DOI: 10.1002/cssc.201500318
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C¢N and N¢H Bond Metathesis Reactions Mediated by Carbon Dioxide Yehong Wang,[a] Jian Zhang,[a] Jing Liu,[a] Chaofeng Zhang,[a, b] Zhixin Zhang,[a] Jie Xu,*[a] Shutao Xu,[a] Fangjun Wang,[a] and Feng Wang*[a] Herein, we report CO2-mediated metathesis reactions between amines and DMF to synthesize formamides. More than 20 amines, including primary, secondary, aromatic, and heterocyclic amines, diamines, and amino acids, are converted to the corresponding formamides with good-to-excellent conversions and selectivities under mild conditions. This strategy employs CO2 as a mediator to activate the amine under metal-free con-
ditions. The experimental data and in situ NMR and attenuated total reflectance IR spectroscopy measurements support the formation of the N-carbamic acid as an intermediate through the weak acid–base interaction between CO2 and the amine. The metathesis reaction is driven by the formation of a stable carbamate, and a reaction mechanism is proposed.
Introduction The selective N-formylation of amines to formamides is a significant reaction in organic, medicinal, and biological chemistry.[1] Formic acid[2] or in situ-generated formic acid,[3] DMF,[4] aldehydes,[5] and their derivatives have been used as formylation reagents. However, the majority of examples require high temperatures, water-sensitive reagents, or complex workups and, thus, are unsuitable for use with fine chemicals, pharmaceuticals, and molecules bearing diverse functional groups, such as proteins and thiophenes. Reactions induced by weak acid–base interactions play a key role in living systems and in the chemical industry.[6] For example, CO2 generated from cellular respiration is expired in part through the reversible formation of a carbamate between CO2 and the amino groups of hemoglobin.[7] Furthermore, the reactions of primary and secondary amines with CO2 are used to capture CO2 through the formation of a zwitterion first and then a carbamate.[8] Encouraged by these previous studies, we proposed the possibility of utilizing the weak interactions between CO2 and amines to functionalize N¢H bonds. We report here the results on the N-formylation of amines mediated by CO2 through a metathesis reaction [Eq. (1)]. Usually, C¢N bond activation requires metal catalysts.[9] This method is markedly [a] Y. Wang, J. Zhang, J. Liu, C. Zhang, Z. Zhang, Prof. Dr. J. Xu, Dr. S. Xu, Dr. F. Wang, Prof. Dr. F. Wang State Key Laboratory of Catalysis (SKLC) Dalian National Laboratory for Clean Energy (DNL) Dalian Institute of Chemical Physics (DICP) Chinese Academy of Sciences 457 Zhongshan Road, Dalian 116023 (PR China) E-mail: [email protected] [email protected] [b] C. Zhang University of the Chinese Academy of Sciences No.19A Yuquan Road, Beijing 100049 (PR China) Supporting Information for this article is available on the WWW under http://dx.doi.org/10.1002/cssc.201500318.
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different to previous ones that required activated formylation reagents, metal-containing catalysts, and strong additives. In addition, the reaction can be performed in air ( 400 ppm CO2 in the atmosphere) with comparable results. Moreover, it has broad substrate compatibility.
Results and Discussion First, we optimized the reaction temperature and time. The temperature dependence of the conversion of benzylamine in DMF under 1 bar of CO2 gas is summarized in Figure S1. The onset temperature for the reaction has been reported to be more than 80 8C or even as high as 150 8C.[10] In this study, the onset temperature ( 40 8C, defined as the 30 % conversion temperature) is clearly much lower. The conversion increased with increasing reaction temperature and reached 92 % after 4 h at 100 8C. The selectivity for N-benzylformamide is also presented in Figure S1. An increased reaction temperature of 60 8C or higher offered almost pure N-benzylformamide. The reaction did not proceed under Ar gas. The reaction in air offered comparable results in 48 h. In 1973, Kraus reported that the formylation of aliphatic amines occurred in pure DMF.[11] Up to 100 h was required to complete the reaction. Our study revealed that the reaction conducted by Kraus might be mediated by the slow absorption of atmospheric CO2 into the reaction mixture. The progress of the reaction as monitored by GC is displayed in Figure 1. The formylation of benzylamine was conducted in DMF at 100 8C under 1 bar of CO2. The conversion of benzylamine increased significantly to 86 % in 2 h and then slowed down and reached 93 % in 8 h and > 99 % in 24 h.
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Figure 1. Time-on-stream profile of the formylation of benzylamine to benzylformamide. Reaction conditions: benzylamine (1.5 mmol), DMF (2 mL), 1 bar CO2, 100 8C.
