ii THESIS SUMMARY This thesis describes the synthesis, characterization and catalytic applications of four copper-based metal-organic frameworks Cu-MOFs including Cu3BTC2, Cu2BDC2DABCO,
Introduction to metal-organic frameworks
There are a variety of porous materials have been increasingly studied such as nanotubes [1], mesoporous silicas [2], mesoporous carbons [3], microporous and mesoporous metal-organic frameworks (MOFs) [4] since the invention of aluminophosphate molecular sieves [5] In comparison with other porous materials, MOFs possess unique structures, in which the metal ions combine with organic linkers to form secondary building units (SBUs), which dictate the final topology of a whole framework [6] The combination of numerous kinds of linkers and metal ions can lead to the considerate diversity of this material [7] Some examples of MOFs structures are shown in Figure 1.1
Figure 1.1 The 3D structures of representative MOFs [7]
4 Since the exploration of MOFs, several synthetic strategies for the preparation of crystalline MOFs materials have been developed A summary of various approaches for MOFs preparation is presented in Figure 1.2 [8]
Figure 1.2 (a) Synthesis conditions commonly used for MOFs preparation;
(b) indicative summary of the percentage of MOFs synthesized using various preparation routes [8]
5 MOFs are usually synthesized by solvothermal method, based on the change in polarity of solvents combining with appropriate temperature In detail, a mixture of ligands and metal salts dissolved in a solvent (or a mixture of solvents) is heated below 300 °C during 48-96h for the grow of crystals [8] Solvent selection depended on different criteria including solubility, stability, reactivity, redox potential [8] etc
Preferred solvents are polar solvents with high boiling points including dialkyl formamide, ethanol or water Solvothermal method can afford MOFs with crystallinity being high enough for their structure determination by Single Crystal X-Ray Diffraction (SC-XRD) However, this method also suffers from drawbacks including long reaction time is required, large-scale synthesis is limited and many trials and errors are necessary To overcome these disadvantages, other methods have been studied including microwave-assisted synthesis [9], biphasic solvothermal synthesis [10], electrochemical synthesis [11], high-throughput [12] or mechanochemical synthesis [13] However, these methods cannot yield the crystals with sufficient quality for their structure determination by SC-XRD compared to solvothermal method
Owing to their unique composition, MOFs show outstanding characteristics including diverse, predetermined and flexible structures, tunable pore size, large surface areas, high crystallinity, ultrahigh porosity, and sustainable frameworks [14] Thanks to these exceptional properties, MOFs have been investigated for many potential applications including gas adsorption and storage [15-19], catalysis [20], drug delivery [21], chemical separation [22, 23] and chemical sensors [24] Although investigations on catalytic applications of MOFs are relatively lagging behind other topics, the situation has improved dramatically since 2009 Figure 1.3 shows the development of MOF fields on the basis of articles appeared in the last twenty years [25] It is clear that MOF catalysis underwent a rapid development in recent five years
6 Figure 1.3 Development of MOF fields in comparison to the MOF catalysis in the last ten years (SciFinder until Jan 15, 2014) [25]
In catalysis, MOFs can be used as heterogeneous catalysts to overcome drawbacks of traditional homogeneous catalytic systems such as high catalysts amount and irrecoverbility [20, 26-29] In addition, MOFs have highly organized structures, large specific surface areas and uniform size distributions of pore and voids The system of channels with a strict geometry in MOFs allows their use in size- and shape-selective catalysis, which is similar to zeolites [30] Moreover, their highly open metal sites and high metal contents can lead to their highly catalytic activity [6] In some reactions requiring harsh conditions, MOFs cannot compete with zeolites due to their low thermal stability However, MOFs can offer striking features consisting of diverse structures and tunable pore size [20, 31] The features and physicochemical properties of common porous materials and MOFs materials are shown in the Table 1.1
7 Table 1.1 The comparison of structural features and physicochemical properties between some common porous materials used in industry and MOFs materials [20, 31]
Silica gel amorphous; shapes, pore sizes are not uniform; surface functional groups are mainly neutral hydroxyl groups
Activated alumina amorphous; shapes, pore sizes are not uniform; surface functional groups are mainly acidic or basic hydroxyl groups
Zeolite crystalline; shapes, pore sizes are uniform
Activated carbons amorphous; shapes, pore sizes are not uniform; different degrees of local surface polarities
Molecular sieve carbons amorphous; pore sizes are larger than activated carbons
MOFs crystalline; shapes, pore sizes and surface functional groups can be adjusted flexibly
Among a variety of transition metal MOFs, Cu-MOFs emerge as the most used materials Many studies reported MOFs containing copper active sites as efficient heterogeneous catalysts [32-41] According to previous reports, Cu-MOFs are usually made up from the paddle-wheel shaped SBU These Cu-MOFs contain many open metal sites that enable the reactivity of organic compounds in organic transformations (Fig 1.4) Among organic linkers that are often used for Cu-MOFs synthesis, 1,4- benzenedicarboxylic acid (BDC), 1,3,5-benzenetricarboxylic acid (BTC) and 4,4’-
8 biphenyldicarboxylic acid (BPDC) have advantages that they are commercial and relatively cheap In another approach, MOFs can be constructed from mixed linkers to provide greater flexibility in terms of surface area, modifiable pore size and chemical environment [42] Linkers BDC and BPDC could be easily combined with pillar linkers such as 1,4-diazabicyclo [2.2.2]octane (DABCO) or 4,4’-bipyridine (BPY) to form rigid Cu-MOFs [43-47] Therefore, Cu-MOFs constructed from BDC, BTC or BPDC recently attracted great attention In this chapter, literature review of structure, physicochemical properties, synthesis methods, characterization, and catalytic applications of four Cu-MOFs including Cu3(BTC)2, Cu(BDC), Cu2(BDC)2(DABCO) and Cu 2 (BPDC) 2 (BPY) has been discussed
Figure 1.4 Cu-MOFs (M=Cu, Lboxylate) contain open metal sites that enable the reactivity of organic compounds in organic transformations.
Cu 3 (BTC) 2 , Cu(BDC), Cu 2 (BDC) 2 (DABCO) and Cu 2 (BPDC) 2 (BPY)
1.2.1 Structures and properties of Cu 3 (BTC) 2 , Cu(BDC), Cu 2 (BDC) 2 (DABCO) and Cu 2 (BPDC) 2 (BPY)
Cu3(BTC)2 [46], Cu(BDC) [44], Cu2(BDC)2(DABCO) [47] and Cu2(BPDC)2(BPY) [45] constitute Cu-MOFs that contain common SBUs of two 5-coordinate copper cations bridged in a paddle wheel-type configuration (Fig 1.5)
9 Figure 1.5 Common coordination geometry of paddle wheel building units of Cu3(BTC)2, Cu2(BDC)2(DABCO), Cu2(BPDC)2(BPY), Cu(BDC) and their framework structures (L = Carboxylate linker, P = N-containing bidentate pillar linker and G Guest molecule) [44-47]
As shown in Figure 1.5, in these frameworks carboxylates act as grid-forming ligands
In the case of Cu 3 (BTC) 2 and Cu(BDC), each copper completes its pseudooctohedral coordination sphere with a guest ligand G (G = H 2 O and DMF, respectively) opposite to the Cu-Cu vector in the as-synthesized structures The guest molecules present after synthesis can be removed through activation, to yield a desolvated structure, which has unsaturated open metal sites In the case of Cu 2 (BDC) 2 (DABCO) and Cu 2 (BPDC) 2 (BPY), N-containing bidentate ligands P (P = DABCO and BPY, respectively) play the role of pillars The geometry and bond distances within the paddle-wheel fragment are comparable for all of four Cu-MOFs (Cu−Cu = 2.627–
2.628 Å, Cu−OCO = 1.952–2.001 Å, Cu–G = 2.165 Å and Cu−P = 2.101–2.103 Å)
As Cu 3 (BTC) 2 was constructed from the tritopic ligand BTC and Cu 2 (BDC) 2 (DABCO), Cu 2 (BPDC) 2 (BPY) were constructed from two different types of ligand, the framework structures of these Cu-MOFs are three dimention Whereas Cu(BDC) appears to have a stacking lamellar structure that forms two-dimensional
10 tunnels According to Carson et al., the structural transformation of Cu(BDC) from a lamellar to a compact structure upon DMF desorption can be reversed by re-adsorption of molecules containing carbonyl groups (Fig 1.6) [40]
Figure 1.6 Reversible crystalline phase transformation of Cu(BDC) from the lamellar to the compact structure upon desorption/adsorption of DMF [40]
Long organic linkers provide larger pore and a greater number of adsorption sites within MOFs However, the large space within the crystal framework makes it prone to form interpenetrating structures (two or more frameworks grow and mutually intertwine together) X-Ray crystal structure of Cu2(BPDC)2(BPY) shows that two equivalent networks mutually interpenetrate which may be resulted from the use of two long linkers BPDC and BPY (Figure 1.7)
11 Figure 1.7 X-Ray structure of the doubly interpenetrating pillared-grid framework
A summary of physicochemical properties of Cu 3 (BTC) 2 , Cu(BDC), Cu2(BDC)2(DABCO) and Cu2(BPDC)2(BPY) is presented in Table 1.2
Thermogravimetric analysis showed that all the materials are thermally stable up to 300C or higher Gas adsorption/desorption isotherm studies gave the Brunauer-Emmett-Teller (BET) surface area of the Cu-MOFs higher than 1000 m 2 /g except for Cu(BDC) Although Cu(BDC) has about half of the surface area of the other Cu-MOFs, it may be desired if a comparison to determine the effect of pore geometry on a particular materials property is to be made Besides surface area values, a key parameter in porosity is the pore aperture (or pore window, pore opening) The pore apertures are the pore-opening sizes that allow access of molecules into the pore for storage, separation or conversion applications An example of the pore apertures of Cu 2 (BDC) 2 (DABCO) is shown in Figure1.8 There are two types of cage windows in cubical cages While the windows formed by the DABCO linkers have a much smaller diameter (3.8 4.7 Å), the window formed by the terephthalate linkers have a free diameter of approximately (7.5 7.5 Å) (Fig 1.8) [48] The largest pore apertures of Cu 2 (BDC) 2 (DABCO), Cu 3 (BTC) 2 and Cu 2 (BPDC) 2 (BPY) are in the range of 7.5 – 9.0 Å which can allow average size substrates to enter the pores to reach catalytic sites
12 Figure 1.8 Pore apertures of Cu2(BDC)2(DABCO) [48]
Table 1.2: Physicochemical properties of Cu 3 (BTC) 2 , Cu(BDC), Cu 2 (BDC) 2 (DABCO) and Cu2(BPDC)2(BPY)
We have been also described the structures and properties of Cu 3 (BTC) 2 , Cu2(BDC)2(DABCO), Cu2(BPDC)2(BPY) and Cu(BDC) In reality, their structures and properties are much dependent on synthetic methods and experimental conditions
In the next section, the synthesis methods for those Cu-MOFs are reviewed
1.2.2 Synthesis of Cu 3 (BTC) 2 , Cu(BDC), Cu 2 (BDC) 2 (DABCO) and Cu 2 (BPDC) 2 (BPY)
There are various approaches for MOFs preparation as illustrated in Figure 1.2 The most commonly used method for MOFs synthesis is solvothermal condition (Fig 1.9)
Figure 1.9 Solvothermal synthesis of MOFs [10]
Cu3(BTC)2, Cu2(BDC)2(DABCO), Cu2(BPDC)2(BPY) and Cu(BDC) were synthesized by solvothermal methods as described in Scheme 1.1
Scheme 1.1 Solvothermal synthesis of Cu3(BTC)2, Cu2(BDC)2(DABCO),
Cu 2 (BPDC) 2 (BPY) and Cu(BDC) [44-47]
14 In 1997, Mori et al initially synthesized Cu(BDC) from copper (II) formate and terephthalic acid (H 2 BDC) in methanol solution at room temperature after several weeks [44] In 2009, Cantwell et al reported new synthetic conditions for Cu(BDC) [52] Herein, a mixture of Cu(NO3)2.3H2O and H2BDC was dissolved in DMF and then heated at 110 o C in an isothermal oven for 36 hours to form a blue powder The BET surface areas of 625 m 2 /g and Langmuir surface areas of m 2 /g 752 were achieved
Other groups also followed this method to synthesize Cu(BDC) for catalytic applications [37, 40, 41]
