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Author’s Accepted Manuscript A Rapid Screening Platform for Catalyst Discovery in Azide–Alkyne Cycloaddition by ICP-MS/MS Qian He, Jia Wang, Yuxiang Mo, Chao Wei, Xiang Fang, Xing Zhi, Sichun Zhang, Xinrong Zhang www.elsevier.com/locate/talanta
PII: DOI: Reference:
S0039-9140(16)30958-4 http://dx.doi.org/10.1016/j.talanta.2016.12.014 TAL17104
To appear in: Talanta Received date: 24 October 2016 Revised date: 1 December 2016 Accepted date: 6 December 2016 Cite this article as: Qian He, Jia Wang, Yuxiang Mo, Chao Wei, Xiang Fang, Xing Zhi, Sichun Zhang and Xinrong Zhang, A Rapid Screening Platform for Catalyst Discovery in Azide–Alkyne Cycloaddition by ICP-MS/MS, Talanta, http://dx.doi.org/10.1016/j.talanta.2016.12.014 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
A Rapid Screening Platform for Catalyst Discovery in Azide–Alkyne Cycloaddition by ICP-MS/MS Qian He1, Jia Wang2, Yuxiang Mo2, Chao Wei3, Xiang Fang3, Xing Zhi1, Sichun Zhang1, Xinrong Zhang1* 1 Department of Chemistry, Tsinghua University, Beijing 100084, China 2 Department of Physics, Tsinghua University, Beijing 100084, China 3 National Institute of Metrology, Beijing 100029, China * Corresponding author email: [email protected]
ABSTRACT We developed a rapid high-throughput screening platform using a modified ICP-MS/MS system for monovalence metal ions catalysts discovery in azide–alkyne cycloaddition. Among the ten monovalence metal ions in the first row of periodic table containing Sc+, Ti+, V+, Cr+, Mn+, Fe+, Co+, Ni+, Cu+, and Zn+, five monovalence metal ions of Sc+, Co+, Ni+, Cu+ and Zn+ ions show relatively stronger catalytic activities than others. The catalytic mechanism of Sc+, Co+ and Ni+ ions is similar to the Cu+ ions, but Zn+ ions take a different catalytic route. A yields range of 77%-98% for azide-alkyne cycloaddition was achieved with Sc+, Co+, Ni+, Cu+ and Zn+ ions as catalyst, respectively by using a UV laser ablation reactor in 20 min, notable that the yields of Co+ and Sc+ ions were even higher than the common catalyst of Cu+ ions. The proposed platform would be used not only for catalyst discovery in azide-alkyne cycloaddition, but also for the discovery of single atom/ion catalysts in other organic reactions. Keywords: azide–alkyne cycloaddition • catalyst • high-throughput screening • ICP-MS/MS • monovalence metal ions
1
1. Introduction In the past, the azide-alkyne cycloaddition[1] required high temperatures and resulted in a mixture of 1,4 and 1,5 regioisomers [2,3]. To solve this problem, Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) was therefore introduced by the Meldal and the Sharpless laboratories independently in 2002 [4,5]. This CuAAC reaction succeeded with high yields, purity and reaction rate (up to 107 times) over a broad temperature range (0-160°C)[6] thus obtained the widespread application in industry. Along with the great success of CuAAC, scientists have continued their efforts attempted to search other metal catalysts with higher catalytic activity than Cu(I) ions. Many new catalysts have been discovered for the azide-alkyne cycloaddition in recent years. They could be down to three categories briefly: the noble metals (Ru [7, 8], Pd [9], Pt [9], Au [10, 11], Ag [12-16], and Ir[17, 18]), the rare earth metals (Sm [19], Nd [19], Y [19], Gd [19], and Sc[20]) and the other transition metals (Ni[9,21] and Zn[22,23]). For the noble metals, whether using [Cp*RuCl] [7], nanoporous titania-supported gold nanoparticles [10], or Ag(OAc)[12] as catalyst, the yields of triazole were all satisfactory with the highest yields nearly 100%. Despite the highly catalytic activities of the noble metals, the high cost of them limits their widely application in industry. For the rare earth metals, however, the highest catalytic yields of Sm, among the four metals of Sm, Nd, Y and Gd in Ln[N(SiMe3)2]3 form, were found no more than 80% without the additive [19]. For the other transition metals, the catalytic activity of NiCl2 coupling at 80 °C was demonstrated at least 10 times slower than that of CuBr catalyzed reaction at room temperature [9]. And for ZnEt2 as catalyst, the yields of 1,5-triazole were found still no more than 76% among 21 examples [22]. In our preliminary study, we found some monovalence metal ions offer higher catalytic activities than Cu(I) ions in azide-alkyne cycloaddition. However, these monovalence metal ions are unstable under ordinary chemical conditions that kept the scientists from reaching their discovery as new catalysts. Herein, we established a 2
high-throughput platform for rapid screening unstable monovalence metal catalysts in azide-alkyne cycloaddition through a modified ICP-MS/MS system. Ten unstable monovalence metal ions in the first row of periodic table, containing 45Sc+, 48Ti+, 51V+, 52
Cr+, 55Mn+, 54Fe+, 59Co+, 58Ni+, 63Cu+, and 64Zn+ were studied as a proof-of-principle
experiment, respectively. Moreover, the metal related intermediates were successfully observed to learn the chemical mechanisms. This proposed platform would be used not only for catalyst discovery in azide-alkyne cycloaddition, but also for the discovery of single atom/ion catalysts in other organic reactions.
2. Experimental Section 2.1 Chemicals. The stock standard solution of Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, and Zn were purchased from National Research Center for Standard Materials (Beijing, China). Working standard solution was prepared daily by stepwise dilution of the stock solutions with 1% (v/v) nitric acid. Phenylacetylene, 4-ethynyl-N,N-dimethylaniline and
benzylazide
were
purchased
from
Alfa
Aesar
(Shanghai,
China).