Through the whole reaction, the selectivity for N-benzylformamide was > 99 %. A reaction with isotopically labelled [D7]DMF was conducted to clarify the reaction route (Figure S2). The molecular ion (M+) peak of N-benzylformamide (normal m/z = 135) increased to m/z = 136 (labeled), and the M+ peak of dimethylamine (m/z = 45) increased accordingly to m/z = 51 (Figures S3 and S4). We also used 13CO2 instead of CO2 in this reaction system. There was no increase for the molecular ion peak of N-benzylformamide and it remained at m/z = 135. However, if the C atom came from 13CO2, the M+ peak of N-benzylformamide should have an m/z value of 136. The results confirm that (1) a metathesis reaction occurs between the amine and DMF, (2) DMF is the formylation reagent, and (3) CO2 is a mediator, not a reactant. In some other studies, although CO2 was added and formamides were products, the real reaction involved the hydrogenation of CO2 to formic acid, which functioned as the formylation reagent.[3h, i, 5a, 12] In contrast, the CO2-mediated method requires no metal catalyst and no hydrogen. Moreover, it can be used to prepare 13C-labeled formamides. We then investigated the dependence of the initial amine conversion (2 h) on the pKa(N¢H) values. The larger the pKa(N¢H) value, the stronger the amine basicity. A plot of pKa(N¢H) versus conversion produces symmetric linear fits that intercept at the maximum point of pKa(N¢H) = 9.9 (Figure 2). The left end point was determined by extending the left half line to y = 0, which intercepted the x axis at pKa(N¢H) = 8.6. The right end point was determined by dipropylamine [pKa(N¢H) = 10.6]. The experimental data showed that the metathesis reaction relies greatly on the amine pKa(N¢H), and only amines within the pKa(N¢H) range 8.6–10.6 were converted into formamides. This explains why the reactions with aniline and some diamines were sluggish.[13] The basicity of the amine affects the strength of the interaction between the N atom of the amine and the C atom of CO2 : weak basicity [such as aniline, pKa(N¢H) < 8.6] results in an instable amine–CO2 adduct; strong basicity [pKa(N¢H) > 10.6] generates an interaction that is too stable, and the CO2 is bound strongly. The amines in Figure 2 were selected after consideration of both the pKa(N¢H) and steric hindrance; therefore, some amines fall out of this range. However, as a simple rule of ChemSusChem 2015, 8, 2066 – 2072
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Figure 2. Relationship between amine conversion and pKa(N¢H) values. Reaction conditions: amine (0.6 mmol), DMF (2 mL), 1 bar CO2, 100 8C, 2 h.
thumb, it helps to determine which kind of amine can be converted by this method. We then studied the substrate scope (Table 1). Sterically unhindered linear aliphatic amines with chains of up to 12 carbon atoms were converted to the corresponding formamides with > 99 % selectivity and > 99 % conversion (1–5); these results are better than those reported previously.[10, 14] Alicyclic cyclohexylamine and cyclopentylamine were converted satisfactorily to the corresponding formamides (4 and 5). No conversion was observed for dipropylamine and diethylamine (6 and 7). However, a hydroxy-terminated amine (8) and piperidine (9) achieved 23 % and > 99 % conversion, respectively, with > 99 % formamide selectivity. These amines were different at the terminal group. Steric as well as electronic and solvation effects might affect their activity. The two terminal hydroxy groups might form hydrogen bonds and, thus, expose more space for the N¢H bond activation. Piperidine, which could be viewed as a molecule in which the terminal groups are bonded, achieved better results. In contrast, a piperidine formamide was obtained with only 36 % yield in a B(OCH2CF3)3– DMF system.[10] To show the practical application of the procedure, a gram-scale synthesis of dodecylamine (2.78 g) was performed. The reaction offered 97 % isolated yield of dodecylformamide (3). Heterocyclic amines such as furfurylamine and 2-thiophenemethylamine were converted to formamides (10 and 11, respectively) with selectivities of > 99 %. To the best of our knowledge, this method represents a rare example of the formylation of a thiophene amine because sulfur may poison most catalytic metal centers. Several benzylamines were converted with excellent formamide selectivities (12–18). A slight substituent effect was evidenced by the lower conversion of the CF3-substituted benzylamine than for the F-substituted one. The less-nucleophilic aniline was inactive (19) because of its weak basicity (Figure 2). The formylation of the sterically unhindered hexane-1,6-diamine afforded 99 % of the diformamide (20). A worse result than that for hexane-1,6-diamine was
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Full Papers methods remains a hot topic.[16] In this study, we tested the labeling of protein amine groups with DMF through metathesis reactions. We added a little water to promote solubility but sacrificed some activity. After the reaction, both unreacted arginine (m/z = 175) and formylated arginine (m/z = 203) were detected by means of matrix-assisted laser desorption/ionization–time of flight (MALDI-TOF)/TOF MS (Figure 3 A). The reaction was further quantified by LC–MS (Figure 3 B) using an identical amount of lysine as internal standard. After the reaction, the relative intensity of arginine decreased greatly. The arginine conversion was 81 %, as analyzed by LC–MS. We further applied the method to more-complex amines from trypsin-digested bovine serum albumin (BSA). Trypsin is a pancreatic serine endoprotease that hydrolyzes peptide bonds specifically at the carboxyl side of arginine and lysine residues and leads to two classes of peptides. One is the peptide with the arginine residue at the carboxyl side, in which only the amine group of the N-terminus and the guanidine group of the arginine residue could be formylated, and the other is the peptide with the lysine residue at the carboxyl side, in which the amine group of the N-terminus and the lysine residue could be formylated. For the former, 57 % of the amine groups of the N-terminus, 14 % of the guanidine groups, and 0 % of both were formylated (Figure S5). For the later, these data were 67 %, 72 %, and 46 %, respectively. For
Table 1. Substrate scope of the reaction.[a] Structure
Compound
Conversion Selectivity [%] [%]
1 2 3
> 99 > 99 > 99
> 99[b] > 99 > 99
4
> 99
> 99[b]
5
> 99
> 99
6 7
n=3 n=5 n = 11
n=1 n=2
trace trace
– –
8
23
> 99
9
> 99
> 99
10
> 99
> 99
11
94
> 99
> 99 95 92 93 96
> 99 94 90 > 99 68
12 13 14 15 16
X=H X = p-Cl X = o-Cl X = p-F X = p-CF3
17
91
> 99[b]
18
98
98
19
trace
20
–
> 99
> 99
21[c] carried out in CO2 > 99 70 22[d] catalyzed by CeO2 instead of CO2
72 4
23[e]
> 99
68
24
> 99
> 99
[a] Reaction conditions: amine (1.5 mmol), DMF (2 mL), 100 8C, 24 h, 1 bar CO2 ; results were analyzed by GC and are presented as conversion/selectivity. [b] 48 h. [c] The remaining product was 1,4-diazepane-1-carbaldehyde (selectivity 28 %). [d] Amine (1.5 mmol), DMF (2 mL), CeO2 (100 mg), 150 8C, 24 h.[4k] 1,4-Diazepane-1-carbaldehyde selectivity 96 %. [e] Piperazine-1-carbaldehyde selectivity 32 %.