In 1999, Cu 3 (BTC) 2 was initially discovered by Chui et al and named as HKUST-1 In that synthesis, Cu(NO3)2.3H2O was heated with 1,3,5-benzenetricarboxylic acid (H 3 BTC) in a mixed solvent system H 2 O:EtOH at high temperature and pressure [46]
Since the publication of Chui et al., there have been a large number of synthesis studies conducted under different synthesis conditions (solvent, synthesis temperature, time,…) in an effort to improve the physicochemical properties of Cu 3 (BTC) 2 A summary of Cu3(BTC)2 synthesis studies was provided by Jun Kim et al [50]
Cu3(BTC)2 synthesized in a mixed solvent system H2O:EtOH may have Cu2O impurity with low porosity [53] Reflux synthesis in EtOH [54], DMF [55], or DMF/H 2 O [46] afforded Cu2O-free Cu3(BTC)2 with excellent specific surface areas (BET surface areas of 1624, 1239, and 1333 m 2 /g, respectively)
In 2001, Seki initially synthesized Cu 2 (BDC) 2 (DABCO) by heterogeneous reactions between porous copper dicarboxylates and DABCO as a pillar ligand in methanol solution [56] In that synthesis, a methanol solution of copper (II) sulfate pentahydrate, terephthalic acid and formic acid was stand for several days at 313 K A toluene solution of DABCO was then added to the mixture, which was allowed to react at 433 K for several hours The BET surface areas of 3265 m 2 /g were achieved for this material but no structural confirmation was reported With the same synthetic condition, the structure of Cu2(BDC)2(DABCO) was confirmed by SC-XRD after one year [47] In 2007, Lee et al reported a new shorter procedure for Cu2(BDC)2(DABCO) synthesis Herein, Cu(NO3)2.3H2O was mixed with H2BDC and triethylenediamine (DABCO) in DMF and heated at 120C 36 h Other groups also
15 followed this method to prepare Cu2(BDC)2(DABCO) for liquid phase separation [48, 57], gas adsorption [58], loading ferrocene [59] and catalytic applications [33, 60]
In 2007, Cu 2 (BPDC) 2 (BPY) was initially discovered by James and co-workers [45] In that synthesis, a mixture of Cu(NO3)2.3H2O, 4,4’-biphenyldicarboxylic acid (H 2 BPDC) and 4,4’-Bipyridine (BPY) was dissolved in DMSO The mixture was then heated at 125 C for 24h The small green crystals were obtained as Cu2(BPDC)2(BPY) Although the structure of Cu2(BPDC)2(BPY) was confirmed by SC-XRD, its surface area was not reported In 2013, Phan et al reported new synthetic conditions for Cu 2 (BPDC) 2 (BPY) for catalytic application [35, 61] Herein, the solid mixture of Cu(NO3)2.3H2O, H2BPDC and BPY was dissolved in a mixture of DMF:EtOH:Pyridine The resulting solution was then heated at 120 C for 24h to yield Cu 2 (BPDC) 2 (BPY) with a Langmuir surface areas of 1547 m 2 /g
1.2.3 Characterization of Cu 3 (BTC) 2 , Cu(BDC), Cu 2 (BDC) 2 (DABCO) and Cu 2 (BPDC) 2 (BPY)
Cu3(BTC)2, Cu(BDC), Cu2(BDC)2(DABCO) and Cu2(BPDC)2(BPY) can be characterized by various techniques, such as single crystal X-ray diffraction (SC- XRD), powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), Fourier transform infrared (FT-IR), transmission electron microscopy (TEM), thermogravimetric analysis (TGA), inductively coupled plasma mass spectrometry (ICP-MS), and gas physisorption measurement, etc
CC cross coupling reactions
The Carbon-Carbon (CC) cross coupling reactions play an important role in organic synthesis Usually, the central methods of connecting two simple molecules to generate a complex one are nucleophilic additions and substitutions There is a formation of a CC bond in acyclic structures [68] Initially, substantial amount of protocols have been developed via cross-coupling with Grignards or (pseudo)halides [69] (Scheme 1.8) The results focused on the use of stoichiometric quantities of a transition metal to carry out the desired transformation The later results focused on the development of high yielding reactions achieved with excellent selectivity and high functional group tolerance under mild reaction condition However, the cross-coupling with Girgnards or (pseudo)halides required highly reactive organometallic reagents in order to prepare the nucleophilic compound Another drawback of these methods was the requirement of several steps [69] Therefore, an alternative should be considered to overcome those advantages
27 Scheme 1.8 Aryl −Aryl bond formation by CC cross coupling [69]
Over the last few decades, transition-metal catalysis has been sparingly exploited in reactions creating CC bonds [70] (Scheme 1.9) Among them, a huge amount of attention has been paid to direct arylations of aryl and heteroaryl CH bonds due to their straightforwardness and many efforts have been made to take advantage of this kind of reaction It has been actually applied to synthesize of important compounds including natural products, pharmaceuticals, catalyst ligands, and materials [70] On the other hand, many scientists have focused on fine-tuning catalytic systems to improve their activities as well as to make themselves can work with inexpensive and industrially attractive aryl chlorides [70]
Scheme 1.9 Aryl −Aryl bond formation by transition-metal-catalyzed direct arylation [70]
Despite significant advancements, the type of reaction still remains limited by requirement of pre-functionalized starting materials Recent developments in chemistry and catalysis provide more efficient routes allowing to use CH bonds as starting coupling components [71, 72] (Scheme 1.10) Although the transition-metal- catalyzed functionalization of CH bonds is a powerful method for CC formation, there are still many challenges remained For the conversion of CH bonds to CC bonds, the precious metallic sources such as palladium, rhodium and ruthenium are expensive [71]
28 Scheme 1.10 Pd, Rh-Catalyzed Arylation via CH bond functionalization [71, 72]
Confronting this drawback, Daugulis et al revealed that several less costly and more available metals (e.g., copper, iron) could be successful for direct CH activations [71,
73-75] In the presence of lithium t- butoxide base, copper-catalyzed arylation of electron-rich five-membered heterocycle CH bonds with aryl iodide occurred with high yield Besides, electron-deficient pyridine oxides can also be arylated [73]
However, no reaction was observed when aryl iodide was replaced by other aryl haildes (PhBr, PhCl, PhOTf) So far, the CC bonds of polyfluobenzene (heterocycle CH bonds) and various aryl halides could be formed in the presence of copper satls under suitable conditions [74] Because fluorinated polyaryls are important in medicinal chemistry, direct methods for syntheses of these compounds lead to new efficient pathways to pharmaceuticals [76] Using copper-catalyzed arylation of sp 2 CH bonds, Do and co-workers also reported that a variety of electron-rich and electron-poor heterocycles such as azoles, caffeine, thiophenes, benzofurane, pyridine oxides, pyridazine, and pyrimidine can be arylated in the presence of aryl halides as the coupling partner [75] The reactions proceed via initial deprotonation of a relatively acidic sp 2 CH bond by an alkali metal base (or tBuOCu) followed by transmetalation and coupling with an aryl or vinyl halide (Scheme 1.11)
It should be noted that considerable attempt has been made toward the functionalizations of sp CH and sp 2 CH while direct sp 3 CH bonds has been still rare in literature [77] (Scheme 1.12) Progress in method development for propargylamine synthesis is a typical example Addition of sp CH bond in terminal alkynes into in-situ generated imines was first reported as an excellent alternative for tradition routes in 2003 [78-80] (Scheme 1.13) The three-component coupling of aldehyde, alkyne and amine via CH activation affored a diverse range of propargylamines in excellent yields This process is simple and applicable to both aromatic and aliphatic aldehydes and amines
Scheme 1.12 A general diagram of the CC cross-coupling reaction [77]
Scheme 1.13 Propargylamines synthesis under transition metal catalysis [78-80]
30 Based on literature reports, a tentative mechanism was proposed as shown in Scheme 1.14 [78-80] Transition metals are often employed as catalysts for these two-step reactions The metal acetylide intermediate added to iminium ion generated in situ from aldehydes and secondary amines to give the final proparylamine with the metal (I) catalyst being released for further cycle of reactions In spite of effectiveness, the intermediate formation of imine compounds from aldehydes and amines is mandatory in this protocol Therefore, the direct CC coupling reactions of terminal alkyne are obviously more preferable
Scheme 1.14 A tentative mechanism of three-component reaction for synthesizing propargylamines [78-80]
On the other hand, cross-dehydrogenative coupling (CDC) of aliphatic C-H bonds using peroxides has been paid much attention [68, 81] A typical CDC reaction involves the formation of iminium ion from a tertiary amine followed by addition of a nucleophile under various transition metal catalysis [82, 83] (Scheme 1.15) The combination of sp 3 CH and aryl-sp 2 CH leaded to direct indolation of tetrahydroisoquinoline Moreover, indolyl tetrahydroisoquinoline derivatives were also efficiently synthesized in excellent yields by this way This method is really considered as an alternative to traditional functional group organic chemistry for the synthesis of such alkaloids [82, 83]
31 Scheme 1.15 Cross-Dehydrogenative Coupling for the formation of CC bonds
Under Mannich-type reaction conditions, it is previously reported that many catalysts have been used to promote the process of dehydrogenation of amines to generate intermediate iminium compounds These catalysts generally are acid Lewis such as Rh [84-87], Ru [85, 88], Ir [89], Cu [68, 83, 90], Fe [82, 91-93] Herein, Cu and Fe have been investigated for direct alkynylation of tertiary amine to form proparylamine [68, 83, 91, 93] It is worth noting that Cu and Fe are cheaper and less toxic than Rh, Ru and Ir Li and co-workers therefore decided to investigate the effects of catalytic copper salts on the alkynylation reactions with tert -butyl hydroperoxide (TBHP) as oxidant [94] (Scheme 1.16) In comparision with previous methods, the most striking advantage of this work is that the alkynylation reaction could carry out under mild condition Experimental results also indicated that the reactions provided good yields of the desired products for aromatic alkynes but the corresponding products were formed in lower yields for aliphatic alkynes [94]
Scheme 1.16 Copper-Catalyzed alkynylation of amines [94]
A plausible mechanism of the alkynylation reaction was shown in Scheme 1.17 [94]
Firstly, copper not only activated the terminal alkyne but also catalyzed the formation of an imine-type intermediate through activation of sp 3 C-H adjacent to nitrogen
32 Secondly, the two intermediates coupled to each other to yield proparylamine and the copper catalyst was regenerated [68, 83, 90] Other intermediates from tert- butylperoxide products were involed in this mechanism [95] They were further converted into the corresponding alkynylated amine via copper salts So far, the scope, mechanism and synthetic application of this reaction is still under investigation
Scheme 1.17 Tentative mechanism for the direct oxidative coupling of amine with alkyne [94]
Homogeneous catalysts have usually been used in these alkynylation reactions [68, 78- 84, 90, 93, 94] However, one major disadvantage of this type of catalysts is inability of recovery and difficulty in product separation The removal of metallic contamination and disposal of catalysis in product purification results in environmental as well as economical problem It is apparent that cheap heterogeneous catalysts should be prefer to overcome these disadvantages [91, 92] In specific, solid catalysts can be removed readily from reaction mixture by simple and energy-saved methods such as centrifugation and filtration Thanks to this, the polluting, complex and pricy isolation can be avoided Moreover, the heterogeneous catalyst can be reused and recycled Until now, this field has been withdrawn interests from many reseachers in the world and day by day brings us more positive and feasible results
Beside CC cross coupling reactions, CN cross coupling reactions also play an important role in organic synthesis In the next part of this chapter, based on CN
33 formation, the oxidative reaction between α-hydroxyacetoketone and o- phenelenediamine is reviewed.