Phenylacetylene-D was purchased from Santa Cruz (USA). Acetonitrile and dichloromethane (chromatographical grade) purchased from Mreda (USA) were used as the solvents. Acetic acid (guarantee grade) purchased from Sinopharm Chemical Reagent Co., Ltd (Beijing, China) was used as the accelerated agent for the AAC reaction [24]. Triethylamine (analytical grade) purchased from J&K Scientific (Beijing, China) was used as the base to accelerate the AAC reaction [25]. Alkynyl analogy of [C42H28IrN4]+ synthesized by our lab was used as the internal standard. 2.2 Materials. The pure nickel, zinc, iron, copper, cobalt, scandium and silicon sample plates (100×100×0.1mm, 99.99%) were all purchased from Jinjia metal materials co., ltd (Hebei, China). These plates were pre-cut into the shape of a ship to hold the reactants solution and ultrasonicated in 1:1 methanol/water for several minutes before use. 2.3 Apparatus A triple quadrupole ICP–MS/MS instrument (Agilent 8800, Japan) was chosen 3
in this work. The set-up of the modified ICP-MS/MS system and the operational parameters of the instrument used in this work were similar to our previous study [26]. Figure 1 showed the schematic of the modified ICP-MS/MS platform. The metal ions with different valences in solution were introduced into the ICP ion source through a nebulizer to produce continuous and gaseous monovalence metal ions, which were acted as the catalyst in this study. Each isotope of the monovalence metal ions were selected by the first mass analyzer (Q1) and then introduced to the collision reaction cell (ORS) to meet the reactants introduced from another inlet of the ORS. Once the final product and the intermediates formed in the ORS, they were separated by the second mass analyzer (Q2) and detected immediately. All the processes were accomplished within a few milliseconds and controlled at 10-3–10-4 Pa under oxygen-free conditions. An Nd–Yag (Spectra Physics, Pro 290, 20 Hz) pumped dye laser system with sum frequency unit (Sirah, Cobra-Stretch) was used to prepare the UV laser beam (255 nm). The laser beam was focused onto the sample by a quartz lens (f=100 mm). A linear ion trap quadrupole ESI-MS(/MS) instrument (Thermo Scientific, San Jose CA) was used. Glass capillaries were pulled by P-2000 (Sutter Instrument CO.) and cut manually to make the emitter (tip O.D. = 15~20 μm, observed by a microscope, YX20L20, Dayueweijia, Beijing Co.) for sample introduction. The detail parameters of ICP-MS/MS, UV laser ablation system and nano ESI-MS(/MS) were listed in Table 1. 2.4 General procedure For ICP-MS/MS system, when M+ ions separated from co-existed ions at Q1, isotopic xM+ ions were chosen and introduced separately into the ORS to meet the azide-alkyne mixture (1:1, v/v, phenyacetylene 2.5mM dissolved in dichloromethane with 0.25mM triethylamine; benzylazide 2.7mM dissolved in dichloromethane with 0.25mM acetic acid) introduced from the third inlet of the ORS through two T-junction mixing systems. The azide or alkyne was pre-stored in a 1 mL injector, respectively, and pushed to the T-junction gas mixing system by a micro-injection 4
pump (Pump 11 Elite, Harvard) in a predetermined speed. When the final product and the intermediates were formed in the ORS, it would be immediately separated by Q2 and then introduced to the detector. For UV laser ablation system, a 300 uL 4-ethynyl-N,N-dimethylaniline (2.5mM, dissolved in acetonitrile with 0.25mM triethylamine) and 300 uL benzylazide (2.7mM， dissolved in acetonitrile with 0.25mM acetic acid) were deposited on the metal substrate. The UV laser was used to ablate the metal substrates to generate the in situ “naked” metal ions with the monovalence state to finally catalyze the click reaction. After the UV laser irradiation for 20min, the rest solution was collected and detected by nanoESI-MS(/MS). For the sample analysis by nanoESI-MS(/MS), 5 μL of spray solution was added into the emitter, and a copper wire was pulled through the emitter to connect the sample solution and an extra DC voltage. When the extra voltage was turn on, the sample solution in the emitter was sprayed into the cone by electrical force and analyzed by ESI(+)-MS(/MS). This process was similar to the literature [27].
3. Results and discussion 3.1 High-throughput screening of monovalence metal ions as catalyst for the azide-alkyne cycloaddition by ICP-MS/MS Before study of other monovalence metal ions as catalyst for the azide-alkyne cycloaddition, the
63
Cu+ ions as catalyst were firstly studied to validate this system.
The net-mass spectra of phenylacetylene or phenylacetylene-D reacted with benzylazide catalyzed by 63Cu+ ions were shown in Fig. 2. The net-mass spectra were calculated by subtraction one mass spectrum catalyzed by nitric acid blank from the mass spectrum catalyzed by Cu+ ions with the same reaction condition. When phenylacetylene was used as reactant, a peak with the m/z of 235 was obtained, which was well matched with the mass of final product (Fig.2a). And a new peak at m/z of 236 was appeared when phenylacetylene-D was used as reactant instead of phenylacetylene (Fig.2b). In addition, when no reactants were added in the reaction system, no intensity of the peak with the m/z of 235 was found as shown in Fig. S1 5
(see supporting information). Therefore, we could confirm that the peak with the m/z of 235 in Fig.2a and the peak with the m/z of 236 in Fig.2b were all attributed to the final products. Considering this result, we used the peak (m/z 235) to estimate the catalytic activities of other monovalence metal ions in the subsequent experiments with the reactants of phenylacetylene and benzylazide. Figure 3 shows the results of the azide-alkyne cycloaddition with ten unstable monovalence metal ions as catalysts, respectively. These metal ions all lie in the first row of the period table, containing 45Sc+, 48Ti+, 51V+, 52Cr+, 55Mn+, 54Fe+, 59Co+, 58Ni+, 63
Cu+ and 64Zn+, at the same isotope concentration. From the net- intensities obtained