obtained for an alicyclic diamine with > 99 % conversion and 72 % selectivity for the diformamide and 28 % for the monoformamide (21). This might be due to the robust structure of the alicyclic diamine. However, this method was still superior to one with solid CeO2 catalyst, for which only 70 % conversion and 4 % of the diformamide was obtained (22).[4k] The formylation of piperazine offered 68 % diformamide and 32 % monoformamide (23). For dimethyl-substituted piperazine, monoformamide was obtained with > 99 % selectivity (24). Carbamylation reactions play important roles in multiple biological processes, such as the transportation of amino acids and protein synthesis in living systems.[15] To date, the protein formylation methods employed use expensive labeling reagents and complex procedures, but the development of new ChemSusChem 2015, 8, 2066 – 2072
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Figure 3. (A) MALDI-TOF results for arginine with a-cyano-4-hydroxycinnamic acid (CHCA) as the matrix. The y axis for arginine was vertically adjusted. (B) LC–MS results for the N-formylation of arginine.
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Full Papers histidine, 28 % of the side imidazole groups were formylated, which shows its inertness. The reaction was governed by the pKa(N¢H) rule (Figure 2) and the effect of steric hindrance. Usually, acetylation labeling through chemical reactions can only be performed for the primary amino group on the protein or peptide N-terminus and the lysine side chain. In this study, the method can be performed not only on the N-terminus and lysine but also on the guanidine group of the side chain of arginine. Although the CO2-mediated metathesis reaction is less efficient than the mature acetylation method, it provides a possible next-generation labeling strategy, especially for amines with coexisting functional groups sensitive to metal ions and strong acids or bases. In previous studies, DMF and its derivatives were activated by strong additives such as HClO4, iodine, NaOMe, and RSO2Cl. In our study, CO2 is a weakly acidic molecule and cannot activate DMF. We believed CO2 would activate amines and confirmed this through IR and NMR spectroscopy characterizations. The attenuated total reflectance (ATR)-IR spectra of benzylamine were measured before and after CO2 was bubbled through it at room temperature (Figure 4 A). The CO2 dissolved in the benzylamine, as indicated by a peak at n˜ = 2340 cm¢1 for the asymmetric stretch of CO2. Two peaks at n˜ = 1720 and 1648 cm¢1 were assigned to the ¢COOH vibration of the N-carbamic acid.[17] No carbamate was formed, as indicated by the absence of an absorption at n˜ 1570 cm¢1.[17] For DMF with CO2 bubbling at room temperature (Figure 4 B), the spectrum resembled that of pure DMF, which indicates that no interaction occurred between DMF and CO2. More detailed reaction information for benzylamine, DMF, and CO2 was obtained by monitoring the initial 30 min reaction through ATR-IR spectroscopy (Figure 5). The bubbling of CO2 generated three peaks at n˜ = 1231, 1542, and 1720 cm¢1, which indicated the formation of the N-carbamic acid. The formation of N-benzylformamide was evidenced by the peaks at n˜ = 1673 and 1382 cm¢1. The formation of the N-carbamic acids of dipropylamine and benzylamine after CO2 bubbling in [D6]DMSO was further characterized by 13C NMR spectroscopy. The signals at d = 157 ppm
Figure 4. In situ ATR-IR spectra of (A) benzylamine and (B) DMF, flushed with Ar gas and in the presence of CO2.
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Figure 5. Stacked in situ FTIR spectra for initial 30 min. Reaction conditions: benzylamine (3 mmol), DMF (24 mL), 1 bar CO2, 100 8C.
for dipropylamine and d = 158 ppm for benzylamine were assigned to the carbonyl C atoms of the N-carbamic acids [Figure 6 A and B].[17] The discernible low-field shifts of the C atoms next to the N atoms from d = 52–48 ppm for dipropylamine and from d = 46–44 ppm for benzylamine indicated the gain of electron density after the formation of the N-carbamic acids. The chemical shift at 39 ppm for both amines was due to the trace residue of normal DMSO in the [D6]DMSO solvent. The presence of the N-carbamic acid was again confirmed by 1 H NMR spectroscopy in [D6]DMSO. After the CO2 bubbling, the d(O¢H) of the N-carbamic acid appeared at 7.7 ppm, whereas the d(C¢H) of dipropylamine at 2.4 ppm was upshifted to 3.0 ppm (Figure 6 C), which was assigned to the d(C¢H) of the N-carbamic acid.[17] After the bubbling of CO2 into benzylamine, the d(C¢H) of the amine at 3.7 ppm shifted to 4.2 ppm, which was indicative of d(C¢H) of the N-carbamic acid. The newly formed d(O¢H) of the N-carbamic acid appeared at 8.7 ppm (Figure 6 D). Signals at d = 3.4 and 1.1 ppm were attributed to ethanol contamination from the tube for CO2 bubbling. The signal at d = 2.5 ppm originated from normal DMSO in [D6]DMSO. We then studied the solvent effect by 13C NMR spectroscopy (Figure 7). The addition of CO2 into a mixture of benzylamine and dipropylamine in [D6]DMSO and [D7]DMF at room temperature resulted in 100 % conversion to the N-carbamic acids. This was illustrated by the presence of two new C=O signals at d < 160 ppm (159 and 158 ppm in [D6]DMSO, 160 and 159 ppm in [D7]DMF, respectively), in good agreement with the results in Figure 6. In contrast, only a single signal appeared at d = 163 ppm in CDCl3, but it was stronger than the signals recorded in [D6]DMSO and [D7]DMF. The value was larger than the normal shift of the C atoms of carbamic acids (less than 160 ppm). This signal originated from ammonium carbamate [PhCH2NHCOO¢ (CH3CH2CH2)2NH2+], the adduct of the amine and CO2 in CDCl3 ; thus, only one signal was discerned.[17] The reaction of an amine and CO2 to form an N-carbamic acid (CA) is rapid and has a reaction rate k1 of 104 m¢1 s¢1. The reverse reaction is slow with k1’ = 101 m¢1 s¢1.[18] Previous studies mentioned that the C¢N bond might undergo an exchange reaction of the carboxyl group with CO2.[19] The formation of
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Figure 6. 13C and 1H NMR spectroscopy characterization of dipropylamine (A and C) and benzylamine (B and D) in Ar or CO2.