CN cross coupling reactions
Quinoxaline and its derivatives are nitrogenous compounds that are widely used in various industrial applications like paints, pharmaceuticals and medicines [96]
Numerous synthetic strategies for the preparation of quinoxaline derivatives have been claimed By far, the traditional method is the condensation of an aryl o-diamines with a 1,2-dicarbonyl compounds in appropriate conditions (Scheme 1.22) [97]
Scheme 1.18 General synthesis of quinoxalines [97]
Mechanistically, a transition-metal catalyst is required because of its empty orbital could act as a Lewis acid activating the activate carbonyl part of 1,2-dicarbonyl compounds (Scheme 1.19) [96] Thereafter, the electrophilic carbon atom of the carbonyl group is attacked by the electron rich nitrogen atom of the amine, to give a hemiaminal intermediate, then the elimination of water provides the imine [98] This mechanism is repeated until the removal of two water molecules and quinoxaline should be obtained [96] The acid catalyst is required herein to eliminate water, otherwise the reaction is very slow
34 Scheme 1.19 The mechanism for the synthesis of different quinoxalines [98]
A various kind of catalysts was tested in these reactions such as acetic acid [99], molecular iodine [100], nickel nanoparticles [101] , gallium (III) triflate [102], CuSO4.5H2O [103], Montmorillonite K-10 [104], magnetic material separated from coal fly ash [105] , Well-Dawson heteropolyacid, and Yb(OTf) 3 [106] Alternative ways of preparation of quinoxalines, including the reactions of o-phenylenediamines and terminal alkynes in the presence of bases and copper-catalysts [107] , or the Bi- catalyzed oxidative couplings of epoxides and o-phenylenediamines, were also developed [108] However, the highly reactivity of 1,2-dicarbonyl compounds make the reaction hard to control [109] Therefore, a similar way for the synthesis of quinoxalines from the cyclization of another reagent: α-hydroxyketones – much less reactive than 1,2-dicarbonyl compounds – and aryl o-diamines has been studied recently The general mechanism of this reaction is nucleophilic substituted reaction
The proposed mechanism consists of two main steps (Scheme 1.20) [110]
35 Scheme 1.20 The proposed mechanism of the synthesis of quinoxaline [110]
In the first step, the initial oxidation of α-hydroxyacetophenone 1 is proceeded under copper catalyst/air system to form a 1,2-dicarbonyl 3 In this process, the Cu II is reduced into an intermediate Cu I species by oxidizing the alcohol group in 1 to the carbonyl group The Cu II is regenerated by the oxidation of Cu I in the presence of O2 to continue the catalytic cycle After that, the condensation of the 1,2-dicarbonyl compound 3 with o-phenylenediamine 2 to form imine is the rate-determining step
The nucleophilic nitrogen in 2 attacks the electrophilic carbonyl carbon, via several steps to form imine This imine formation mechanism is repeated twice, until the desired quinoxaline 4 is produced Alternatively, 4 can also be formed by the route via the condensation between 1 and 2 to form the ketimine 5, followed by oxidation to 6 and cyclization
The number of catalysts applied for the synthesis of quinoxaline from α- hydroxyketone and o-phenylenediamine has been increased rapidly, including
Pd(OAc) 2 , RuCl 2 -(PPh 3 ) 3 -TEMPO [111], Ru/C [109] and MnO 2 [112-114] Copper based catalysts were then focused due to its cheapness and high activity producing moderate to good yields [110, 115] Further studies using copper catalytic system, especially as heterogeneous catalysts, are currently under investigation
Aims and objectives
Propargylamines, produced by C–C cross coupling reactions, are frequently found as the versatile intermediates for the synthesis of many nitrogen-containing biologically active compounds Besides, quinoxalines, prepared by C–N cross coupling reactions, are also important nitrogenous heterocyclic compounds, constituting the basis of many applications Many transition-metal catalytic systems, both in homogeneous and heterogeneous catalysis, were applied for the preparation of propargylmines and quinoxalines However, many of those processes suffered from one or more limitations such as harsh reaction conditions, low product yields, tedious work-up procedures, and the use of toxic metal salts as catalysts (Section 1.4) Consequently, study for the high- effective, sustainable synthetic routes of proparylamines and quinoxalines is an unquestionable trend in near future
Owing to many advantageous features, MOFs have been proved as a convincing candidate for heterogeneous catalysis Among a variety of transition metal MOFs, Cu- MOFs emerge as the most used materials As mentioned in section 1.2, there are four Cu-MOFs including Cu3(BTC)2, Cu2(BDC)2(DABCO), Cu2(BPDC)2(BPY) and Cu(BDC) recently attracted great attention They have advantages that their surface areas are higher than 1000 m 2 /g (except for Cu(BDC)) and thermally stable up to 300 °C or higher Moreover, the largest pore apertures of Cu 2 (BDC) 2 (DABCO), Cu 3 (BTC) 2 and Cu 2 (BPDC) 2 (BPY) are in the range of 7.5 – 9.0 Å which can allow average size substrates to enter the pores to reach catalytic sites In addition, Cu 3 (BTC) 2 , Cu 2 (BDC) 2 (DABCO), Cu 2 (BPDC) 2 (BPY) and Cu(BDC) contain many open metal sites that enable reactivity of organic compounds in organic transformations However, to the best of our knowledge, the direct C–C and C–N coupling reactions for synthesizing proparylamines and quinoxalines using these Cu- MOFs were not previously mentioned in the literature
Inspired by those reasons, the main aim of this thesis is using the Cu-MOFs as catalysts for the synthesis of proparylamines and quinoxalines In details, the thesis focuss on two parts: i) synthesis and characterization of the Cu-MOFs including Cu 3 (BTC) 2 , Cu 2 (BDC) 2 (DABCO), Cu 2 (BPDC) 2 (BPY) and Cu(BDC); ii) catalytic
37 studies of Cu3(BTC)2, Cu2(BDC)2(DABCO), Cu2(BPDC)2(BPY) on C–C coupling reactions between amine compounds and terminal alkynes, catalytic studies of Cu(BDC) on C–N coupling reaction between α-hydroxyacetophenone and o- phenylenediamine.
SYNTHESIS AND CHARACTERIZATION OF Cu 3 (BTC) 2 , Cu 2 (BDC) 2 (DABCO), Cu 2 (BPDC) 2 (BPY), AND Cu(BDC) Cu3(BTC)2, Cu2(BDC)2(DABCO), Cu2(BPDC)2(BPY), AND Cu(BDC)
Introduction
Among several kinds of MOFs, it was previously reported that copper-based frameworks (Cu-MOFs) exhibited high activity for many organic reactions due to their unsaturated open copper metal sites [35, 37, 40, 41, 62-65, 116] Especially, Cu-MOFs constructed from 1,4-benzenedicarboxylic acid (BDC), 1,3,5-benzenetricarboxylic acid (BTC) or 4,4’-biphenyldicarboxylic acid (BPDC) recently attracted great attention These organic linkers have advantage that they are commercial and relatively cheap The BDC and BPDC could be easily combined with pillar linkers such as 1,4-diazabicyclo [2.2.2]octane (DABCO) or 4,4’-bipyridine (BPY) to form rigid Cu-MOFs [43-47] They are known as Cu3(BTC)2, Cu2(BDC)2(DABCO), Cu 2 (BPDC) 2 (BPY) and Cu(BDC) The structures of those MOFs are shown in Figure 2.1 These Cu-MOFs have advantages that their surface areas are higher than 1000 m 2 /g (except for Cu(BDC)) and thermally stable up to 300 °C or higher Moreover, the largest pore apertures of Cu 2 (BDC) 2 (DABCO), Cu 3 (BTC) 2 and Cu 2 (BPDC) 2 (BPY) are in the range of 7.5 – 9.0 Å which can allow average size substrates to enter the pores to reach catalytic sites In addition, Cu3(BTC)2, Cu2(BDC)2(DABCO), Cu 2 (BPDC) 2 (BPY) and Cu(BDC) contain many open metal sites that enable reactivity of organic compounds in organic transformations In this chapter, the synthesis, characterization methods, physicochemical properties of Cu 3 (BTC) 2 , Cu 2 (BDC) 2 (DABCO), Cu 2 (BPDC) 2 (BPY) and Cu(BDC) were studied
40 Figure 2.1 Structure of Cu3(BTC)2 (a) [46], Cu(BDC) (b) [44], Cu2(BDC)2(DABCO)
Experimental
All reagents and starting materials were obtained commercially from Sigma-Aldrich and Merck, and were used as received without any further purification unless otherwise noted Nitrogen physisorption measurements were conducted using a Micromeritics 2020 volumetric adsorption analyzer system Samples were pretreated by heating under vacuum at 150 o C for 3 h A Netzsch Thermoanalyzer STA 409 was used for thermogravimetric analysis (TGA) with a heating rate of 10 o C/min under a nitrogen atmosphere Scanning electron microscopy studies were conducted on a S400 Scanning Electron Microscope (SEM) Transmission electron microscopy studies were performed using a JEOL JEM 1010 Transmission Electron Microscope (TEM) at 80 kV The material sample was dispersed on holey carbon grids for TEM observation
Elemental analysis with atomic absorption spectrophotometry (AAS) was performed on an AA-6800 Shimadzu Fourier transform infrared (FT-IR) spectra were obtained
41 on a Nicolet 6700 instrument, with samples being dispersed on potassium bromide pallets The chemisorption experiments were studied in a Micromeritics 2020 analyzer
For hydrogen temperature programmed reduction (H 2 -TPR), the sample was outgassed at 100 o C for 30 min with helium, then cooled down to room temperature, and exposed to 50 mL/min of 10% H 2 /Ar as the temperature ramped at 2.5 o C/min to 600 o C The amount of hydrogen consumption was determined from TCD signal intensities, which were calibrated using an Ag2O reference sample X-ray powder diffraction (XRD) patterns were recorded using a Cu Kα radiation source on a D8 Advance Bruker powder diffractometer
Nitrogen physisorption measurements, X-ray powder diffraction (XRD) patterns, Fourier transform infrared (FT-IR), Hydrogen temperature programmed reduction (H 2 - TPR) samples were measured at Vietnam National University (VNU)-Ho Chi Minh City (HCMC) Key Laboratory of Material Structure Analysis Inductively coupled plasma mass spectrometry (ICP-MS) samples were analyzed at Institute for Enviroment and Resources, Ho Chi Minh City University of Technology (HCMUT)- VNU Thermogravimetric analysis (TGA) samples were measured at Facutly of Material Technologies, HCMUT-VNU and The Center for Molecular and Nanoarchitecture (MANAR), VNU-HCM Scanning Electron Microscope (SEM) and Transmission Electron Microscope (TEM) samples were analyzed at National Institute Of Hygiene And Epidemiology, Hanoi Capital-Vietnam
Cu 3 (BTC) 2 was synthesized by a procedure similar to that previously reported in the literature [34, 118] In a typical preparation, a solid mixture of Cu(NO 3 ) 2 3H 2 O (2
.42g, 10 mmol) and 1,3,5-benzenetricarboxylic acid (H3BTC) (1.18 g, 5.6 mmol) was dissolved in a mixture of DMF (DMF = N,N′-dimethylformamide; 15 mL), ethanol (20 mL) and water (10 mL) The resulting solution was then distributed into five 20 mL vials The vials were heated at 85 o C in an isothermal oven for 24 h, yielding light blue crystals After cooling the vial to room temperature, the solid product was obtained by decanting with mother liquor and washed with DMF (3 x 10 mL) Solvent exchange was then carried out with methanol (3 x 10 mL) at room temperature The product was
42 then dried under vacuum at 170 o C for 6 h, yielding 0.96 g of Cu3(BTC)2 in the form of deep purple crystals (85 % based on 1,3,5-benzenetricarboxylic acid)
2.2.3 Synthesis of Cu 2 (BDC) 2 (DABCO)
The Cu2(BDC)2(DABCO) was prepared according to a slightly modified literature procedure [47, 57, 58, 119] In a typical preparation, a mixture of H 2 BDC (H 2 BDC 1,4-benzenedicarboxylic acid; 0.506 g, 3.1 mmol), DABCO (DABCO = 1,4- diazabicyclo[2.2.2]octane; 0.188 g, 1.67 mmol), and Cu(NO3)2ã3H2O (0.8 g, 3.3 mmol) was dissolved in DMF (80 mL) The mixture was stirred for 2 h, and the resulting solution was then distributed to eight 10 mL vials The vial was heated at 120 oC in an isothermal oven for 48 h, forming green crystals After cooling the vial to room temperature, the solid product was removed by decanting with mother liquor and washed with DMF (3 x 10 mL) Solvent exchange was carried out with methanol (3 x 10 mL) at room temperature The product was then dried at 140 o C for 6 h under vacuum, yielding 0.57 g of the metal-organic framework Cu 2 (BDC) 2 (DABCO) as light blue crystals (66% based on 1,4-benzenedicarboxylic acid)
2.2.4 Synthesis of Cu 2 (BPDC) 2 (BPY)
In a typical preparation [32, 61], a solid mixture of H 2 BPDC (H 2 BPDC = 4,4’- biphenyldicarboxylic acid; 0.630 g, 2.4 mmol), bpy (bpy = 4,4’-bipyridine; 0.198 g, 1.2 mmol), and Cu(NO3)2 3H2O (0.630 g, 2.4 mmol) was dissolved in a mixture of DMF (180 mL), pyridine (1.8 mL), and methanol (18 mL) The resulting solution was stirred at 70 o C for 5 min, and then distributed to twenty 20 mL vials The vials were then heated at 120 o C in an isothermal oven for 24 h After cooling the vials to room temperature, the solid product was removed by decanting with mother liquor and washed in DMF (3 x 20 mL) for 3 days Solvent exchange was carried out with methanol (3 x 20 mL) at room temperature for 3 days The material was then evacuated under vacuum at 140 o C for 6 h, yielding 0.605 g of Cu 2 (BPDC) 2 (BPY) in the form of green crystals (66 % based on 4,4’-biphenyldicarboxylic acid)
The Cu(BDC) was prepared according to a slightly modified literature procedure [52]
In a typical preparation, a solid mixture of H 2 BDC (H 2 BDC = 1,4-benzenedicarboxylic acid; 0.332 g, 2.0 mmol) and Cu(NO3)2ã3H2O (0.484 g, 2.0 mmol) was dissolved in DMF (40 mL), and the resulting solution was distributed to six 10 mL vials The vial was then heated at 130 o C in an isothermal oven for 48 h After cooling the vial to room temperature, the solid product was removed by decanting with mother liquor and washed in DMF (3 x 10 mL) for 3 days Solvent exchange was then carried out with dichloromethane (DCM) (3 x 10 mL) at room temperature for 3 days The material was then evacuated under vacuum at 160 o C for 6 h and stored in a desiccator, yielding 0.3 g of Cu(BDC) in the form of blue crystals (66% based on 1,4-benzenedicarboxylic acid).