from the net-mass spectra of the final product (m/z=235) catalyzed by these ten monovalence metal ions, respectively, five of them (Sc+, Co+, Ni+, Cu+ and Zn+ ions) were found have higher intensities compared with that of other five ones. From Table S1, these five metal ions were also found have higher net-intensities ratios of the final product and the metal ions in the ORS than the other five ones. These results indicated that these five monovalence metal ions (Sc+, Co+, Ni+, Cu+ and Zn+) not only could effectively catalyze the azide-alkyne cycloaddition, but also had stronger catalytic activities than that of other five ones. Except Cu+ ions, the feasibility of Sc+, Co+, Ni+ and Zn+ ions as catalyst for azide-alkyne cycloaddition reaction all have not been reported yet by other methods previously. 3.2 Observing the intermediates of azide-alkyne cycloaddition catalyzed by screened monovalence metal ions by ICP-MS/MS According to the simplified mechanism of CuAAC (Fig.S2, see supporting information) in literature and our previous report [28, 26], when copper ion was met with alkyne, a π-bound mononuclear copper-alkyne intermediate I was immediately formed and rapidly transformed to a σ-bound mononuclear copper-alkyne intermediate II through deprotonation. These intermediates I and II indicated in the literature was successful observed in the present study from the reaction of phenyacetylene or phenylacetylene-D with the catalyst of
63
Cu+ ions (Fig.S3, see
supporting information). Moreover, we have also observed the possible intermediates 6
I and II resulting from the reaction of phenyacetylene with other four monovalence metal catalysts including
45
Sc+,
59
Co+,
58
Ni+ and
64
Zn+, respectively by the MS
platform. As shown in Fig.4, four monovalence metal ions (Sc+, Co+, Ni+ and Cu+ ions) were found have significantly stronger intensities for the possible intermediates I. While Zn+ ions were found to have a stronger intensity for the possible intermediate II, which may indicate that Zn+ ions take a different catalytic mechanism for azide-alkyne cycloadditionas others. Therefore, according to the results between the possible intermediates I and II formed by phenyacetylene and the five different monovalence metal ions, respectively, one can deduced that the catalytic mechanism of Sc+, Co+ and Ni+ ions is similar to the Cu+ ions, but Zn+ ions take a different catalytic route. 3.3 The yields evaluation of azide-alkyne cycloaddition catalyzed by screened monovalence metal ions by a UV laser ablation reactor Since the catalytic yields could not be obtained in a dynamic environment like in ICP-MS/MS, a UV laser ablation reactor (Fig.S4, see supporting information) was used to evaluate the catalytic yields, as Cu(I)-ions could be excited by laser irradiation on a metal substrate [29]. After the UV laser irradiation on a metal substrate for a certain time, the reactants solution with 4-ethynyl-N,N-dimethylaniline and benzylazide, which deposited on the metal substrate, was collected and detected by ESI(+)-MS/MS immediately. To evaluate the yields catalyzed by the monovalence metal ions, the effect of the time on the yields by UV laser irradiation was investigated firstly, taken Cu+ ions catalyst as example. The yields were estimated by comparison the peak intensities of 4-ethynyl-N,N-dimethylaniline (m/z=146) in the reaction solution before and after the UV laser irradiation on Cu substrate at different irradiation times, with an alkynyl analogy of [C42H28IrN4]+ ions (Fig.S5, see supporting information) (m/z=781) as internal standard and considering the dilution ratio for determination by ESI-MS and the volume change before and after the reaction. The alkynyl analogy of [C42H28IrN4]+ ions were just added into the reactants solution after UV laser irradiation and before 7
determination by ESI-MS. Fig.S6 (see supporting information) showed that the Ir containing alkynyl compound and the few Cu+ ions produced in the nano ESI emitter[30] as catalyst all could not obtain the obvious intensities of the final product at the m/z of 279 without the laser ablation reactor. Therefore, the yields obtained in Table 2 were only related to the metal substrate itself. As shown in Table 2, the yields catalyzed by Cu+ ions were found increased sharply from 0 to 87% along with the UV laser irradiation times from 0 to 20 min and then increased slowly when the irradiation time up to 30 min. Considering the suitable time catalyzed by Cu+ ions was needed as the standard to evaluate other monovalence metal ions, an irradiation time of 20 min was chosen for evaluation other monovalence metal ions in the subsequent experiment. As shown in Table 3, a yields range of 77%-98% was found for the five monovalence metal ions of Cu+, Ni+, Zn+, Co+ and Sc+ as catalysts, respectively after the UV laser irradiation for 20 min on each metal substrate. It was worth noting that the yields of Co+ and Sc+ ions as catalysts were even higher than the common catalyst of Cu+ ions, which had never been reported before. The single photon energy in the UV laser (255nm) used here was high enough to activate the metal ions from different metal substrates. Therefore, the activity of different metal ions was the main factor to influence the yields in the laser ablation system. These results not only demonstrated the feasibility of ICP-MS/MS as a rapid screening platform for catalyst discovery, but also indicated that the unstable monovalence metal ions might have a higher catalytic activity. 3.4 Verify the catalytic species in UV laser ablation system To verify the catalytic species was monovalence metal but not zero-valence metal in UV laser ablation system in this work, the ESI(+)-MS/MS spectrum of the intermediate [31] combined with metal and 4-ethynyl-N,N- dimethylaniline were further studied, since there were already reports about metal ions (plasmas), clusters and nano-materials that could be generated by laser ablation on a metal substrate [32-34]. Taking Ni substrate for example, if Ni(I) species was the catalyst, the 8
intermediate of (CH3)2NC6H4C258Ni+ ions with m/z of 203 might be produced and detected as the peak with the m/z of 203 by ESI(+)-MS/MS (Fig.S7b, see supporting information). However, if Ni(0) species was the catalyst, the intermediate of (CH3)2NC6H4C258Ni (M=203) would be produced [21] and detected as the hydrogenation peak with the m/z of 204 by ESI(+)-MS/MS (Fig.S7c). To further identify the component of the intermediate with Ni and alkynyl, we also investigated the ESI(+)MS/MS spectrum of the 4-ethynyl-N,N-dimethylaniline itself with a hydrogenation peak at the m/z of 146 (Fig. S7a). Comparing the fragmentation pathways between Fig. S7a, b and c, it was demonstrated that the peak with the m/z of 203 was referred to the intermediate of (CH3)2NC6H4C258Ni+. In another words, it was also confirmed that Ni(I) ions was participated in the azide-alkyne cycloaddition as catalyst. Therefore, one could deduce that the catalytic species was all monovalence metal ions in the UV laser ablation system.