Figure 7. 13C NMR spectra of a mixture of benzylamine and dipropylamine in CDCl3, [D6]DMSO, or [D7]DMF after CO2 bubbling.
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CA was confirmed by 1H NMR, 13C NMR, and ATR-IR spectroscopy. The key reaction is that the CA further reacts with DMF to generate the formamide (FA) product and release CO2, which was also confirmed by IR and NMR spectroscopy. The reaction of DMF with CA may involve a C¢N bond-metathesis transient state. We isolated pure ammonium carbamate zwitterion (AC) and reacted it with DMF (Figure S6). As the reaction selectivity was > 99 %, we used the FA production rate as the reaction rate. The initial rate of 0 L mol¢1 s¢1 might infer that AC was converted to CA during this period. Further, the reaction rates decreased with time with an average rate k2 of 10¢6 L mol¢1 s¢1. This rate was much smaller than k1; therefore step 2 is the rate-determining step. Therefore, the initial reaction quickly generated CA and then AC, as an amine reservoir (Figure 8). The FA was generated from CA and DMF. The addition of a small amount of water irreversibly hydrolyzed CA to carbonate. A control reaction in a 1:1 volumetric ratio mixture of DMF and water at 100 8C for
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Figure 8. The possible reaction mechanism.
4 h gave 24 % conversion of benzylamine, in comparison with 92 % conversion in pure DMF. Moreover a reaction of the separated carbonate with DMF generated no product. These facts indicate that carbonate is not the reaction intermediate and its production is irreversible. The steric hindrance of the methyl groups (R1, R2) connected to the N atom of the amine interrupt the interaction of DMF with the amine and retard this reaction. The metathesis product dimethylamine, as the leaving group of DMF, has a pKa(N¢H) value of 10.6, which is large enough to form a stable carbamic acid product with CO2 under the reaction conditions and drive the reaction to the right. After the reaction, an increase in temperature or flushing with N2 would remove dimethylamine and CO2 gas; therefore, the reaction is clean and convenient.
Conclusions We have reported the use of CO2 as a mediator in the transformation of amines to their corresponding formamides in DMF. The metathesis reaction is conducted without the use of any metals. This will provide a useful method for the formylation and protection of amine groups in a simple, green, and economical way.
Experimental Section Methods: All chemicals were analytical grade and used as purchased without further purification. Most of the chemicals were purchased from Aladdin Chemicals, except DMF, aniline, and diethylamine, which were purchased from Tianjin Kemiou Chemical Reagent Co., Ltd., n-butylamine and cyclohexylamine were purchased from Sinopharm Chemical Reagent Co., Ltd., and 2,6-dimethylpyrazine was purchased from J&K chemicals. Catalytic reactions: The reactions were conducted in a 50 mL glass batch reactor (heavy wall, maximum pressure: 0.6 MPa, Synthware Glass). Typically, benzylamine (1.5 mmol), DMF (2 mL), and a stirring bar were placed in the reactor, which was then charged with CO2 gas (1 bar) from a gas cylinder. The reaction solution changed gradually into a thick white gel over several minutes. The reactor was sealed tightly with a Teflon stopper and then immersed in an oil bath preheated at the desired temperature. The ChemSusChem 2015, 8, 2066 – 2072
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gradual disappearance of the gel indicated the end of reaction, which was also tracked by GC (Agilent 7890A). The reaction solution was cooled to room temperature, and then a sample of the reaction mixture ( 0.2 mL) was analyzed by GC–MS (Agilent 7890A5975C). In most cases, the reaction was very clean and, thus, the conversion of amine and the selectivity for formamide were obtained from the normalized GC integration peak areas. General characterizations and analyses: All liquid NMR spectroscopy experiments were performed with a Bruker Avance III-400 spectrometer with [D6]DMSO, [D7]DMF, or CDCl3 as the deuterated solvent for locking. 1H and 13C NMR spectroscopy experiments with proton decoupling were conducted at 100.62 MHz with 200 scans and a 2 s recycle delay. The chemical shifts were referenced to tetramethylsilane (TMS). In situ ATR-IR spectra were recorded with a Mettler Toledo React IR 4000 spectrometer with a DiCom probe. The IR spectra were recorded with [benzylamine] = 0.75 m in DMF after CO2 degassing for at least 2 min under continuous stirring. Bovine serum albumin (BSA) digestion: The BSA was denatured with 8 m urea/100 mm tetraethylammonium bromide (TEAB, pH 8.0), reduced by 10 mm dithiothreitol at 60 8C for 1 h, and alkylated with 20 mm iodoacetamide in darkness at room temperature for 30 min, followed by dilution with 100 mm TEAB buffer (pH 8.0) and digestion with trypsin at 37 8C for 16 h. Finally, the