Results and discussions
2.3.1 Synthesis and characterization of Cu 3 (BTC) 2
The synthetic route of the Cu 3 (BTC) 2 is described in Scheme 2.1 In this procedure, a solid mixture of Cu(NO3)2.3H2O and H3BTC was dissolved in a mixture of DMF, ethanol and water Then the solution was heated at 85 o C in an isothermal oven for 24 h to form light blue crystals After the crystals were exchanged solvents and activated, the desolvated Cu3(BTC)2 was yielded The synthesis yield was approximately 85 % based on H 3 BTC The characterization of the Cu 3 (BTC) 2 is discussed in the next paragraph
3Cu(NO3)2 + 2H3BTC + 3H2O → Cu3(BTC)2.3H2O + 6 HNO3
Scheme 2.1 Synthesis procedure of the Cu 3 (BTC) 2
44 Figure 2.2 X-ray powder diffractograms of the synthesized Cu3(BTC)2
The powder X-ray diffraction pattern of the synthesized Cu3(BTC)2 was shown in
Figure 2.2 The X-ray diffraction pattern of the Cu3(BTC)2 demonstrated the presence of the peaks at 2θ of approximately 6.5°, 7.5°, 9.5 o , 13.5° proving the highly crystallinity of the Cu3(BTC)2 The result was also similar to the simulated pattern previously reported in the literature [46] Elemental analysis by Inductively Couple Plasma mass spectrometry (ICP-MS) indicated the copper content in the Cu 3 (BTC) 2 was about 31 % This result showed only a slight change when compared with the calculated value of 31.5 % of copper content in the Cu 3 (BTC) 2 It could approved that the structure of the Cu 3 (BTC) 2 was successfully formed
45 Figure 2.3 FT-IR spectra of the Cu 3 (BTC) 2 (a) and 1,3,5- benzenetricarboxylic acid (b)
As seen in Figure 2.3, the FT-IR spectrum of H 3 BTC exhibited the stretching vibration of a C=O of the carboxylic acid at approximately 1721 cm -1 The FT-IR spectrum of Cu 3 (BTC) 2 exhibited a significant shift as compared to that of H 3 BTC when the presence of a strong peak at 1624 cm -1 , which was confirmed as the stretching vibration of the carboxylate ion It could be explained that the carboxylate ion, formed by the deprotonation of –COOH groups in H 3 BTC upon the reaction with copper (II) ions, exhibited a lower value for C=O stretching vibration when compared with the free carboxylic acid These results were in a good agreement with the literature [34]
46 Figure 2.4 SEM micrograph of the
Figure 2.5 TEM micrograph of the
Furthermore, morphology, size and regularity of the Cu3(BTC)2 sample were studied by Scanning electron microscopy (SEM) (Figure 2.4) and Transmission electron microscopy (TEM) (Figure 2.5) Similar to the previous literature [34, 50, 120], the SEM micrograph indicated Cu3(BTC)2 exhibited a cubic octahedral morphology
Meanwhile, the porous structure of the Cu 3 (BTC) 2 was also revealed in the TEM micrograph The BET surface areas of Cu3(BTC)2 were achieved approximately 1799 m 2 /g, while its Langmuir surface areas were achieved approximately 2007 m 2 /g, as calculated from nitrogen adsorption/desorption isotherm data (Fig S1) The values obtained are higher than those reported in literature [65, 66, 118] Nitrogen physisorption measurements revealed that the material would contain mainly micropores (diameter < 20 Å), with a median pore width of 6.1 Å being observed as calculated by the HK method (Fig S2)
47 Figure 2.6 TGA analysis of the Cu3(BTC)2
The thermal stability of the Cu3(BTC)2 was also examined by the thermalgravimetric analysis (TGA) The TGA profile in Figure 2.6 showed that a significant weight loss of the Cu3(BTC)2 started at 80 °C The initial weight loss of 5 %, occurring from 80°C to approximately 100 °C, corresponded well to the loss of ethanol, water solvent molecule per monomer The next remarkable decreasing in weight of 4.73 %, occurring from 100°C to approximately 310 °C, corresponded well to the loss of water, DMF solvent molecule per monomer At nearly 310 °C, the pyrolysis began to occur The thermal degradation proceeded until the structure of Cu3(BTC)2 was completely decomposed at about 370 °C with the weight loss of 37.16 % The mass percentage of the remained Cu 3 (BTC) 2 was about 45 %, corresponding with the copper oxide The TGA curve was comparable to the previous report [34, 50], and confirmed the high thermal stability of the resulting Cu 3 (BTC) 2
48 Figure 2.7 H2-TPR profile of the Cu3(BTC)2
The H 2 -TPR result revealed the nature of copper species within Cu 3 (BTC) 2 structure (Fig 2.7) There were two broad reduction peaks at 280 °C and 400 °C that could be attributed to the reduction of Cu 2+ and Cu + ions, respectively Although these assignments were previously reported in several copper-based catalytic systems in the literature [121, 122] , further investigations would be necessary to clarify the nature of copper sites in the MOFs structure
In conclusion, Cu 3 (BTC) 2 is one of the highly cited MOFs due to its relatively easy synthesis, excellent thermal stability, high surface area These properties enable it to be a potential candidate for catalysis [34, 50, 64-66, 120] In the next section, characterization of another copper based metal-organic framework such as Cu 2 (BDC) 2 (DABCO) is also reviewed
2.3.2 Synthesis and characterization of Cu 2 (BDC) 2 (DABCO)
The synthetic route of the Cu2(BDC)2(DABCO) is described in Scheme 2.2 In this procedure, a mixture of Cu(NO3)2.3H2O, H2BDC and DABCO was dissolved in DMF
Then the solution was heated at 120 o C in an isothermal oven for 48 h to form green crystals After the crystals were exchanged solvents and activated, the desolvated Cu2(BDC)2(DABCO)was yielded The synthesis yield was approximately 66 % based
49 on H2BDC The characterization of the Cu2(BDC)2(DABCO)is discussed in the next paragraph
2Cu(NO 3 ) 2 + 2H 2 BDC + DABCO → Cu 2 (BDC) 2 (DABCO) + 4HNO 3 Scheme 2.2 Synthesis procedure of the Cu2(BDC)2(DABCO)
Figure 2.8 X-ray powder diffractograms of the synthesized Cu 2 (BDC) 2 (DABCO)
PXRD pattern of the synthesized Cu 2 (BDC) 2 (DABCO) indicated the characteristic reflexed on 2 theta of 8, 9,12,13, 16 and 18 (Fig 2.8) The result was also similar to the previously reported PXRD pattern by Seki et al [47], Maes et al [48] and other groups [33, 57, 58, 119, 123] Besides, elemental analysis by Inductively Couple Plasma mass spectrometry (ICP-MS) indicated the copper content in the Cu 2 (BDC) 2 (DABCO) was about 21.5 % Compared with the calculated value of 22.4% of copper content in the Cu2(BDC)2(DABCO), although the result was slight change but it could be concluded that the structure of the Cu2(BDC)2(DABCO) was obtained
50 Figure 2.9 SEM micrograph of the
Figure 2.10 TEM micrograph of the
As expected, Figure 2.9 showed that SEM micrograph of Cu 2 (BDC) 2 (DABCO) revealed that well-shaped, high- quality cubic crystals were formed [33] Moreover, Figure 2.10 indicated that Cu 2 (BDC) 2 (DABCO) possesses a porous structure Based on SEM and TEM images, in conjunction with the PXRD pattern, confirmed that a crystalline material was achieved Moreover, Langmuir surface areas of Cu 2 (BDC) 2 (DABCO) were achieved approximately 1174 m 2 /g as calculated from nitrogen adsorption/desorption isotherm data (Fig S3) The Cu 2 (BDC) 2 (DABCO) contained mainly micropores with a median pore width of 6.3 Å as calculated by the HK method (Fig S4) Indeed, Achman et al [57] and Mishra et al [58] previously synthesized Cu2(BDC)2(DABCO), and surface areas of approximately 1400 m 2 /g was observed
51 Figure 2.11 FT-IR spectra of 1,4-benzenedicarboxylic acid (a), diazabicyclo[2.2.2]octane (b) and the Cu 2 (BDC) 2 (DABCO) (c)
As seen in Figure 2.11, the FT-IR spectrum of Cu 2 (BDC) 2 (DABCO) was significantly different to those of H 2 BDC and DABCO The presence of a strong peak at 1577 cm -1 was confirmed as the stretching vibration of the carboxylate ion, formed by the protonation of COOH groups in H 2 BDC upon the reaction with copper (II) ions It exhibited a lower value for C=O stretching vibration when compared with the free carboxylic acid Moreover, in the free DABCO, the strong peak appeared at wavenumber 1060 cm -1 corresponding to C–N bond but it exhibited a lower value in Cu2(BDC)2(DABCO) It could be explained that Cu ions linked to N in DABCO The result was similar to the previous literature by Tan and co-workers [119]
52 Figure 2.12 TGA analysis of the Cu2(BDC)2(DABCO)
Thermalgravimetric analysis (TGA) (Figure 2.12) indicated that a significant weight loss of the Cu2(BDC)2(DABCO) started at 50 °C The initial weight loss of 2 %, from 50 °C to approximately 200 °C, corresponded well to the loss of water and DMF solvent molecule per monomer From 300 °C, the pyrolysis began to occur The thermal degradation proceeded until the structure of Cu2(BDC)2(DABCO) was completely decomposed at about 440 °C with the weight loss of 63.23 % The copper oxide was about 35 % corresponding with the mass percentage of the remained Cu2(BDC)2(DABCO) (Figure 2.11) Indeed, Seki and co-workers [47] and Lee and co-workers [117] also reported that the Cu 2 (BDC) 2 (DABCO) was stable up over 300 °C
53 Figure 2.13 H2-TPR profile of the Cu2(BDC)2(DABCO)
Similar to Cu 3 (BTC) 2 , H 2 -TPR profile exhibited the nature of copper species within Cu2(BPDC)2(BPY) structure (Fig 2.13) The presence of two broad reduction peaks were at 350 °C and 390 °C could be signed to the reduction of Cu 2+ and Cu + ions, respectively [121, 122] Nonetheless, extra examinations would be needed to demonstrate the nature of copper sites in the MOFs structure
Based on the above results, it could be approved that Cu 2 (BDC) 2 (DABCO) exhibited thermal stability, easy synthesis and high surface area These properties enable it to be a potential candidate for catalysis In the next section, characterization of another copper based metal-organic framework such as Cu 2 (BPDC) 2 (BPY) is reviewed
2.3.3 Synthesis and characterization of Cu 2 (BPDC) 2 (BPY)
Conclusion
On the whole, the four Cu-MOFs such as Cu 3 (BTC) 2 , Cu 2 (BDC) 2 (DABCO), Cu 2 (BPDC) 2 (BPY) and Cu(BDC) were successfully synthesized and characterized by PXRD, FT-IR, TGA, H 2 TPR, ICP-MS and nitrogen physisorption measurements
The analysis of X-ray data revealed that the structures of Cu-MOFs were consistent with the simulated patterns Based on SEM micrograph, Cu3(BTC)2 appeared as octahedral crystals while Cu 2 (BDC) 2 (DABCO), Cu 2 (BPDC) 2 (BPY) and Cu(BDC) presented as well-shaped cubic crystals According to TEM micrograph and nitrogen
64 physisorption measurements, these materials possessed porous structures In addition, those materials were stable up over 300 °C (TGA results) FT-IR spectra of four Cu- MOFs showed the coordination of copper ions and organic linkers based on significant difference as compared to those of organic linkers Those results, showing a good agreement with previously literature, indicated that the structures of the desired Cu- MOFs and their properties were successfully formed
The potential open metal sites and high copper content in the structures of Cu-MOFs make them promising candidates for heterogeneous catalysts In the next chapter, the catalytic performance of Cu 3 (BTC) 2 , Cu 2 (BDC) 2 (DABCO), Cu 2 (BPDC) 2 (BPY) and Cu(BDC) on the CC, CN coupling reactions will be investigated
CATALYTIC STUDIES OF Cu 3 (BTC) 2 , Cu 2 (BDC) 2 (DABCO), Cu 2 (BPDC) 2 (BPY) AND Cu(BDC) ON CC AND Cu2(BDC)2(DABCO), Cu2(BPDC)2(BPY) AND Cu(BDC) ON CC AND
Introduction