4. Conclusion In this report, we demonstrated a rapid high-throughput screening platform for catalyst discovery in azide–alkyne cycloaddition. Ten monovalence metal ions were evaluated as catalysts for the reaction of azide-alkyne cycloaddition. Among them, five metal ions, including Sc+, Co+, Ni+, Cu+ and Zn+ ions, offer stronger catalytic activity than others. The yields of Co+ and Sc+ ions as catalysts were even higher than the common catalyst of Cu + ions, which had not been reported previously. It is worth noted that it is significant to study the unstable metal catalysts, not only the reason for understanding the catalytic mechanism, but also for providing ideas to synthesize new catalytic compounds or coordination complex, since the catalytic species of metal ions loaded on the surface of some specific materials such as nanomaterials may be sometime unstable (unsaturate) [35]. Moreover, the higher yields catalyzed by the unstable species might inspire the scientists to invent new reactor for catalytic reactions.
9
Acknowledgments XR Zhang thanks to the financial support provided by the 973 program (2013CB933804) and the National Natural Science Foundation of China (21390410). SC Zhang thanks to the National Natural Science Foundation of China (21621003), and the Ministry of Science and Technology of China (2011YQ6008402). X Fang and C Wei thank to the Ministry of Science and Technology of China (2011YQ090005). Z Xing thanks to National Natural Science Foundation of China (21575075). Q. He thanks to the China Postdoctoral Science Foundation (2015M581064).
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11
Figures and Tables Fig.1 The set up of the modified ICP-MS/MS system for rapid screening the monovalence metal (M+) ions catalyst for azide-alkyne cycloaddition reaction with phenylacetylene and benzylazide as reactants. Fig.2 The net-mass spectrum of the final product produced by the reactants of phenylacetylene a) or phenylacetylene-D b) with benzylazide catalyzed 63Cu+ ions (5 ppm calculated by the isotope ions concentration of
63
Cu+ ions in standard solution)
by a modified ICP-MS/MS system with the m/z range from 230 to 240. Fig.3 The net-intensities of the final product at the m/z of 235 produced with the reactants of phenylacetylene and benzylazide catalyzed by ten different monovalence metal ions (M+) with the same isotope concentration of 5 ppm (45Sc+, 52
Cr+,
55
Mn+,
54
Fe+,
59
Co+,
58
Ni+,
63
Cu+ and
64
48
Ti+,
51
V+,
Zn+, calculated by the isotope ions
concentration in standard solution), respectively by a modified ICP-MS/MS system. Fig.4 The net-mass spectra for intermediates I and II resulting from 45Sc+ a), 59Co+ b), 58
Ni+ c),
63
Cu+ d) and
64
Zn+ e) ions and with the same isotope ions concentration of
500ppb (calculated by the each isotope of
45
Sc+,
59
Co+,
58
Ni+,
63
Cu+ and
64
Zn+ ions
concentration in standard solution) reacted with phenylacetylene by a modified ICP-MS/MS system with the m/z range from 140 to 150 a), 154 to 164 b), 153 to 163 c), 158 to 168 d) and 159 to 169 e).
Table 1 The detail parameters of ICP-MS/MS, UV laser ablation system and nano ESI-MS(/MS). Table 2 The yields estimated by a UV laser ablation ESI(+)-MS system with Cu+ ions as catalysts at different reaction times. Table 3 The yields estimated by a UV laser ablation ESI(+)-MS system with the selected monovalence metal ions as catalysts.
12
Table 1 The detail parameters of ICP-MS/MS, UV laser ablation system and nano ESI-MS(/MS). Parameter Value ICP-MS/MS
Collision He gas (mLmin -1)
1.0
The third gas (%)
5 -1
UV laser ablation
ESI-MS(/MS)
Reactants flow rate (µL min )
10
Scan type
MS/MS
RF power(W)
1550
Extract 1 (V)
0
Q1 bias (V)
1.0
Q1→Q2
x→x+1~260
Octopole bias (V)
-5.0
Octopole RF (V)
150
Energy discrimination (V)
-7.0
Extract 2 (V)
-165
Wait time offset (ms)
2
Sweeps / replicate
5
Integration time / mass (s)
0.1
Replicates Wavelength (nm) Frequency (Hz) Energy (mJ/pluse) Pluse width (ns) Capillary temperature(℃)
3 255.0 20 2.0 10 275
Capillary voltage (V)
9
tube lens voltage (V)
100
Glass capillaries (mm)
I.D. 0.6; O.D. 1
Extra DC voltage (V)
2500
13
Table 2 The yields estimated by a UV laser ablation ESI(+)-MS system with Cu+ ions as catalysts at different reaction times. UV laser irradiation time (min)
4-ethynyl-N,N-dimethylaniline at m/z 146(cps)
Alkynyl internal standard at m/z 781(cps)
Diluted ratio
Volume (uL)
Yields
0 5 10
8698 10845 8802
20689 25814 22732
1：3 1：2 1：2
600 330 280
0 45% 57%
20 30
3660 10697
23452 27613
1：2 1：2
210 65
87% 90%
Table 3 The yields estimated by a UV laser ablation ESI(+)-MS system with the selected monovalence metal ions as catalysts. Catalyst (M+)
Diluted ratio
Volume (uL)
Yields
0
20min
0
20min
0
20min
0
20min
8698
3660
20689
23452
1：3
1：2
600
210
87%
+
5236
2696
19913
23443
1：3
1：2
600
220
84%
+
6207
5868
25477
49774
1：3
1：2
600
285
77%
+
8844
3322
17412
46327
1：3
1：2
600
170
96%
+
8844
2156
17412
56596
1：3
1：2
600
160
98%
Zn
Co Sc
Alkynyl internal standard at m/z 781(cps)
+
Cu Ni
4-ethynyl-N,N -dimethylaniline at m/z 146(cps)
Highlights 1. A rapid high-throughput screening platform using a modified ICP-MS/MS system for monovalence metal ions catalysts discovery in azide–alkyne cycloaddition was realized in this work. 2. The yields of Co+ and Sc+ ions as catalysts screened by ICP-MS/MS were even higher than the common catalyst of Cu+ ions for azide–alkyne cycloaddition, which had not been reported previously. 3. The proposed platform of ICP-MS/MS would be used not only for catalyst discovery in azide-alkyne cycloaddition, but also for the discovery of single atom/ion catalysts in other organic reactions.