BSA digests were desalted with C18 solid-phase extraction (SPE) columns and lyophilized for use. MALDI-TOF MS analysis: The MALDI-TOF MS experiments were performed using an AB Sciex 5800 MALDI-TOF/TOF mass spectrometer (AB Sciex) equipped with a pulsed Nd–YAG laser at 355 nm in reflective positive-ion mode. The sample ( 0.5 mL) and matrix (0.5 mL; 25 mg mL¢1 2,5-dihydroxybenzoic acid in 50 % acetonitrile/ H2O) were spotted on the MALDI plate for MS analysis. The liquid chromatography coupled with mass spectrometry/mass spectrometry (LC–MS/MS) experiments were performed using a Thermo Q Exactive mass spectrometer (Thermo) with a nanospray ion source and a U3000 RSLCnano system (Thermo). After lyophilization, the samples were redissolved with 0.1 % formic acid solution and loaded on a C18 capillary trap column (200 mm i.d., 4 cm) packed with C18 AQ beads (5 mm, 120 æ, Daison) and separated by a capillary analysis column (75 mm i.d.) with C18 AQ beads (3 mm, 120 æ, Daison). The buffers used for the online analysis were 0.1 % (v/v) formic acid in water and 0.1 % (v/v) formic acid in acetonitrile, the flow rate was 300 nL min¢1 for nanoflow LC–MS/MS analysis. A gradient from 5 to 35 % (v/v) acetonitrile was achieved in 15 min for arginine samples and 90 min for BSA samples. The MS and MS/MS spectra were collected by higher-energy collision-induced dissociation (HCD) at 28 % energy in a data-dependent mode with one MS scan followed by 10 MS/MS scans. The RAW files collected by Xcalibur 2.1 were converted to MGF files by Proteome Discoverer (v1.2.0.208, Thermo) and searched with Mascot (version 2.3.0, Matrix Science). Cysteine carboxamidomethylation was set as a static modification of 57.0215 Da, and formylation and methionine oxidation were set as variable modifications of 27.9949 Da and 15.9949 Da, respectively. The mass tolerances were 10 ppm and 0.5 Da for the parent and fragment ions, respectively. A maxi-
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[5] a) C. L. Allen, B. N. Atkinson, J. M. J. Williams, Angew. Chem. Int. Ed. 2012, 51, 1383 – 1386; Angew. Chem. 2012, 124, 1412 – 1415; b) B. N. Atkinson, A. R. Chhatwal, H. V. Lomax, J. W. Walton, J. M. J. Williams, Chem. Commun. 2012, 48, 11626 – 11628; c) S. Joseph, P. Das, B. Srivastava, H. Nizar, M. Prasad, Tetrahedron Lett. 2013, 54, 929 – 931; d) A. E. Pasqua, M. Matheson, A. L. Sewell, R. Marquez, Org. Process Res. Dev. 2011, 15, 467 – 470; e) C. Zhang, Z. J. Xu, T. Shen, G. L. Wu, L. R. Zhang, N. Jiao, Org. Lett. 2012, 14, 2362 – 2365. [6] B. M. Brandsen, T. E. Velez, A. Sachdeva, N. A. Ibrahim, S. K. Silverman, Angew. Chem. Int. Ed. 2014, 53, 9045 – 9050; Angew. Chem. 2014, 126, 9191 – 9196. [7] W. H. Schaefer, Curr. Drug Metab. 2006, 7, 873 – 881. [8] a) B. Dutcher, M. Fan, A. G. Russell, ACS Appl. Mater. Interfaces 2015, 7, 2137 – 2148; b) M. X. Tan, Y. Zhang, J. Y. Ying, ChemSusChem 2013, 6, 1186 – 1190; c) J. R. Switzer, A. L. Ethier, E. C. Hart, K. M. Flack, A. C. Rumple, J. C. Donaldson, A. T. Bembry, O. M. Scott, E. J. Biddinger, M. Talreja, M.-G. Song, P. Pollet, C. A. Eckert, C. L. Liotta, ChemSusChem 2014, 7, 299 – 307; d) C. S. Srikanth, S. S. C. Chuang, ChemSusChem 2012, 5, 1435 – 1442; e) S. Saravanamurugan, A. J. Kunov-Kruse, R. Fehrmann, A. Riisager, ChemSusChem 2014, 7, 897 – 902. [9] a) J. Hu, Y. Xie, H. Huang, Angew. Chem. Int. Ed. 2014, 53, 7272 – 7276; Angew. Chem. 2014, 126, 7400 – 7404; b) S. Guo, B. Qian, Y. Xie, C. Xia, H. Huang, Org. Lett. 2011, 13, 522 – 525; c) Y. Xie, B. Qian, P. Xie, H. Huang, Adv. Synth. Catal. 2013, 355, 1315 – 1322. [10] R. M. Lanigan, P. Starkov, T. D. Sheppard, J. Org. Chem. 2013, 78, 4512 – 4523. [11] M. A. Kraus, Synthesis 1973, 361 – 362. [12] a) E. Blondiaux, J. Pouessel, T. Cantat, Angew. Chem. Int. Ed. 2014, 53, 12186 – 12190; Angew. Chem. 2014, 126, 12382 – 12386; b) Q. Liu, L. Wu, R. Jackstell, M. Beller, Nat. Commun. 2015, 6, 5933. [13] In some cases, steric hindrance should be considered, for example, for dipropylamine. Overall, the effect of pKa(N¢H) should play a key role here. [14] N. Ortega, C. Richter, F. Glorius, Org. Lett. 2013, 15, 1776 – 1779. [15] C. Francklyn, P. Schimmel, Nature 1989, 337, 478 – 481. [16] a) T. Jiang, X. F. Zhou, K. Taghizadeh, M. Dong, P. C. Dedon, Proc. Natl. Acad. Sci. USA 2007, 104, 60 – 65; b) D. Mader, M. Liebeke, V. Winstel, K. Methling, M. Leibig, F. Gotz, M. Lalk, A. Peschel, BMC Microbiol. 2013, 13, 7. [17] a) Z. J. Dijkstra, A. R. Doornbos, H. Weyten, J. M. Ernsting, C. J. Elsevier, J. T. F. Keurentjes, J. Supercrit. Fluids 2007, 41, 109 – 114; b) K. Masuda, Y. Ito, M. Horiguchi, H. Fujita, Tetrahedron 2005, 61, 213 – 229. [18] W. Conway, X. Wang, D. Fernandes, R. Burns, G. Lawrance, G. Puxty, M. Maeder, Environ. Sci. Technol. 2012, 46, 7422 – 7429. [19] a) C. S. McCowan, M. T. Caudle, Dalton Trans. 2005, 238 – 246; b) Y. Otsuji, N. Matsumura, E. Imoto, Bull. Chem. Soc. Jpn. 1968, 41, 1485 – 1485.