The potential applications of propargylamine in optical materials, molecular devices, or pharmaceutical are well-recognized [124] Traditional routes to access these molecules often suffer from disadvantages such as hard conditions, low yields, and limited reaction scope [125] Nucleophilic addition of alkynyl Grignards to imines or enamines is example in which functional group tolerance is limited and low yields were observed in most cases [126, 127] Therefore, it is interesting to develop more convenient methods for propargylamine synthesis Recently, the most attractive synthetic route is the use of Mannich-type reaction, a three component procedure of terminal alkynes, formaldehyde, and secondary amines [128] Transition metals are often employed as catalysts for these two-step reactions Over the past few decades, many excellent reports have been described using various transition-metal catalysis including copper, gold, and silver [78-80] However, difficulties in removing catalysts contaminated in final products narrow the application of homogeneous catalytic systems, especially in pharmaceutical industry [129] As a consequent, a few supported reactions or reactions using heterogeneous catalysts have recently been demonstrated [40, 130-133] However, the aldehyde-free, oxidative Mannich reactions have not been previously reported under catalysis In addition, secondary amines such as piperidines, pyrrolidines, morpholines, and dialkylamines were starting materials, giving no opportunity to investigate the regioselectivity of the protocol Recently, Yu and co-workers developed a first CuI-catalyzed A 3 reaction of tetrahydroisoquinolines, aldehydes, and alkynes to form C1-alkynylated tetrahydroisoquinolines with high regioselectivity to the endo-yne-product (95%) [134] Although interesting results have been obtained for the transformation, the development of more environmentally benign approaches is still the target of further research in the near future To achieve greener processes, solid catalysts should be explored for the transformation with advantages in terms of the ease of handing, simple workup, recyclability and reusability [135]
Besides propargylamines, quinoxalines have merged as important intermediates commonly employed in the synthesis of numerous pharmaceutical candidates and
67 agrochemicals as well as a variety of functional organic materials [136-140]
Traditionally, these structures have been prepared by the acid-catalyzed condensation of 1,2-aryldiamines with 1,2-diketones [100, 141, 142] The synthesis protocol has been improved by using 1,2-diketone alternatives, such as epoxides [108], α- bromoketones [143, 144], and α-hydroxyketones [139, 145] Although the contamination of the desired products with transition metals or other solids would be minimized under heterogeneous catalysts conditions [101, 104, 115, 145-150], developing an efficient heterogeneous catalyst system for the quinoxaline synthesis still remains to be explored
As the previous reports, the common Cu-MOFs including Cu3(BTC)2, Cu 2 (BDC) 2 (DABCO), Cu 2 (BPDC) 2 (BPY) and Cu(BDC) exhibited high activity for many reactions due to their unsaturated open metal sites Their synthesis, characterization methods have already described in chapter 2 In this chapter, the catalytic performance of Cu 3 (BTC) 2 , Cu 2 (BDC) 2 (DABCO), Cu 2 (BPDC) 2 (BPY) and Cu(BDC) on the C–C, C–N coupling reactions will be discussed (Scheme 3 1 and Scheme 3.2)
Scheme 3.1 The synthesis of propargylamines
Scheme 3.2 The synthesis of quinoxaline
Experimental
All reagents and starting materials were obtained commercially from Sigma-Aldrich and Merck, and were used as received without any further purification unless otherwise noted Fourier transform infrared (FT-IR) spectra were obtained on a Nicolet 6700 instrument, with samples being dispersed on potassium bromide pallets X-ray powder diffraction (XRD) patterns were recorded using a Cu Kα radiation source on a D8 Advance Bruker powder diffractometer
Gas chromatographic (GC) analyses were performed using a Shimadzu GC 2010-Plus equipped with a flame ionization detector (FID) and an SPB-5 column (length = 30 m, inner diameter = 0.25 mm, and film thickness = 0.25 μm) For the reaction (1) and (2), the temperature program for GC analysis heated samples from 80 o C and held them at 80 o C for 0.5 min; heated them from 80 o C to 120 o C at 20 o C/min and held them at 120 o C for 1.40 min; then heated from 120 o C to 280 o C at 40 o C/min and held them at 280 o C for 2.5 min Inlet and detector temperatures were set constant at 280 o C n-
Hexadecane was used as an internal standard to calculate reaction conversions For the reaction (3), the temperature program for GC analysis held samples at 80 o C for 1 min; heated them from 80 to 280 o C at 35 o C/min; held them at 280 o C for 10 min Inlet and detector temperatures were set constant at 290 o C Diphenyl ether was used as an internal standard to calculate reaction conversions For the reaction (4), the temperature program for GC analysis heated samples from 120 o C to 180 o C at 40 oC/min and held them at 180 o C for 0.5 min; then heated from 180 o C to 280 o C at 50 oC/min and held them at 280 o C for 2 min Inlet and detector temperatures were set constant at 280 o C Diphenyl ether was used as an internal standard to calculate reaction conversions GC-MS analyses were performed using a Hewlett Packard GC-MS 5972 with a RTX-5MS column (length = 30 m, inner diameter = 0.25 mm, and film thickness = 0.5 μm) The temperature program for GC-MS analysis heated samples from 60 to 280 o C at 10 o C/min and held them at 280 o C for 2 min Inlet temperature was set constant at 280 o C MS spectra were compared with the spectra
69 gathered in the NIST library The 1 H and 13 C NMR were recorded on Bruker AV 500 and Bruker AV 300 spectrometers using residual solvent peak as a reference
X-ray powder diffraction (XRD) patterns, Fourier transform infrared (FT-IR), Gas chromatographic (GC) samples were measured at Vietnam National University (VNU)-Ho Chi Minh City (HCMC) Key Laboratory of Material Structure Analysis
Gas chromatography–mass spectrometry (GC-MS) samples were analyzed at Hoan Vu Scientific Ltd Ho Chi Minh City NMR samples were analyzed at Institute of Chemistry, Vietnam Academy of Science and Technology (VAST) and The Research Laboratories of Saigon High-Tech Park (SHTP Labs), Ho Chi Minh City-Vietnam
3.2.2 Catalytic studies on C C, C N cross coupling reactions
3.2.2.1 Catalytic studies of Cu 3 (BTC) 2 on C-C cross coupling reaction between N.N-dimethylanines and terminal alkynes (1)
In a typical experiment, a pre-determined amount of the Cu3(BTC)2 was added to the flask containing a mixture of phenylacetylene (0.11 mL, 1 mmol), N,N-dimethylaniline (0.25 mL, 2 mmol), tert-butyl hydroperoxide (TBHP) (70 % in water, 0.41 mL, 3 mmol) as an oxidant, and n-hexadecane (0.1 mL) as an internal standard in N,N- dimethylacetamide (DMA) (4 mL) under an argon atmosphere The catalyst amount was calculated based on the molar ratio of copper/phenylacetylene The reaction mixture was stirred at 120 o C for 150 min The reaction conversion was monitored by withdrawing aliquots from the reaction mixture at different time intervals, quenching with water (1 mL), drying over anhydrous Na2SO4, analyzing by GC with reference to n-hexadecane, and further confirming product identity by GC-MS, and 1 H NMR and
13C NMR To investigate the recyclability of the Cu 3 (BTC) 2 , the catalyst was filtered from the reaction mixture after the experiment, washed with copious amounts of DMF and ethanol, dried at 170 o C under vacuum in 6 h, and reused if necessary For the leaching test, a catalytic reaction was stopped after 25 min, analyzed by GC, and filtered to remove the solid catalyst The reaction solution was then stirred for a further 125 min Reaction progress, if any, was monitored by GC as previously described
3.2.2.2 Catalytic studies of Cu 2 (BDC) 2 (DABCO) on CC cross coupling reaction between N-methylanilines and terminal alkynes (2)
In a typical experiment, a pre-determined amount of the Cu2(BDC)2(DABCO) was added to the flask containing a mixture of phenylacetylene (0.11 mL, 1 mmol), N- methylaniline (0.22 mL, 2 mmol), tert-butyl hydroperoxide (TBHP) (70 % in water,
0.41 mL, 3 mmol) as an oxidant, and n-hexadecane (0.1 mL) as an internal standard in
N,N-dimethylacetamide (DMA) (4 mL) under an argon atmosphere The catalyst amount was calculated based on the molar ratio of copper/phenylacetylene The reaction mixture was stirred at 120 o C for 180 min The reaction conversion was monitored by withdrawing aliquots from the reaction mixture at different time intervals, quenching with water (1 mL), drying over anhydrous Na 2 SO 4 , analyzing by GC with reference to n-hexadecane, and further confirming product identity by GC-
MS, and 1 H NMR and 13 C NMR To investigate the recyclability of the Cu 2 (BDC) 2 (DABCO), the catalyst was filtered from the reaction mixture after the experiment, washed with copious amounts of DMF, dried at 140 o C under vacuum in 6 h, and reused if necessary For the leaching test, a catalytic reaction was stopped after 10 min, analyzed by GC, and filtered to remove the solid catalyst The reaction solution was then stirred for a further 170 min Reaction progress, if any, was monitored by GC as previously described
3.2.2.3 Catalytic studies of Cu 2 (BPDC) 2 (BPY) on CC cross coupling reaction from tetrahydrosioquinoline, benzaldehydes and terminal alkynes (3)
In a typical experiment, a mixture of phenylacetylene (0.11 mL, 1.0 mmol) and diphenyl ether (0.07 mL) as an internal standard in toluene (4 mL) was added into a 25 ml flask containing the pre-determining amount of Cu 2 (BPDC) 2 (BPY) catalyst The catalyst amount was calculated with respect to the copper/phenylacetylene molar ratio
The reaction mixture was stirred at 80 o C for 180 min Reaction conversion was monitored by withdrawing aliquots from the reaction mixture at different time intervals, quenching with water (1 mL) The organic components were then extracted into ethyl acetate (2 mL), dried over anhydrous Na2SO4, analyzed by GC with reference to diphenyl ether The product identity was further confirmed by GC-MS and NMR To investigate the recyclability of the Cu2(BPDC)2(BPY), the catalyst was
71 separated from the reaction mixture by simple centrifugation, washed with copious amounts of methanol, dried 140 o C under vacuum in 2 h, and reused if necessary For the leaching test, a catalytic reaction was stopped after 15 min, analyzed by GC, and centrifuged to remove the solid catalyst The reaction solution was then stirred for a further 165 min at 80 o C Reaction progress, if any, was monitored by GC as previously described
3.2.2.4 Catalytic studies of Cu(BDC) on CN cross coupling reaction between alpha-hydroxyacetophenone and phenyldiamines (4)
In a typical experiment, a pre-determined amount of Cu(BDC) was added to the flask containing a mixture of α-hydroxyacetophenone (0.136 g, 1.0 mmol), phenylenediamine (0.119 g, 1.1 mmol), and diphenylether (0.05 mL) as internal standard in toluene (4 mL) The catalyst amount was calculated based on the molar ratio of copper/α-hydroxyacetophenone The reaction mixture was stirred at 100 o C for 180 min Reaction conversion was monitored by withdrawing aliquots from the reaction mixture at different time intervals, quenching with ethylacetate (3 mL), drying over anhydrous Na 2 SO 4 , and analyzing by GC with reference to diphenylether The product identity was further confirmed by GC-MS, 1 H NMR, and 13 C NMR To investigate the recyclability of Cu(BDC), the catalyst was separated from the reaction mixture by simple filtration, washed with copious amounts of DMF, soaked in DMF, dried under vacuum at 140 o C for 2 h For the leaching test, a catalytic reaction was stopped after 30 min, analyzed by GC, and hot filtered to remove the solid catalyst
The reaction solution was then stirred for a further 150 min Reaction progress, if any, was monitored by GC as previously described.