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PII: DOI: Reference:
S0039-9140(16)30958-4 http://dx.doi.org/10.1016/j.talanta.2016.12.014 TAL17104
To appear in: Talanta Received date: 24 October 2016 Revised date: 1 December 2016 Accepted date: 6 December 2016 Cite this article as: Qian He, Jia Wang, Yuxiang Mo, Chao Wei, Xiang Fang, Xing Zhi, Sichun Zhang and Xinrong Zhang, A Rapid Screening Platform for Catalyst Discovery in Azide–Alkyne Cycloaddition by ICP-MS/MS, Talanta, http://dx.doi.org/10.1016/j.talanta.2016.12.014 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
A Rapid Screening Platform for Catalyst Discovery in Azide–Alkyne Cycloaddition by ICP-MS/MS Qian He1, Jia Wang2, Yuxiang Mo2, Chao Wei3, Xiang Fang3, Xing Zhi1, Sichun Zhang1, Xinrong Zhang1* 1 Department of Chemistry, Tsinghua University, Beijing 100084, China 2 Department of Physics, Tsinghua University, Beijing 100084, China 3 National Institute of Metrology, Beijing 100029, China * Corresponding author email: [email protected]
ABSTRACT We developed a rapid high-throughput screening platform using a modified ICP-MS/MS system for monovalence metal ions catalysts discovery in azide–alkyne cycloaddition. Among the ten monovalence metal ions in the first row of periodic table containing Sc+, Ti+, V+, Cr+, Mn+, Fe+, Co+, Ni+, Cu+, and Zn+, five monovalence metal ions of Sc+, Co+, Ni+, Cu+ and Zn+ ions show relatively stronger catalytic activities than others. The catalytic mechanism of Sc+, Co+ and Ni+ ions is similar to the Cu+ ions, but Zn+ ions take a different catalytic route. A yields range of 77%-98% for azide-alkyne cycloaddition was achieved with Sc+, Co+, Ni+, Cu+ and Zn+ ions as catalyst, respectively by using a UV laser ablation reactor in 20 min, notable that the yields of Co+ and Sc+ ions were even higher than the common catalyst of Cu+ ions. The proposed platform would be used not only for catalyst discovery in azide-alkyne cycloaddition, but also for the discovery of single atom/ion catalysts in other organic reactions. Keywords: azide–alkyne cycloaddition • catalyst • high-throughput screening • ICP-MS/MS • monovalence metal ions
1
1. Introduction In the past, the azide-alkyne cycloaddition[1] required high temperatures and resulted in a mixture of 1,4 and 1,5 regioisomers [2,3]. To solve this problem, Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) was therefore introduced by the Meldal and the Sharpless laboratories independently in 2002 [4,5]. This CuAAC reaction succeeded with high yields, purity and reaction rate (up to 107 times) over a broad temperature range (0-160°C)[6] thus obtained the widespread application in industry. Along with the great success of CuAAC, scientists have continued their efforts attempted to search other metal catalysts with higher catalytic activity than Cu(I) ions. Many new catalysts have been discovered for the azide-alkyne cycloaddition in recent years. They could be down to three categories briefly: the noble metals (Ru [7, 8], Pd [9], Pt [9], Au [10, 11], Ag [12-16], and Ir[17, 18]), the rare earth metals (Sm [19], Nd [19], Y [19], Gd [19], and Sc[20]) and the other transition metals (Ni[9,21] and Zn[22,23]). For the noble metals, whether using [Cp*RuCl] [7], nanoporous titania-supported gold nanoparticles [10], or Ag(OAc)[12] as catalyst, the yields of triazole were all satisfactory with the highest yields nearly 100%. Despite the highly catalytic activities of the noble metals, the high cost of them limits their widely application in industry. For the rare earth metals, however, the highest catalytic yields of Sm, among the four metals of Sm, Nd, Y and Gd in Ln[N(SiMe3)2]3 form, were found no more than 80% without the additive [19]. For the other transition metals, the catalytic activity of NiCl2 coupling at 80 °C was demonstrated at least 10 times slower than that of CuBr catalyzed reaction at room temperature [9]. And for ZnEt2 as catalyst, the yields of 1,5-triazole were found still no more than 76% among 21 examples [22]. In our preliminary study, we found some monovalence metal ions offer higher catalytic activities than Cu(I) ions in azide-alkyne cycloaddition. However, these monovalence metal ions are unstable under ordinary chemical conditions that kept the scientists from reaching their discovery as new catalysts. Herein, we established a 2
high-throughput platform for rapid screening unstable monovalence metal catalysts in azide-alkyne cycloaddition through a modified ICP-MS/MS system. Ten unstable monovalence metal ions in the first row of periodic table, containing 45Sc+, 48Ti+, 51V+, 52
Cr+, 55Mn+, 54Fe+, 59Co+, 58Ni+, 63Cu+, and 64Zn+ were studied as a proof-of-principle
experiment, respectively. Moreover, the metal related intermediates were successfully observed to learn the chemical mechanisms. This proposed platform would be used not only for catalyst discovery in azide-alkyne cycloaddition, but also for the discovery of single atom/ion catalysts in other organic reactions.
2. Experimental Section 2.1 Chemicals. The stock standard solution of Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, and Zn were purchased from National Research Center for Standard Materials (Beijing, China). Working standard solution was prepared daily by stepwise dilution of the stock solutions with 1% (v/v) nitric acid. Phenylacetylene, 4-ethynyl-N,N-dimethylaniline and
benzylazide
were
purchased
from
Alfa
Aesar
(Shanghai,
China).