Received: March 3, 2015 Revised: April 3, 2015 Published online on June 3, 2015
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C¢N and N¢H Bond Metathesis Reactions Mediated by Carbon Dioxide Yehong Wang,[a] Jian Zhang,[a] Jing Liu,[a] Chaofeng Zhang,[a, b] Zhixin Zhang,[a] Jie Xu,*[a] Shutao Xu,[a] Fangjun Wang,[a] and Feng Wang*[a] Herein, we report CO2-mediated metathesis reactions between amines and DMF to synthesize formamides. More than 20 amines, including primary, secondary, aromatic, and heterocyclic amines, diamines, and amino acids, are converted to the corresponding formamides with good-to-excellent conversions and selectivities under mild conditions. This strategy employs CO2 as a mediator to activate the amine under metal-free con-
ditions. The experimental data and in situ NMR and attenuated total reflectance IR spectroscopy measurements support the formation of the N-carbamic acid as an intermediate through the weak acid–base interaction between CO2 and the amine. The metathesis reaction is driven by the formation of a stable carbamate, and a reaction mechanism is proposed.
Introduction The selective N-formylation of amines to formamides is a significant reaction in organic, medicinal, and biological chemistry.[1] Formic acid[2] or in situ-generated formic acid,[3] DMF,[4] aldehydes,[5] and their derivatives have been used as formylation reagents. However, the majority of examples require high temperatures, water-sensitive reagents, or complex workups and, thus, are unsuitable for use with fine chemicals, pharmaceuticals, and molecules bearing diverse functional groups, such as proteins and thiophenes. Reactions induced by weak acid–base interactions play a key role in living systems and in the chemical industry.[6] For example, CO2 generated from cellular respiration is expired in part through the reversible formation of a carbamate between CO2 and the amino groups of hemoglobin.[7] Furthermore, the reactions of primary and secondary amines with CO2 are used to capture CO2 through the formation of a zwitterion first and then a carbamate.[8] Encouraged by these previous studies, we proposed the possibility of utilizing the weak interactions between CO2 and amines to functionalize N¢H bonds. We report here the results on the N-formylation of amines mediated by CO2 through a metathesis reaction [Eq. (1)]. Usually, C¢N bond activation requires metal catalysts.[9] This method is markedly [a] Y. Wang, J. Zhang, J. Liu, C. Zhang, Z. Zhang, Prof. Dr. J. Xu, Dr. S. Xu, Dr. F. Wang, Prof. Dr. F. Wang State Key Laboratory of Catalysis (SKLC) Dalian National Laboratory for Clean Energy (DNL) Dalian Institute of Chemical Physics (DICP) Chinese Academy of Sciences 457 Zhongshan Road, Dalian 116023 (PR China) E-mail: [email protected] [email protected] [b] C. Zhang University of the Chinese Academy of Sciences No.19A Yuquan Road, Beijing 100049 (PR China) Supporting Information for this article is available on the WWW under http://dx.doi.org/10.1002/cssc.201500318.
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different to previous ones that required activated formylation reagents, metal-containing catalysts, and strong additives. In addition, the reaction can be performed in air ( 400 ppm CO2 in the atmosphere) with comparable results. Moreover, it has broad substrate compatibility.
Results and Discussion First, we optimized the reaction temperature and time. The temperature dependence of the conversion of benzylamine in DMF under 1 bar of CO2 gas is summarized in Figure S1. The onset temperature for the reaction has been reported to be more than 80 8C or even as high as 150 8C.[10] In this study, the onset temperature ( 40 8C, defined as the 30 % conversion temperature) is clearly much lower. The conversion increased with increasing reaction temperature and reached 92 % after 4 h at 100 8C. The selectivity for N-benzylformamide is also presented in Figure S1. An increased reaction temperature of 60 8C or higher offered almost pure N-benzylformamide. The reaction did not proceed under Ar gas. The reaction in air offered comparable results in 48 h. In 1973, Kraus reported that the formylation of aliphatic amines occurred in pure DMF.[11] Up to 100 h was required to complete the reaction. Our study revealed that the reaction conducted by Kraus might be mediated by the slow absorption of atmospheric CO2 into the reaction mixture. The progress of the reaction as monitored by GC is displayed in Figure 1. The formylation of benzylamine was conducted in DMF at 100 8C under 1 bar of CO2. The conversion of benzylamine increased significantly to 86 % in 2 h and then slowed down and reached 93 % in 8 h and > 99 % in 24 h.