Results and discussions
3.3.1 Catalytic studies of Cu 3 (BTC) 2 on C C cross coupling reaction (1)
The Cu 3 (BTC) 2 was assessed for its catalytic activity in the direct oxidative CC coupling reaction between N,N-dimethylaniline and phenylacetylene to form N- methyl-N-(3-phenylprop-2-ynyl)benzenamine as the principal product (Scheme 3.3)
72 Scheme 3.3 The direct oxidative C-C coupling reaction between N,N-dimethylaniline and phenylacetylene using Cu3(BTC)2 as catalyst
Initial studies addressed the effect of temperature on the conversion of phenylacetylene to N-methyl-N-(3-phenylprop-2-ynyl)benzenamine The direct CC coupling reaction was carried out at 5 mol % Cu3(BTC)2 catalyst in DMA, using two equivalents of N,N-dimethylaniline, in the presence of three equivalents of tert-butyl hydroperoxide as the oxidant, at room temperature, 100 o C, 110 o C, and 120 o C, respectively, for 150 min It was found that the transformation proceeded readily at 120 o C, affording 96 % conversion after 150 min As expected, decreasing the reaction temperature resulted in a significant drop in the reaction conversion, with 76 % and 56
% conversions being detected after 150 min for the reaction carried out at 110 o C and
100 o C, respectively (Fig 3.1) It should be noted that more than 99 % conversion was observed after 150 min for the direct CC coupling reaction carried out at 130 o C
However, the Cu3(BTC)2 catalyst was partially decomposed under this condition
Moreover, the direct CC coupling reaction could not occur at room temperature, with no trace amount of the product being detected after 150 min
Figure 3.1 Effect of temperature on reaction conversions Figure 3.2 Effect of catalyst amount on reaction conversions
In the first example of the propargylamine synthesis via a combination of sp 3 CH bond and sp CH bond activations and CC bond formations, Li and co-workers employed 5 mol % CuBr as catalyst for the transformation [94] Vogel and co-workers used 10 mol % FeCl2 as catalyst for the direct CC coupling reaction between 4-N,N- trimethylaniline and phenylacetylene [18] It was therefore decided to investigate the effect of catalyst amount on the reaction conversion The direct CC coupling reaction was carried out at 120 o C in DMA for 150 min, using two equivalents of N,N- dimethylaniline, in the presence of three equivalents of tert-butyl hydroperoxide as the oxidant, at 1 mol %, 3 mol %, and 5 mol % Cu3(BTC)2 catalyst, respectively No product was detected after 150 min in the absence of the Cu3(BTC)2, confirming the necessity of using the Cu-MOF as catalyst for the transformation It was found that the direct CC coupling reaction using 1 mol % catalyst proceeded with difficulty, though 65 % conversion was still observed after 150 min Increasing the catalyst amount led to an enhancement in the reaction rate, with 83 % and 96 % conversions being obtained after 150 min at the catalyst amount of 3 mol % and 5 mol %, respectively
(Fig 3.2) Moreover, it was observed that the reagent molar ratio also exhibited a slightly effect on the conversion of the direct CC coupling reaction using the Cu 3 (BTC) 2 catalyst Indeed, using more than two equivalents of N,N-dimethylaniline was not necessary for the transformation, while the reaction using one equivalent of the reagent afforded only 85 % conversion after 150 min (Fig 3.3)
TBHP in water TBHP in decane DTBP
N,N-dimethylaniline molar ratio on reaction conversions
Figure 3.4 Effect of oxidant on reaction conversions
Similar to other CC coupling transformations via direct CH bond functionalization
[68], the presence of at least one equivalent of an oxidant should be necessary for the direct oxidative CC coupling reaction between N,N-dimethylaniline and phenylacetylene using the Cu3(BTC)2 catalyst We therefore decided to investigate the effect of different oxidants on the reaction conversion, having employed several oxidants for the direct CC coupling reaction, including tert-butyl hydroperoxide in water, tert-butyl hydroperoxide in decane, di-tert-butyl peroxide (DTBP), cumyl hydroperoxide (CHP), hydrogen peroxide, and K2S2O8 The direct CC coupling reaction was carried out at 120 o C in DMA for 150 min, using two equivalents of N,N- dimethylaniline, in the presence of three equivalents of the oxidant, at 5 mol %
Cu 3 (BTC) 2 catalyst It was found that hydrogen peroxide and K 2 S 2 O 8 should not be used for the direct CC coupling reaction, as no trace amount of the desired product was detected after 150 min Tert-butyl hydroperoxide in decane exhibited the best performance for the transformation, with more than 99 % conversion being achieved after 150 min Moreover, it was observed that the reaction using tert-butyl hydroperoxide in decane could proceed with higher rate than that using tert-butyl hydroperoxide in water, though 96 % conversion was still obtained after 150 min for the latter case (Fig 3.4) Indeed, due to the high cost of tert-butyl hydroperoxide in decane, tert-butyl hydroperoxide in water was previously employed as the oxidant for several oxidative coupling transformations [35, 61, 151-153] Although the reaction
75 using cumyl hydroperoxide as the oxidant proceeded with high rate, a large amount of by-products were observed in the product mixture Furthermore, it was found that the concentration of the tert-butyl hydroperoxide also affected the rate of the direct CC coupling reaction, and using three equivalents of tert-butyl hydroperoxide was necessary for the transformation (Fig 3.5 and Fig 3.6) It should be noted that no CC coupling product was detected in the absence of the oxidant
Figure 3.5 Effect of oxidant concentration on reaction conversions
Figure 3.6 The selectivity of reaction with different oxidant concentrations on reaction conversions
DMA DMF DEF NMP Clorobenzene
Figure 3.7 Effect of different solvents on reaction conversions
Figure 3.8 The selectivity of reaction with different solvents on reaction conversions Investigate the effect of different solvents on the reaction conversion was conducted with DMA, NMP, DMF, DEF, chlorobenzene, o-xylene, respectively [154, 155] The
76 direct C–C coupling reaction was carried out at 120 o C for 150 min, using two equivalents of N,N-dimethylaniline, in the presence of three equivalents of tert-butyl hydroperoxide as the oxidant, at 5 mol % Cu 3 (BTC) 2 catalyst NMP was found to be not suitable for the direct C–C coupling reaction as a large amount of by-products were produced in the reaction mixture Indeed, it was found that N-(tert- butoxymethyl)-N-methylbenzenamine, and N-(tert-butoxymethyl)benzenamine were also produced as by-products due to the reaction between N,N-dimethylaniline and tert-butyl hydroperoxide [93] As mentioned, the reaction carried out in DMA could afford 96% conversion after 150 min The transformation also proceeded readily in either DMF or DEF, with 99 % and 95 % conversions being obtained after 150 min
However, GC analysis clearly indicated that the direct C–C coupling reaction carried out in DMA produced less by-product than the case of DMF or DEF It was observed that the reaction occurred with difficulty in chlorobenzene, affording 45 % conversion after 150 min O-xylene was also found to be unsuitable for the direct C–C coupling reaction using the Cu3(BTC)2 catalyst, with the coupling product being detected in trace amounts after 150 min (Fig 3.7 and Fig 3.8)
Cu2(BDC)2(DABCO) Cu2(BDC)2(BPY)
Figure 3.9 Leaching test indicated no contribution from homogeneous catalysis of active species leaching into reaction solution
Figure 3.10 Different Cu-MOFs catalysts for the direct CC coupling reactions
In order to investigate if active copper species dissolved from the solid Cu 3 (BTC) 2 catalyst could contribute to the total conversion, a control experiment was carried out
77 using a simple filtration during the course of the reaction The direct C-C coupling reaction was carried out in DMA at 120 o C for 150 min, using two equivalents of N,N- dimethylaniline, in the presence of three equivalents of tert-butyl hydroperoxide as the oxidant, at 5 mol % Cu3(BTC)2 catalyst After 25 min with a conversion of 66 % being detected, the Cu-MOF catalyst was separated from the reaction mixture by simple filtration The liquid reaction mixture was then transferred to a new reactor vessel, and magnetically stirred for an additional 125 min at 120 o C with aliquots being sampled at different time intervals, and analyzed by GC Experimental results showed that almost no further conversion was detected after the Cu3(BTC)2 catalyst was removed from the reaction mixture (Fig 3.9) These observations confirmed that the direct CC coupling reaction between between N,N-dimethylaniline and phenylacetylene could only proceed in the presence of the solid Cu 3 (BTC) 2 catalyst, and there should be no contribution from leached active copper species, if any, in the liquid phase
With the attempt of exploring heterogeneous catalysts for the direct CC coupling reaction between N,N-dimethylaniline and phenylacetylene, we also tested the catalytic activity of several MOFs for the transformation, including Cu2(BDC)2(BPY), Cu(BDC), Cu 3 (BTC) 2 , Cu 2 (BDC) 2 (DABCO), Co-MOF-74, and Ni 2 (BDC) 2 (DABCO)
These MOFs were synthesized by solvothermal methods, and characterized as previously reported [37, 38, 61, 119, 156, 157] The direct CC coupling reaction was carried out in DMA at 120 o C for 150 min, using two equivalents of N,N- dimethylaniline, in the presence of three equivalents of tert-butyl hydroperoxide as the oxidant, at 5 mol % MOF catalyst It was found that copper sites should be necessary for the direct CC coupling transformation between N,N-dimethylaniline and phenylacetylene Starting material decomposition was observed under Co-MOF-74,
Ni 2 (BDC) 2 (DABCO) and no product was detected after 150 min for the reaction using and as catalyst Indeed, in the first example of the direct CC coupling reaction between N,N-dimethylaniline and phenylacetylene, only copper salts were tested as catalyst [94] Vogel and co-workers employed FeCl2 as catalyst for the direct CC coupling reaction between 4,N,N-trimethylaniline and phenylacetylene [93] Other metals have not been reported as catalysts for this transformation Furthermore,
78 Cu2(BDC)2(BPY), Cu(BDC), and Cu2(BDC)2(DABCO) were also found to be active and could be used as alternative catalysts to the Cu 3 (BTC) 2 for the transformation (Fig
Conclusion
In summary, the catalytic activities of Cu3(BTC)2, Cu2(BDC)2(DABCO), Cu 2 (BDC) 2 (BPY) and Cu(BDC) for CC and CN coupling reactions were studied
113 While Cu3(BTC)2, Cu2(BDC)2(DABCO), Cu2(BDC)2(BPY) were used as heterogeneous catalysts for direct CC coupling reactions to form propargylamines, Cu(BDC) was employed as heterogeneous catalyst for direct CN coupling reaction to get quinoxalines
For reaction 1, based on the direct oxidative CC coupling reaction via CH functionalization between N,N-dimethylanilines and terminal alkynes, the Cu3(BTC)2 demonstrated a good heterogeneous catalyst The direct CC coupling transformation could proceed to 96 % conversion after 180 min in the presence of 5 mol % Cu3(BTC)2 catalyst at 120 o C The Cu3(BTC)2 exhibited similar activity to Cu 2 (BDC) 2 (BPY), Cu(BDC), and Cu 2 (BDC) 2 (DABCO) in the copper-catalyzed direct oxidative C-C coupling reaction
For reaction 2, the Cu2(BDC)2(DABCO) was used as a heterogeneous catalyst for the direct CC coupling reaction via CH functionalization between N-methylaniline and phenylacetylene Herein, tert-butyl hydroperoxide also served as the methylating reagent in the transformation, and N-methyl-N-(3-phenylprop-2-ynyl)benzenamine but not N-(3-phenylprop-2-ynyl)benzenamine was produced as the principal product The direct C-C coupling reaction could proceed to 95 % conversion with a selectivity of 80
% to N-methyl-N-(3-phenylprop-2-ynyl)benzenamine being achieved after 180 min
Similar to reaction 1 and reaction 2, based on CC coupling reaction, the
Cu 2 (BPDC) 2 (BPY) could be used as a heterogeneous catalyst for the copper-catalyzed A 3 reaction of tetrahydroisoquinoline, aldehydes, and alkynes to form C1-alkynylated tetrahydroisoquinolines (reaction 3) The Cu 2 (BPDC) 2 (BPY)-catalyzed C1- alkynylation reaction of tetrahydroisoquinoline offered high regioselectivity to the endo-yne-product, with more than 99 % of 2-benzyl-1-(phenylethynyl)-1,2,3,4- tetrahydroisoquinoline being achieved, leaving less than 1 % of 2-(1,3-diphenylprop-2-ynyl)-1,2,3,4-tetrahydroisoquinoline in the product mixture The Cu 2 (BPDC) 2 (BPY) also exhibited higher catalytic activity for the transformation than that of other Cu-MOFs such as Cu(BDC), Cu 2 (BDC) 2 (BPY), Cu 2 (EDB) 2 (BPY), Cu 3 (BTC) 2 and Cu 2 (BDC) 2 (DABCO) No product was detected for the reaction using other MOFs
114 including Mn(BDC), Co-MOF-74, Zn-IRMOF-61, and Ni2(BDC)2(DABCO), indicating the importance of copper sites for the transformation
Both reaction 1 and reaction 2, the nature of the solvent as well as the nature of the oxidant exhibited a significant effect on the reaction conversion and selectivity
Interestingly, the direct CC coupling transformations of reaction 1, 2 and 3 could only proceed in the presence of the solid Cu-MOF catalyst with no contribution from homogeneous leached active copper species
On the other words, based on CN coupling reaction, the Cu(BDC) was employed as a heterogeneous catalyst for the oxidative cyclization reaction between - hydroxyacetophenone and phenylenediamine derivatives to form 2-arylquinoxaline as the principal product (reaction 4) The simple optimal conditions involved the use of air atmosphere oxidant in toluene solvent at 100 o C in 3 h The Cu(BDC) exhibited higher catalytic activity in the quinoxaline synthesis reaction than that of others Cu- MOFs such as Cu3(BTC)2, MOF-118, and Cu2(BDC)2(DABCO), and higher than that of Mn(BDC), and Ni 2 (BDC) 2 (DABCO) The role of the atmospheric oxygen as the oxidant was confirmed Similar to reaction 1, 2, 3, the quinoxaline synthesis reaction could only proceed in the presence of the solid Cu(BDC) catalyst, and there was no contribution from leached active species present in the liquid phase
These Cu-MOFs could be separated from the reaction mixture by centrifugation or filtration, and could be recovered and reused several times without a significant degradation in catalytic activities Fresh Cu-MOFs and reused Cu-MOFs were also compared by PXRD and FT-IR
CONCLUSION
Summary of current work
The four Cu-MOFs consist of Cu 3 (BTC) 2 , Cu 2 (BDC) 2 (DABCO), Cu(BDC) and Cu2(BPDC)2(BPY) were synthesized and characterized by several techniques including XRD, SEM, TEM, FT-IR, TGA, ICP-MS, H 2 TPR and nitrogen physisorption measurements These Cu-MOFs are the highly cited MOFs due to their relatively easy synthesis by solvothermal methods, thermal stability, high surface area, open metal sites
The Cu 3 (BTC) 2 was used as a heterogeneous catalyst for the direct oxidative CC coupling reaction via CH functionalization between N,N- dimethylanilines and terminal alkynes (reaction 1) The direct CC coupling transformation could proceed to 96 % conversion after 180 min in the presence of 5 mol% Cu 3 (BTC) 2 catalyst at 120 o C
The Cu 2 (BDC) 2 (DABCO) was used as a heterogeneous catalyst for the direct CC coupling reaction via CH functionalization between N-methylaniline and phenylacetylene (reaction 2) Tert-butyl hydroperoxide also served as the methylating reagent in the transformation, and N-methyl-N-(3-phenylprop-2- ynyl)benzenamine but not N-(3-phenylprop-2-ynyl)benzenamine was produced as the principal product The direct C-C coupling reaction could proceed to 95
% conversion with a selectivity of 80 % to N-methyl-N-(3-phenylprop-2- ynyl)benzenamine being achieved after 180 min
The Cu 2 (BPDC) 2 (BPY) could be used as a heterogeneous catalyst for the copper-catalyzed A 3 reaction of tetrahydroisoquinoline, aldehydes, and alkynes to form C1-alkynylated tetrahydroisoquinolines (reaction 3) The Cu 2 (BPDC) 2 (BPY)-catalyzed C1-alkynylation reaction of tetrahydroisoquinoline offered high regioselectivity to the endo-yne-product, with more than 99 % of 2-benzyl-1-(phenylethynyl)-1,2,3,4-
116 tetrahydroisoquinoline being achieved, leaving less than 1 % of 2-(1,3- diphenylprop-2-ynyl)-1,2,3,4-tetrahydroisoquinoline in the product mixture
The Cu(BDC) was employed as a heterogeneous catalyst for the oxidative cyclization reaction between -hydroxyacetophenone and phenylenediamine derivatives to form 2-arylquinoxaline as the principal product (reaction 4) The simple optimal conditions involved the use of air atmosphere oxidant in toluene solvent at 100 o C in 3 h
These Cu-MOFs could be separated from the reaction mixture by centrifugation or filtration, and could be recovered and reused several times without a significant degradation in catalytic activities
Our results here confirm the feasibility of employing the Cu-MOFs as recyclable heterogeneous catalysts in the field of organic synthesis, expanding applications of these porous metal-organic frameworks from the gas separation and storage to catalysis The fact that available Cu-MOFs could be used as recyclable heterogeneous catalysts would be interested to the chemical industry.