Phenylacetylene-D was purchased from Santa Cruz (USA). Acetonitrile and dichloromethane (chromatographical grade) purchased from Mreda (USA) were used as the solvents. Acetic acid (guarantee grade) purchased from Sinopharm Chemical Reagent Co., Ltd (Beijing, China) was used as the accelerated agent for the AAC reaction [24]. Triethylamine (analytical grade) purchased from J&K Scientific (Beijing, China) was used as the base to accelerate the AAC reaction [25]. Alkynyl analogy of [C42H28IrN4]+ synthesized by our lab was used as the internal standard. 2.2 Materials. The pure nickel, zinc, iron, copper, cobalt, scandium and silicon sample plates (100×100×0.1mm, 99.99%) were all purchased from Jinjia metal materials co., ltd (Hebei, China). These plates were pre-cut into the shape of a ship to hold the reactants solution and ultrasonicated in 1:1 methanol/water for several minutes before use. 2.3 Apparatus A triple quadrupole ICP–MS/MS instrument (Agilent 8800, Japan) was chosen 3
in this work. The set-up of the modified ICP-MS/MS system and the operational parameters of the instrument used in this work were similar to our previous study [26]. Figure 1 showed the schematic of the modified ICP-MS/MS platform. The metal ions with different valences in solution were introduced into the ICP ion source through a nebulizer to produce continuous and gaseous monovalence metal ions, which were acted as the catalyst in this study. Each isotope of the monovalence metal ions were selected by the first mass analyzer (Q1) and then introduced to the collision reaction cell (ORS) to meet the reactants introduced from another inlet of the ORS. Once the final product and the intermediates formed in the ORS, they were separated by the second mass analyzer (Q2) and detected immediately. All the processes were accomplished within a few milliseconds and controlled at 10-3–10-4 Pa under oxygen-free conditions. An Nd–Yag (Spectra Physics, Pro 290, 20 Hz) pumped dye laser system with sum frequency unit (Sirah, Cobra-Stretch) was used to prepare the UV laser beam (255 nm). The laser beam was focused onto the sample by a quartz lens (f=100 mm). A linear ion trap quadrupole ESI-MS(/MS) instrument (Thermo Scientific, San Jose CA) was used. Glass capillaries were pulled by P-2000 (Sutter Instrument CO.) and cut manually to make the emitter (tip O.D. = 15~20 μm, observed by a microscope, YX20L20, Dayueweijia, Beijing Co.) for sample introduction. The detail parameters of ICP-MS/MS, UV laser ablation system and nano ESI-MS(/MS) were listed in Table 1. 2.4 General procedure For ICP-MS/MS system, when M+ ions separated from co-existed ions at Q1, isotopic xM+ ions were chosen and introduced separately into the ORS to meet the azide-alkyne mixture (1:1, v/v, phenyacetylene 2.5mM dissolved in dichloromethane with 0.25mM triethylamine; benzylazide 2.7mM dissolved in dichloromethane with 0.25mM acetic acid) introduced from the third inlet of the ORS through two T-junction mixing systems. The azide or alkyne was pre-stored in a 1 mL injector, respectively, and pushed to the T-junction gas mixing system by a micro-injection 4
pump (Pump 11 Elite, Harvard) in a predetermined speed. When the final product and the intermediates were formed in the ORS, it would be immediately separated by Q2 and then introduced to the detector. For UV laser ablation system, a 300 uL 4-ethynyl-N,N-dimethylaniline (2.5mM, dissolved in acetonitrile with 0.25mM triethylamine) and 300 uL benzylazide (2.7mM， dissolved in acetonitrile with 0.25mM acetic acid) were deposited on the metal substrate. The UV laser was used to ablate the metal substrates to generate the in situ “naked” metal ions with the monovalence state to finally catalyze the click reaction. After the UV laser irradiation for 20min, the rest solution was collected and detected by nanoESI-MS(/MS). For the sample analysis by nanoESI-MS(/MS), 5 μL of spray solution was added into the emitter, and a copper wire was pulled through the emitter to connect the sample solution and an extra DC voltage. When the extra voltage was turn on, the sample solution in the emitter was sprayed into the cone by electrical force and analyzed by ESI(+)-MS(/MS). This process was similar to the literature [27].
3. Results and discussion 3.1 High-throughput screening of monovalence metal ions as catalyst for the azide-alkyne cycloaddition by ICP-MS/MS Before study of other monovalence metal ions as catalyst for the azide-alkyne cycloaddition, the
63
Cu+ ions as catalyst were firstly studied to validate this system.
The net-mass spectra of phenylacetylene or phenylacetylene-D reacted with benzylazide catalyzed by 63Cu+ ions were shown in Fig. 2. The net-mass spectra were calculated by subtraction one mass spectrum catalyzed by nitric acid blank from the mass spectrum catalyzed by Cu+ ions with the same reaction condition. When phenylacetylene was used as reactant, a peak with the m/z of 235 was obtained, which was well matched with the mass of final product (Fig.2a). And a new peak at m/z of 236 was appeared when phenylacetylene-D was used as reactant instead of phenylacetylene (Fig.2b). In addition, when no reactants were added in the reaction system, no intensity of the peak with the m/z of 235 was found as shown in Fig. S1 5
(see supporting information). Therefore, we could confirm that the peak with the m/z of 235 in Fig.2a and the peak with the m/z of 236 in Fig.2b were all attributed to the final products. Considering this result, we used the peak (m/z 235) to estimate the catalytic activities of other monovalence metal ions in the subsequent experiments with the reactants of phenylacetylene and benzylazide. Figure 3 shows the results of the azide-alkyne cycloaddition with ten unstable monovalence metal ions as catalysts, respectively. These metal ions all lie in the first row of the period table, containing 45Sc+, 48Ti+, 51V+, 52Cr+, 55Mn+, 54Fe+, 59Co+, 58Ni+, 63
Cu+ and 64Zn+, at the same isotope concentration. From the net- intensities obtained
