yield of the secondary amine was obtained at 80°C under 30 bar hydrogen in water and the catalyst recycling was demonstrated in four cycles with conversion slightly decreasing form 93% to 86%. Moreover, reductive amination of ketones has been also demonstrated.
The effect of the aldehyde/ketone structure on the yield of secondary amine has been intensively studied in the literature. The most important catalyst properties are the metal nature and its particle size, loading, support acidity and hydrophobicity, while among the reaction parameter, the source of hydrogen, hydrogen pressure, temperature and solvent are important factors. Both noble and transition metal catalysts have been used in the presence of hydrogen. With NaBH 4 as a reducing agent also acidic catalyst in the absence of a metal could be applied, because no hydrogen dissociation occurring on the metal is required. For example, non acidic metal catalysts promote the undesired hydrogenation of aldehydes/ketones instead of forming the imines and in the second step the desired amines.
Industrial feasibility of reductive amination processes needs to be addressed. Although continuous reductive amination has already been demonstrated, the view toward more engineering approach, such as systematic kinetic studies, also with more concentrated feeds and with a complete product analysis are required. In the next phase these systematic results should be combined with kinetic analysis, modeling and proper catalyst characterization including also quantitative acidity/basicity determination.