Contributions of this thesis
The overarching goal of this thesis is to use four Cu-MOFs as catalysts for direct C–C and C–N coupling reactions to synthesize propargylamines and quinoxalines These compounds are found as the versatile intermediates for the synthesis of many nitrogen- containing biologically active compounds Herein, the following are the main research contributions of this thesis
Cu3(BTC)2, Cu2(BDC)2(DABCO), Cu2(BPDC)2(BPY) and Cu(BDC) were synthesized successfully by solvothermal methods These Cu-MOFs were characterized by characterized by PXRD, FT-IR, SEM, TEM, TGA, ICP-MS, H 2 TPR and nitrogen physisorption measurements
It is first time to use these Cu-MOFs as heterogeneous catalysts for the reactions: i) the Cu 3 (BTC) 2 was used as a heterogeneous catalyst for the direct oxidative CC coupling reaction via CH functionalization between N,N-
117 dimethylanilines and terminal alkynes (reaction 1); ii) the Cu2(BDC)2(DABCO) was used as a heterogeneous catalyst for the direct CC coupling reaction via
CH functionalization between N-methylanilines and terminal alkynes
(reaction 2); iii) the Cu 2 (BPDC) 2 (BPY) could be used as a heterogeneous catalyst for the copper-catalyzed A 3 reaction of tetrahydroisoquinoline, aldehydes, and alkynes (reaction 3); iv) the Cu(BDC) was employed as a heterogeneous catalyst for the oxidative cyclization reaction between α- hydroxyacetophenone and phenylenediamine derivatives (reaction 4)
Cu 3 (BTC) 2 , Cu 2 (BDC) 2 (DABCO), Cu 2 (BPDC) 2 (BPY) and Cu(BDC) showed high catalytic activities for those C–C and C–N coupling reactions
The optimal conditions of the reaction 1, 2, 3, 4 have been found
These Cu-MOFs can be reused and recycled several times without a significant degradation in catalytic activities Fresh Cu-MOFs and reused Cu-MOFs were also compared by PXRD and FT-IR
All major products from the reaction 1, 2, 3, 4 were confirmed by 1 H NMR and
13C NMR Besides, the isolated yields of those reactions were calculated
The most prominent point of this thesis the reaction of N-methylanilines and terminal alkynes (reaction 2) To the best of our knowledge, the reaction 2 has not been previously reported Based on direct C–C coupling reactions, it is contributed to provide a new way to get propargylamines with the aldehyde-free from secondary amines and terminal alkynes The mechanism of this reaction was also proposed
This thesis is based on the following papers:
1 Giao H Dang, Duy T Nguyen, Dung T Le, Thanh Truong, Nam T S Phan,
“Propargylamine synthesis via direct oxidative C-C coupling reaction between N,N-dimethylanilines and terminal alkynes under metal-organic framework catalysis”, Journal of Molecular Catalysis A: Chemical , 395 (2014) 300-306
2 Giao H Dang, Thinh T Dang, Dung T Le, Thanh Truong, Nam T S Phan,
“Propargylamine synthesis via sequential methylation and C-H functionalization of N-methylanilines and terminal alkynes under metal- organic-framwork Cu2(BDC)2(DABCO) catalysis”, Journal of Catalysis, 319
3 Giao H Dang, Yen H T Vu, Quoc A Dong, Dung T Le, Thanh Truong, Nam T S Phan, “Quinoxaline synthesis via oxidative cyclization reaction using metal-organic framework Cu(BDC) as an efficient heterogeneous catalyst”,
4 Giao H Dang, Dung T Le, Thanh Truong, Nam T S Phan, “C1-alkynylation of tetrahydroisoquinoline by A 3 reaction using metal-organic framework Cu 2 (BPDC) 2 (BPY) as an efficient heterogeneous catalyst”, Journal of Molecular Catalysis A: Chemical, 400 (2015) 162-169 (IF=3.679)
1 Giao H Dang, Thanh D Nguyen, Dung T Le, Thanh Truong, Nam T S Phan,
“Direct oxidative amidation of N, N-Dimethylanilines and anhydrides using metal-organic frameworks Cu2(EDB)2(BPY) as an efficient heterogeneous catalyst”, ChemPlusChem, 79 (2014) 1129-1137 (IF=3.242)
2 Lien T L Nguyen, Chi V Nguyen, Giao H Dang, Ky K A Le, Nam T S
Phan, “ Towards application of metal – organic frameworks in catalysis:
Friedel – Crafts acylation reaction over IRMOF-8 as an efficient hetergenerous catalyst”, Journal of Molecular Catalysis A: Chemical, 349 (2011) 28-35
3 Dang Huynh Giao, Nguyen Ngoc Phi, Le Thanh Dung, Phan Thanh Son Nam,
“Aza-Micheal addition reaction using MOF-143 as efficient heterogeneous catalyst under mild condition”, Journal of Catalysis and Adsorption, 2 (2013)
4 Dang Huynh Giao, Nguyen Truong, Le Thanh Dung, Phan Thanh Son Nam,
“MOF-143 as an efficient heterogeneous catalyst for Ullmann-type coupling reaction”, Journal of Catalysis and Adsorption, 2 (2013), 80-88
5 Le Thanh Dung, Dang Huynh Giao, Tran Thi Kim Xuyen, “Synthesis and characterization of the first linker containing both alkyne and nitro functional groups as precursor for the construction of new functionalized MOFs”, Journal of Chemistry, 51 (2C) (2013), 717-723
6 Le Thanh Dung, Dang Huynh Giao, Nguyen Tran Thanh Tai, Le Dang Phuong Thao, “New linkers containing alkyne and amine functionalities as precursors for the construction of new functionalized MOFs: synthesis and characterization”, Journal of Chemistry, 51 (2AB) (2013), 302-307
7 Le Thanh Dung, Dang Huynh Giao, Cao Tuyet Van, “Carboxylate ligands containing pyridinium groups- versitile linkers in construction of new MOFs : One – pot synthesis and characterization”, Journal of Chemistry, 49 (2ABC)
8 Le Thanh Dung, Dang Huynh Giao, Do Dang Thuan, Tong Thanh Danh,
“Fexible zwitterionic ligands – potential linkers for construction of new MOFs : synthesis and characterization” , Journal of Science and Technology, 49 (5A)
9 Le Thanh Dung, Huynh Tan Chien, Huynh Thi Nhu Quynh, Dang Huynh Giao,
“Carboxylic ligands containing amide groups– potential linkers for construction of new MOFs: synthesis and characterization”, , Journal of Science and Technology , 49 (3A) (2011) 240-246
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Synthesis and characterization of Cu-MOFs Cu 3 (BTC) 2 :
Figure S1 Nitrogen adsorption/desorption isotherm of the Cu3(BTC)2 Adsorption data are shown as closed circles and desorption data as open circles
Figure S2 Pore size distribution of the Cu3(BTC)2
BDC) 2 (DABCO)
Figure S3 Nitrogen adsorption/desorption isotherm of the Cu 2 (BDC) 2 (DABCO)
Adsorption data are shown as closed circles and desorption data as open circles
Figure S4 Pore size distribution of the Cu 2 (BDC) 2 (DABCO)
BPDC) 2 (BPY)
Figure S5 Nitrogen adsorption/desorption isotherm of the Cu2(BPDC)2(BPY)
Adsorption data are shown as closed circles and desorption data as open circles
Figure S6 Pore size distribution of the Cu2(BPDC)2(BPY)
Figure S7 Nitrogen adsorption/desorption isotherm of the Cu(BDC) Adsorption data are shown as closed circles and desorption data as open circles
Figure S8 Pore size distribution of the Cu(BDC)
Catalytic studies on C-C and C-N coupling reactions Reaction (1)
137 Figure S9 1 H NMR spectra a) and 13 C NMR b) of N-methyl-N-(3-phenylprop-2- nyl)benzenamine in CDCl 3
N- methyl- N -(3-phenylprop-2-ynyl)benzenamine Phenylacetylene (0.11 mL,
1.0 mmol), N,N-dimethylaniline (0.22 mL, 2.0 mmol), Cu 3 (BTC) 2 (0.010g, 5 mol%), tert-butyl hydroperoxide (0.41 mL, 3.0 mmol), N,N-Dimethylacetamide (4 mL) After chromatography (diethyl ether/hexane = 1:20), 175 mg yellow oil was obtained (79
%) R f = 0.30 1 H NMR (500 MHz, CDCl 3 , ppm): δ = 7.37-7.35 (m, 2H), 7.29-7.24 (m, 5H), 6.91 (d, J=8.5 Hz, 2H), 6.81 (t, J=7.3, 1H), 4.26 (s, 2H), 3.03 (s, 3H) 13 C NMR (125 MHz, CDCl 3 , ppm): δ = 149.3, 131.8, 129.1, 128.2, 128.1, 123.0, 118.1, 114.4,
139 Figure S10 1 H NMR spectra a) and 13 C NMR b) of N-(3-(4-methoxyphenyl)prop-2- yn-1-yl)-N-methylaniline in CDCl3
N -(3-(4-methoxyphenyl)prop-2-yn-1-yl)- N -methylaniline 4-ethynylanisole (0.13 mL, 1.0 mmol), N,N-dimethylaniline (0.22 mL, 2.0 mmol), Cu 3 (BTC) 2 (0.010g, 5 mol%), tert-butyl hydroperoxide (0.41 mL, 3.0 mmol), N,N-Dimethylacetamide (4 mL) After chromatography (diethyl ether/hexane = 1:20), 203 mg pale white solid was obtained (81 %) R f = 0.26 1 H NMR (500 MHz, CDCl 3 , ppm): δ = 7.31-7.24 (m, 4H), 6.90 (dd, J=8.0 Hz, J=1.0 Hz, 2H), 6.86-6.76 (m, 3H), 4.23 (s, 2H), 3.76 (s, 3H), 3.01 (s, 3H) 13 C NMR (125 MHz, CDCl 3 , ppm): δ = 159.4, 149.4, 133.1, 129.0, 118.0, 115.2, 114.3, 113.8, 84.0, 83.5, 55.2, 43.3, 38.6
141 Figure S11 1 H NMR spectra a) and 13 C NMR b) of N-methyl-N-(3-(p-tolyl)prop-2-yn-