from the net-mass spectra of the final product (m/z=235) catalyzed by these ten monovalence metal ions, respectively, five of them (Sc+, Co+, Ni+, Cu+ and Zn+ ions) were found have higher intensities compared with that of other five ones. From Table S1, these five metal ions were also found have higher net-intensities ratios of the final product and the metal ions in the ORS than the other five ones. These results indicated that these five monovalence metal ions (Sc+, Co+, Ni+, Cu+ and Zn+) not only could effectively catalyze the azide-alkyne cycloaddition, but also had stronger catalytic activities than that of other five ones. Except Cu+ ions, the feasibility of Sc+, Co+, Ni+ and Zn+ ions as catalyst for azide-alkyne cycloaddition reaction all have not been reported yet by other methods previously. 3.2 Observing the intermediates of azide-alkyne cycloaddition catalyzed by screened monovalence metal ions by ICP-MS/MS According to the simplified mechanism of CuAAC (Fig.S2, see supporting information) in literature and our previous report [28, 26], when copper ion was met with alkyne, a π-bound mononuclear copper-alkyne intermediate I was immediately formed and rapidly transformed to a σ-bound mononuclear copper-alkyne intermediate II through deprotonation. These intermediates I and II indicated in the literature was successful observed in the present study from the reaction of phenyacetylene or phenylacetylene-D with the catalyst of
63
Cu+ ions (Fig.S3, see
supporting information). Moreover, we have also observed the possible intermediates 6
I and II resulting from the reaction of phenyacetylene with other four monovalence metal catalysts including
45
Sc+,
59
Co+,
58
Ni+ and
64
Zn+, respectively by the MS
platform. As shown in Fig.4, four monovalence metal ions (Sc+, Co+, Ni+ and Cu+ ions) were found have significantly stronger intensities for the possible intermediates I. While Zn+ ions were found to have a stronger intensity for the possible intermediate II, which may indicate that Zn+ ions take a different catalytic mechanism for azide-alkyne cycloadditionas others. Therefore, according to the results between the possible intermediates I and II formed by phenyacetylene and the five different monovalence metal ions, respectively, one can deduced that the catalytic mechanism of Sc+, Co+ and Ni+ ions is similar to the Cu+ ions, but Zn+ ions take a different catalytic route. 3.3 The yields evaluation of azide-alkyne cycloaddition catalyzed by screened monovalence metal ions by a UV laser ablation reactor Since the catalytic yields could not be obtained in a dynamic environment like in ICP-MS/MS, a UV laser ablation reactor (Fig.S4, see supporting information) was used to evaluate the catalytic yields, as Cu(I)-ions could be excited by laser irradiation on a metal substrate [29]. After the UV laser irradiation on a metal substrate for a certain time, the reactants solution with 4-ethynyl-N,N-dimethylaniline and benzylazide, which deposited on the metal substrate, was collected and detected by ESI(+)-MS/MS immediately. To evaluate the yields catalyzed by the monovalence metal ions, the effect of the time on the yields by UV laser irradiation was investigated firstly, taken Cu+ ions catalyst as example. The yields were estimated by comparison the peak intensities of 4-ethynyl-N,N-dimethylaniline (m/z=146) in the reaction solution before and after the UV laser irradiation on Cu substrate at different irradiation times, with an alkynyl analogy of [C42H28IrN4]+ ions (Fig.S5, see supporting information) (m/z=781) as internal standard and considering the dilution ratio for determination by ESI-MS and the volume change before and after the reaction. The alkynyl analogy of [C42H28IrN4]+ ions were just added into the reactants solution after UV laser irradiation and before 7
determination by ESI-MS. Fig.S6 (see supporting information) showed that the Ir containing alkynyl compound and the few Cu+ ions produced in the nano ESI emitter[30] as catalyst all could not obtain the obvious intensities of the final product at the m/z of 279 without the laser ablation reactor. Therefore, the yields obtained in Table 2 were only related to the metal substrate itself. As shown in Table 2, the yields catalyzed by Cu+ ions were found increased sharply from 0 to 87% along with the UV laser irradiation times from 0 to 20 min and then increased slowly when the irradiation time up to 30 min. Considering the suitable time catalyzed by Cu+ ions was needed as the standard to evaluate other monovalence metal ions, an irradiation time of 20 min was chosen for evaluation other monovalence metal ions in the subsequent experiment. As shown in Table 3, a yields range of 77%-98% was found for the five monovalence metal ions of Cu+, Ni+, Zn+, Co+ and Sc+ as catalysts, respectively after the UV laser irradiation for 20 min on each metal substrate. It was worth noting that the yields of Co+ and Sc+ ions as catalysts were even higher than the common catalyst of Cu+ ions, which had never been reported before. The single photon energy in the UV laser (255nm) used here was high enough to activate the metal ions from different metal substrates. Therefore, the activity of different metal ions was the main factor to influence the yields in the laser ablation system. These results not only demonstrated the feasibility of ICP-MS/MS as a rapid screening platform for catalyst discovery, but also indicated that the unstable monovalence metal ions might have a higher catalytic activity. 3.4 Verify the catalytic species in UV laser ablation system To verify the catalytic species was monovalence metal but not zero-valence metal in UV laser ablation system in this work, the ESI(+)-MS/MS spectrum of the intermediate [31] combined with metal and 4-ethynyl-N,N- dimethylaniline were further studied, since there were already reports about metal ions (plasmas), clusters and nano-materials that could be generated by laser ablation on a metal substrate [32-34]. Taking Ni substrate for example, if Ni(I) species was the catalyst, the 8
intermediate of (CH3)2NC6H4C258Ni+ ions with m/z of 203 might be produced and detected as the peak with the m/z of 203 by ESI(+)-MS/MS (Fig.S7b, see supporting information). However, if Ni(0) species was the catalyst, the intermediate of (CH3)2NC6H4C258Ni (M=203) would be produced [21] and detected as the hydrogenation peak with the m/z of 204 by ESI(+)-MS/MS (Fig.S7c). To further identify the component of the intermediate with Ni and alkynyl, we also investigated the ESI(+)MS/MS spectrum of the 4-ethynyl-N,N-dimethylaniline itself with a hydrogenation peak at the m/z of 146 (Fig. S7a). Comparing the fragmentation pathways between Fig. S7a, b and c, it was demonstrated that the peak with the m/z of 203 was referred to the intermediate of (CH3)2NC6H4C258Ni+. In another words, it was also confirmed that Ni(I) ions was participated in the azide-alkyne cycloaddition as catalyst. Therefore, one could deduce that the catalytic species was all monovalence metal ions in the UV laser ablation system.