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Figure 1. Time-on-stream profile of the formylation of benzylamine to benzylformamide. Reaction conditions: benzylamine (1.5 mmol), DMF (2 mL), 1 bar CO2, 100 8C.
Through the whole reaction, the selectivity for N-benzylformamide was > 99 %. A reaction with isotopically labelled [D7]DMF was conducted to clarify the reaction route (Figure S2). The molecular ion (M+) peak of N-benzylformamide (normal m/z = 135) increased to m/z = 136 (labeled), and the M+ peak of dimethylamine (m/z = 45) increased accordingly to m/z = 51 (Figures S3 and S4). We also used 13CO2 instead of CO2 in this reaction system. There was no increase for the molecular ion peak of N-benzylformamide and it remained at m/z = 135. However, if the C atom came from 13CO2, the M+ peak of N-benzylformamide should have an m/z value of 136. The results confirm that (1) a metathesis reaction occurs between the amine and DMF, (2) DMF is the formylation reagent, and (3) CO2 is a mediator, not a reactant. In some other studies, although CO2 was added and formamides were products, the real reaction involved the hydrogenation of CO2 to formic acid, which functioned as the formylation reagent.[3h, i, 5a, 12] In contrast, the CO2-mediated method requires no metal catalyst and no hydrogen. Moreover, it can be used to prepare 13C-labeled formamides. We then investigated the dependence of the initial amine conversion (2 h) on the pKa(N¢H) values. The larger the pKa(N¢H) value, the stronger the amine basicity. A plot of pKa(N¢H) versus conversion produces symmetric linear fits that intercept at the maximum point of pKa(N¢H) = 9.9 (Figure 2). The left end point was determined by extending the left half line to y = 0, which intercepted the x axis at pKa(N¢H) = 8.6. The right end point was determined by dipropylamine [pKa(N¢H) = 10.6]. The experimental data showed that the metathesis reaction relies greatly on the amine pKa(N¢H), and only amines within the pKa(N¢H) range 8.6–10.6 were converted into formamides. This explains why the reactions with aniline and some diamines were sluggish.[13] The basicity of the amine affects the strength of the interaction between the N atom of the amine and the C atom of CO2 : weak basicity [such as aniline, pKa(N¢H) < 8.6] results in an instable amine–CO2 adduct; strong basicity [pKa(N¢H) > 10.6] generates an interaction that is too stable, and the CO2 is bound strongly. The amines in Figure 2 were selected after consideration of both the pKa(N¢H) and steric hindrance; therefore, some amines fall out of this range. However, as a simple rule of ChemSusChem 2015, 8, 2066 – 2072
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Figure 2. Relationship between amine conversion and pKa(N¢H) values. Reaction conditions: amine (0.6 mmol), DMF (2 mL), 1 bar CO2, 100 8C, 2 h.
thumb, it helps to determine which kind of amine can be converted by this method. We then studied the substrate scope (Table 1). Sterically unhindered linear aliphatic amines with chains of up to 12 carbon atoms were converted to the corresponding formamides with > 99 % selectivity and > 99 % conversion (1–5); these results are better than those reported previously.[10, 14] Alicyclic cyclohexylamine and cyclopentylamine were converted satisfactorily to the corresponding formamides (4 and 5). No conversion was observed for dipropylamine and diethylamine (6 and 7). However, a hydroxy-terminated amine (8) and piperidine (9) achieved 23 % and > 99 % conversion, respectively, with > 99 % formamide selectivity. These amines were different at the terminal group. Steric as well as electronic and solvation effects might affect their activity. The two terminal hydroxy groups might form hydrogen bonds and, thus, expose more space for the N¢H bond activation. Piperidine, which could be viewed as a molecule in which the terminal groups are bonded, achieved better results. In contrast, a piperidine formamide was obtained with only 36 % yield in a B(OCH2CF3)3– DMF system.[10] To show the practical application of the procedure, a gram-scale synthesis of dodecylamine (2.78 g) was performed. The reaction offered 97 % isolated yield of dodecylformamide (3). Heterocyclic amines such as furfurylamine and 2-thiophenemethylamine were converted to formamides (10 and 11, respectively) with selectivities of > 99 %. To the best of our knowledge, this method represents a rare example of the formylation of a thiophene amine because sulfur may poison most catalytic metal centers. Several benzylamines were converted with excellent formamide selectivities (12–18). A slight substituent effect was evidenced by the lower conversion of the CF3-substituted benzylamine than for the F-substituted one. The less-nucleophilic aniline was inactive (19) because of its weak basicity (Figure 2). The formylation of the sterically unhindered hexane-1,6-diamine afforded 99 % of the diformamide (20). A worse result than that for hexane-1,6-diamine was