N- methyl- N -(3-(p-tolyl)prop-2-yn-1-yl)aniline p-Tolylacetylene (0.11 mL, 1.0 mmol), N,N-dimethylaniline (0.22 mL, 2.0 mmol), Cu 3 (BTC) 2 (0.014g, 5 mol%), tert-butyl hydroperoxide (0.41 mL, 3.0 mmol), N,N-Dimethylacetamide (4 mL) After chromatography (diethyl ether/hexane = 1:15), 176 mg yellow oil was obtained (75
J=8.0 Hz, 2H), 6.90 (dd, J=8.0 Hz, J=1.0 Hz, 2H), 6.80 (t, J=7.8 Hz, 1H), 4.24 (s, 2H),
143 Figure S12 1 H NMR spectra a) and 13 C NMR b) of N-methyl-N-(non-2-yn-1- yl)aniline in CDCl 3
N- methyl-N-(non-2-yn-1-yl)aniline 1-octyne (0.15 mL, 1.0 mmol), N,N- dimethylaniline (0.22 mL, 2.0 mmol), Cu 3 (BTC) 2 (0.010g, 5 mol%), tert-butyl hydroperoxide (0.41 mL, 3.0 mmol), N,N-Dimethylacetamide (4 mL) After chromatography (used hexane as eluent), 131 mg yellow oil was obtained (57 %) R f 0.3 1 H NMR (500 MHz, CDCl 3 , ppm): δ = 7.26-7.25 (m, 2H), 6.85 (d, J=8.0 Hz, 2H), 6.78 (t, J=7.5 Hz, 1H), 4.00 (s, 2H), 2.95 (s, 3H), 2.14-2.11 (m, 2H), 1.45-1.42 (m, 2H), 1.33-1.21 (m, 6H), 0.86 (t, J=7.0 Hz , 3H) 13 C NMR (125 MHz, CDCl 3 , ppm): δ
144 Figure S13 1 H NMR spectra of N, 4-dimethyl-N-(3-phenylprop-2-yn-1-yl)aniline in
N ,4-dimethyl- N -(3-phenylprop-2-yn-1-yl)aniline Phenylacetylene (0.11 mL, 1.0 mmol), 4,N,N-Trimethylaniline (0.29 mL, 2.0 mmol), Cu 3 (BTC) 2 (0.010g, 5 mol%), tert-butyl hydroperoxide (0.41 mL, 3.0 mmol), N,N-Dimethylacetamide (4 mL) After chromatography (diethyl ether/hexane = 1: 15), 176 mg yellow oil was obtained (75 %) R f =0.37 1 H NMR (300 MHz, CDCl 3 , ppm): δ = 7.38 (dd, J=6.8 Hz,
145 Figure S14 1 H NMR spectra of 4-bromo-N-methyl-N-(3-phenylprop-2-yn-1-yl)aniline in CDCl3
4-bromo- N -methyl- N -(3-phenylprop-2-yn-1-yl)aniline Phenylacetylene (0.11 mL, 1.0 mmol), 4-bromo-N,N-dimethylaniline (0.24 mL, 2.0 mmol), Cu3(BTC)2
(0.010g, 5 mol%), tert-butyl hydroperoxide (0.41 mL, 3.0 mmol), N,N-
Dimethylacetamide (4 mL) After chromatography (dichloromethane/ hexane = 1: 2), 165 mg yellow oil was obtained (55 %) R f = 0.27 1 H NMR (300 MHz, CDCl3, ppm): δ = 7.38-7.27 (m, 7H), 6.81-6.76 (m, 2H), 4.24 (s, 2H), 3.02 (s, 3H)
Figure S15 Effect of temperature on the reaction conversion (a) and selectivity (b)
Figure S16 Effect of catalyst amount on reaction conversion (a) and selectivity (b)
TBHP TBHP in decane DTBP
Figure S18 Effect of oxidant on reaction conversions (a) and selectivity (b)
Figure S17 Effect of phenylacetylene: N-methylaniline molar ratio on reaction conversions (a) and selectivity (b)
149 Figure S19 1 H NMR spectra a) and 13 C NMR b) of N-methyl-N-(3-phenylprop-2- nyl)benzenamine in CDCl3
N- methyl- N -(3-phenylprop-2-ynyl)benzenamine (A) Phenylacetylene (0.11 mL, 1.0 mmol), N-Methylaniline (0.22 mL, 2.0 mmol), Cu2(BDC)2(DABCO) (0.014g, 5 mol%), tert-butyl hydroperoxide (0.41 mL, 3.0 mmol), N,N-Dimethylacetamide (4 mL) After chromatography (diethyl ether/hexane = 1:20), 144 mg yellow oil was obtained (65 %) R f = 0.30 1 H NMR (500 MHz, CDCl3, ppm): δ = 7.37-7.35 (m, 2H), 7.29-7.24 (m, 5H), 6.91 (d, J=8.5 Hz, 2H), 6.81 (t, J=7.3, 1H), 4.26 (s, 2H), 3.03 (s,
20 mmol scale reaction: Phenylacetylene (2.20 mL, 20 mmol), N-Methylaniline (4.40 mL, 40 mmol), Cu2(BDC)2(DABCO) (0.28 g, 5 mol%), tert-butyl hydroperoxide (8.20 mL, 60 mmol), N,N-Dimethylacetamide (80 mL) After chromatography (diethyl ether/hexane = 1:20), 2.74 g yellow oil was obtained (63 %)
151 Figure S20 1 H NMR spectra a) and 13 C NMR b) of N-(3-phenylprop-2- nyl)benzenamine in CDCl3
N -(3-phenylprop-2-ynyl)benzenamine (B) Phenylacetylene (0.11 mL, 1.0 mmol), N-Methylaniline (0.22 mL, 2.0 mmol), Cu 2 (BDC) 2 (DABCO) (0.014g, 5 mol%), tert-butyl hydroperoxide (0.41 mL, 3.0 mmol), N,N-Dimethylacetamide (4 mL) After chromatography (diethyl ether/hexane = 1:20), 29 mg yellow oil was obtained (14 %) R f = 0.27 1 H NMR (500 MHz, CDCl3, ppm): δ = 7.40-7.38 (m, 2H), 7.29-7.27 (m, 3H), 7.24-7.21 (m, 2H), 6.80-6.77 (m, 1H), 6.74-6.72 (m, 1H), 4.15 (s, 2H), 4.00-3.90 (s, 1H) 13 C NMR (125 MHz, CDCl3, ppm): δ = 147.1, 131.7, 129.2,
20 mmol scale reaction: Phenylacetylene (2.20 mL, 20 mmol), N-Methylaniline (4.40 mL, 40 mmol), Cu2(BDC)2(DABCO) (0.28 g, 5 mol%), tert-butyl hydroperoxide (8.20 mL, 60 mmol), N,N-Dimethylacetamide (80 mL) After chromatography (diethyl ether/hexane = 1:20), 0.54 g yellow oil was obtained (13 %)
153 Figure S21 1 H NMR spectra a) and 13 C NMR b) of N-(3-(4-methoxyphenyl)prop-2- yn-1-yl)-N-methylaniline in CDCl3
N -(3-(4-methoxyphenyl)prop-2-yn-1-yl)- N -methylaniline 4-ethynylanisole (0.13 mL, 1.0 mmol), N-Methylaniline (0.22 mL, 2.0 mmol), Cu2(BDC)2(DABCO) (0.014g, 5 mol%), tert-butyl hydroperoxide (0.41 mL, 3.0 mmol), N,N-
Dimethylacetamide (4 mL) After chromatography (diethyl ether/hexane = 1:20), 181 mg pale white solid was obtained (72 %) R f = 0.26 1 H NMR (500 MHz, CDCl3, ppm): δ = 7.31-7.24 (m, 4H), 6.90 (dd, J=8.0 Hz, J=1.0 Hz, 2H), 6.86-6.76 (m, 3H),
155 Figure S22 1 H NMR spectra a) and 13 C NMR b) of N-methyl-N-(3-(p-tolyl)prop-2-yn-
N- methyl- N -(3-(p-tolyl)prop-2-yn-1-yl)aniline p-Tolylacetylene (0.11 mL, 1.0 mmol), N-Methylaniline (0.22 mL, 2.0 mmol), Cu 2 (BDC) 2 (DABCO) (0.014g, 5 mol%), tert-butyl hydroperoxide (0.41 mL, 3.0 mmol), N,N-Dimethylacetamide (4 mL) After chromatography (diethyl ether/hexane = 1:15), 167 mg yellow oil was obtained (71 %) R f = 0.43 1 H NMR (500 MHz, CDCl 3 , ppm): δ = 7.28-7.25 (m, 4H), 7.06 (d, J=8.0 Hz, 2H), 6.90 (dd, J=8.0 Hz, J=1.0 Hz, 2H), 6.80 (t, J=7.8 Hz, 1H), 4.24 (s, 2H), 3.03 (s, 3H), 2.31 (s, 3H) 13 C NMR (125 MHz, CDCl 3 , ppm): δ = 149.4,
157 Figure S23 1 H NMR spectra a) and 13 C NMR b) of N-methyl-N-(non-2-yn-1- yl)aniline in CDCl 3
N- methyl- N -(non-2-yn-1-yl)aniline 1-octyne (0.15 mL, 1.0 mmol), N-
Methylaniline (0.22 mL, 2.0 mmol), Cu 2 (BDC) 2 (DABCO) (0.014g, 5 mol%), tert- butyl hydroperoxide (0.41 mL, 3.0 mmol), N,N-Dimethylacetamide (4 mL) After chromatography (used hexane as eluent), 133 mg yellow oil was obtained (58 %) R f 0.3 1 H NMR (500 MHz, CDCl 3 , ppm): δ = 7.26-7.25 (m, 2H), 6.85 (d, J=8.0 Hz, 2H), 6.78 (t, J=7.5 Hz, 1H), 4.00 (s, 2H), 2.95 (s, 3H), 2.14-2.11 (m, 2H), 1.45-1.42 (m, 2H), 1.33-1.21 (m, 6H), 0.86 (t, J=7.0 Hz , 3H) 13 C NMR (125 MHz, CDCl 3 , ppm): δ
158 Figure S24 1 H NMR spectra of 4-methoxy-N-methyl-N-(3-phenylprop-2-yn-1- yl)aniline in CDCl3
4-methoxy- N -methyl-N-(3-phenylprop-2-yn-1-yl)aniline Phenylacetylene (0.11 mL, 1.0 mmol), N-methyl-p-anisidine (0.274g, 2.0 mmol), Cu 2 (BDC) 2 (DABCO) (0.014g, 5 mol%), tert-butyl hydroperoxide (0.41 mL, 3.0 mmol), N,N-Dimethylacetamide (4 mL) After chromatography (ethyl acetate/hexane
= 1: 9), 181 mg yellow oil was obtained (72 %) R f =0.27 1 H NMR (300 MHz, CDCl3, ppm): δ = 7.40-7.28 (m, 5H), 6.97-6.86 (m, 4H), 4.19 (s, 2H), 3.79 (s, 3H), 2.98 (s, 3H)
159 Figure S25 1 H NMR spectra of 4-chloro-N-methyl-N-(3-phenylprop-2-yn-1- yl)aniline in CDCl 3
4-chloro- N -methyl- N -(3-phenylprop-2-yn-1-yl)aniline Phenylacetylene (0.11 mL, 1.0 mmol), 4-cloro-N-Methylaniline (0.24 mL, 2.0 mmol), Cu2(BDC)2(DABCO) (0.014g, 5 mol%), tert-butyl hydroperoxide (0.41 mL, 3.0 mmol), N,N-Dimethylacetamide (4 mL) After chromatography (diethyl ether/ hexane
= 1: 15), 196 mg yellow oil was obtained (77 %) R f = 0.43 1 H NMR (300 MHz, CDCl3, ppm): δ = 7.38 (dd, J=6.6 Hz, J=3.0 Hz, 2H), 7.29 -7.22 (m, 5H), 6.84 (d, J=9.3 Hz, 2H), 4.25 (s, 2H), 3.03 (s, 3H)
161 Figure S26 1 H NMR a) and 13 C NMR spectra b) of 2-benzyl-1-(phenylethynyl)-
2-benzyl-1-(phenylethynyl)-1,2,3,4-tetrahydroisoquinoline Phenylacetylene (0.11 mL, 1.0 mmol), Benzaldehyde (0.11 mL, 1.1 mmol), Tetrahydroisoquinoline (0.141 mL, 1.1 mmol), Cu2(BPDC)2(BPY) (0.020g, 5 mol%), toluene (4 mL) After chromatography (ethyl acetate/hexane = 1:20), 281mg colorless oil was obtained (87
%) R f = 0.30 1 H NMR (500 MHz, CDCl 3 , ppm): δ = 7.47-7.42 (m, 4H), 7.33 (t, J=7.5 Hz, 2H), 7.29-7.22 (m, 5H), 7.18-7.11 (m, 3H), 4.79 (s, 1H), 3.95 (d, J.0 Hz, 1H),
3.91 (t, J.0 Hz, 1H), 3.11-2.99 (m, 2H), 2.84-2.77 (m, 2H) 13 C NMR (125 MHz, CDCl 3 , ppm): δ = 138.3, 135.5, 134.1, 131.8, 129.3, 129.0, 128.3, 128.2, 128.0, 127.8, 127.2, 126.9, 125.8, 123.3, 87.5, 86.8, 59.6, 54.4, 45.8, 29.0
162 Figure S27 HMBC spectrum of 2-benzyl-1-(phenylethynyl)-1,2,3,4- tetrahydroisoquinoline in CDCl 3
Cu(BDC) CuCl2.2H2O CuCl Cu(NO3)2
Figure S28 Different copper salts as catalyst for the quinoxaline synthesis reaction