4. Conclusion In this report, we demonstrated a rapid high-throughput screening platform for catalyst discovery in azide–alkyne cycloaddition. Ten monovalence metal ions were evaluated as catalysts for the reaction of azide-alkyne cycloaddition. Among them, five metal ions, including Sc+, Co+, Ni+, Cu+ and Zn+ ions, offer stronger catalytic activity than others. The yields of Co+ and Sc+ ions as catalysts were even higher than the common catalyst of Cu + ions, which had not been reported previously. It is worth noted that it is significant to study the unstable metal catalysts, not only the reason for understanding the catalytic mechanism, but also for providing ideas to synthesize new catalytic compounds or coordination complex, since the catalytic species of metal ions loaded on the surface of some specific materials such as nanomaterials may be sometime unstable (unsaturate) [35]. Moreover, the higher yields catalyzed by the unstable species might inspire the scientists to invent new reactor for catalytic reactions.
9
Acknowledgments XR Zhang thanks to the financial support provided by the 973 program (2013CB933804) and the National Natural Science Foundation of China (21390410). SC Zhang thanks to the National Natural Science Foundation of China (21621003), and the Ministry of Science and Technology of China (2011YQ6008402). X Fang and C Wei thank to the Ministry of Science and Technology of China (2011YQ090005). Z Xing thanks to National Natural Science Foundation of China (21575075). Q. He thanks to the China Postdoctoral Science Foundation (2015M581064).
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11
Figures and Tables Fig.1 The set up of the modified ICP-MS/MS system for rapid screening the monovalence metal (M+) ions catalyst for azide-alkyne cycloaddition reaction with phenylacetylene and benzylazide as reactants. Fig.2 The net-mass spectrum of the final product produced by the reactants of phenylacetylene a) or phenylacetylene-D b) with benzylazide catalyzed 63Cu+ ions (5 ppm calculated by the isotope ions concentration of
63
Cu+ ions in standard solution)
by a modified ICP-MS/MS system with the m/z range from 230 to 240. Fig.3 The net-intensities of the final product at the m/z of 235 produced with the reactants of phenylacetylene and benzylazide catalyzed by ten different monovalence metal ions (M+) with the same isotope concentration of 5 ppm (45Sc+, 52
Cr+,
55
Mn+,
54
Fe+,
59
Co+,
58
Ni+,
63
Cu+ and
64
48
Ti+,
51
V+,
Zn+, calculated by the isotope ions
concentration in standard solution), respectively by a modified ICP-MS/MS system. Fig.4 The net-mass spectra for intermediates I and II resulting from 45Sc+ a), 59Co+ b), 58
Ni+ c),
63
Cu+ d) and
64
Zn+ e) ions and with the same isotope ions concentration of
500ppb (calculated by the each isotope of
45
Sc+,
59
Co+,
58
Ni+,
63
Cu+ and
64
Zn+ ions
concentration in standard solution) reacted with phenylacetylene by a modified ICP-MS/MS system with the m/z range from 140 to 150 a), 154 to 164 b), 153 to 163 c), 158 to 168 d) and 159 to 169 e).
Table 1 The detail parameters of ICP-MS/MS, UV laser ablation system and nano ESI-MS(/MS). Table 2 The yields estimated by a UV laser ablation ESI(+)-MS system with Cu+ ions as catalysts at different reaction times. Table 3 The yields estimated by a UV laser ablation ESI(+)-MS system with the selected monovalence metal ions as catalysts.
12
Table 1 The detail parameters of ICP-MS/MS, UV laser ablation system and nano ESI-MS(/MS). Parameter Value ICP-MS/MS
Collision He gas (mLmin -1)
1.0
The third gas (%)
5 -1
UV laser ablation
ESI-MS(/MS)
Reactants flow rate (µL min )
10
Scan type
MS/MS
RF power(W)
1550
Extract 1 (V)
0
Q1 bias (V)
1.0
Q1→Q2
x→x+1~260
Octopole bias (V)
-5.0
Octopole RF (V)
150
Energy discrimination (V)
-7.0
Extract 2 (V)
-165
Wait time offset (ms)
2
Sweeps / replicate
5
Integration time / mass (s)
0.1
Replicates Wavelength (nm) Frequency (Hz) Energy (mJ/pluse) Pluse width (ns) Capillary temperature(℃)
3 255.0 20 2.0 10 275
Capillary voltage (V)
9
tube lens voltage (V)
100
Glass capillaries (mm)
I.D. 0.6; O.D. 1
Extra DC voltage (V)
2500
13
Table 2 The yields estimated by a UV laser ablation ESI(+)-MS system with Cu+ ions as catalysts at different reaction times. UV laser irradiation time (min)
4-ethynyl-N,N-dimethylaniline at m/z 146(cps)
Alkynyl internal standard at m/z 781(cps)
Diluted ratio
Volume (uL)
Yields
0 5 10
8698 10845 8802
20689 25814 22732
1：3 1：2 1：2
600 330 280
0 45% 57%
20 30
3660 10697
23452 27613
1：2 1：2
210 65
87% 90%
Table 3 The yields estimated by a UV laser ablation ESI(+)-MS system with the selected monovalence metal ions as catalysts. Catalyst (M+)
Diluted ratio
Volume (uL)
Yields
0
20min
0
20min
0
20min
0
20min
8698
3660
20689
23452
1：3
1：2
600
210
87%
+
5236
2696
19913
23443
1：3
1：2
600
220
84%
+
6207
5868
25477
49774
1：3
1：2
600
285
77%
+
8844
3322
17412
46327
1：3
1：2
600
170
96%
+
8844
2156
17412
56596
1：3
1：2
600
160
98%
Zn
Co Sc
Alkynyl internal standard at m/z 781(cps)
+
Cu Ni
4-ethynyl-N,N -dimethylaniline at m/z 146(cps)
Highlights 1. A rapid high-throughput screening platform using a modified ICP-MS/MS system for monovalence metal ions catalysts discovery in azide–alkyne cycloaddition was realized in this work. 2. The yields of Co+ and Sc+ ions as catalysts screened by ICP-MS/MS were even higher than the common catalyst of Cu+ ions for azide–alkyne cycloaddition, which had not been reported previously. 3. The proposed platform of ICP-MS/MS would be used not only for catalyst discovery in azide-alkyne cycloaddition, but also for the discovery of single atom/ion catalysts in other organic reactions.
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