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Full Papers methods remains a hot topic.[16] In this study, we tested the labeling of protein amine groups with DMF through metathesis reactions. We added a little water to promote solubility but sacrificed some activity. After the reaction, both unreacted arginine (m/z = 175) and formylated arginine (m/z = 203) were detected by means of matrix-assisted laser desorption/ionization–time of flight (MALDI-TOF)/TOF MS (Figure 3 A). The reaction was further quantified by LC–MS (Figure 3 B) using an identical amount of lysine as internal standard. After the reaction, the relative intensity of arginine decreased greatly. The arginine conversion was 81 %, as analyzed by LC–MS. We further applied the method to more-complex amines from trypsin-digested bovine serum albumin (BSA). Trypsin is a pancreatic serine endoprotease that hydrolyzes peptide bonds specifically at the carboxyl side of arginine and lysine residues and leads to two classes of peptides. One is the peptide with the arginine residue at the carboxyl side, in which only the amine group of the N-terminus and the guanidine group of the arginine residue could be formylated, and the other is the peptide with the lysine residue at the carboxyl side, in which the amine group of the N-terminus and the lysine residue could be formylated. For the former, 57 % of the amine groups of the N-terminus, 14 % of the guanidine groups, and 0 % of both were formylated (Figure S5). For the later, these data were 67 %, 72 %, and 46 %, respectively. For
Table 1. Substrate scope of the reaction.[a] Structure
Compound
Conversion Selectivity [%] [%]
1 2 3
> 99 > 99 > 99
> 99[b] > 99 > 99
4
> 99
> 99[b]
5
> 99
> 99
6 7
n=3 n=5 n = 11
n=1 n=2
trace trace
– –
8
23
> 99
9
> 99
> 99
10
> 99
> 99
11
94
> 99
> 99 95 92 93 96
> 99 94 90 > 99 68
12 13 14 15 16
X=H X = p-Cl X = o-Cl X = p-F X = p-CF3
17
91
> 99[b]
18
98
98
19
trace
20
–
> 99
> 99
21[c] carried out in CO2 > 99 70 22[d] catalyzed by CeO2 instead of CO2
72 4
23[e]
> 99
68
24
> 99
> 99
[a] Reaction conditions: amine (1.5 mmol), DMF (2 mL), 100 8C, 24 h, 1 bar CO2 ; results were analyzed by GC and are presented as conversion/selectivity. [b] 48 h. [c] The remaining product was 1,4-diazepane-1-carbaldehyde (selectivity 28 %). [d] Amine (1.5 mmol), DMF (2 mL), CeO2 (100 mg), 150 8C, 24 h.[4k] 1,4-Diazepane-1-carbaldehyde selectivity 96 %. [e] Piperazine-1-carbaldehyde selectivity 32 %.
obtained for an alicyclic diamine with > 99 % conversion and 72 % selectivity for the diformamide and 28 % for the monoformamide (21). This might be due to the robust structure of the alicyclic diamine. However, this method was still superior to one with solid CeO2 catalyst, for which only 70 % conversion and 4 % of the diformamide was obtained (22).[4k] The formylation of piperazine offered 68 % diformamide and 32 % monoformamide (23). For dimethyl-substituted piperazine, monoformamide was obtained with > 99 % selectivity (24). Carbamylation reactions play important roles in multiple biological processes, such as the transportation of amino acids and protein synthesis in living systems.[15] To date, the protein formylation methods employed use expensive labeling reagents and complex procedures, but the development of new ChemSusChem 2015, 8, 2066 – 2072
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Figure 3. (A) MALDI-TOF results for arginine with a-cyano-4-hydroxycinnamic acid (CHCA) as the matrix. The y axis for arginine was vertically adjusted. (B) LC–MS results for the N-formylation of arginine.
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Full Papers histidine, 28 % of the side imidazole groups were formylated, which shows its inertness. The reaction was governed by the pKa(N¢H) rule (Figure 2) and the effect of steric hindrance. Usually, acetylation labeling through chemical reactions can only be performed for the primary amino group on the protein or peptide N-terminus and the lysine side chain. In this study, the method can be performed not only on the N-terminus and lysine but also on the guanidine group of the side chain of arginine. Although the CO2-mediated metathesis reaction is less efficient than the mature acetylation method, it provides a possible next-generation labeling strategy, especially for amines with coexisting functional groups sensitive to metal ions and strong acids or bases. In previous studies, DMF and its derivatives were activated by strong additives such as HClO4, iodine, NaOMe, and RSO2Cl. In our study, CO2 is a weakly acidic molecule and cannot activate DMF. We believed CO2 would activate amines and confirmed this through IR and NMR spectroscopy characterizations. The attenuated total reflectance (ATR)-IR spectra of benzylamine were measured before and after CO2 was bubbled through it at room temperature (Figure 4 A). The CO2 dissolved in the benzylamine, as indicated by a peak at n˜ = 2340 cm¢1 for the asymmetric stretch of CO2. Two peaks at n˜ = 1720 and 1648 cm¢1 were assigned to the ¢COOH vibration of the N-carbamic acid.[17] No carbamate was formed, as indicated by the absence of an absorption at n˜ 1570 cm¢1.[17] For DMF with CO2 bubbling at room temperature (Figure 4 B), the spectrum resembled that of pure DMF, which indicates that no interaction occurred between DMF and CO2. More detailed reaction information for benzylamine, DMF, and CO2 was obtained by monitoring the initial 30 min reaction through ATR-IR spectroscopy (Figure 5). The bubbling of CO2 generated three peaks at n˜ = 1231, 1542, and 1720 cm¢1, which indicated the formation of the N-carbamic acid. The formation of N-benzylformamide was evidenced by the peaks at n˜ = 1673 and 1382 cm¢1. The formation of the N-carbamic acids of dipropylamine and benzylamine after CO2 bubbling in [D6]DMSO was further characterized by 13C NMR spectroscopy. The signals at d = 157 ppm
Figure 4. In situ ATR-IR spectra of (A) benzylamine and (B) DMF, flushed with Ar gas and in the presence of CO2.
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Figure 5. Stacked in situ FTIR spectra for initial 30 min. Reaction conditions: benzylamine (3 mmol), DMF (24 mL), 1 bar CO2, 100 8C.
for dipropylamine and d = 158 ppm for benzylamine were assigned to the carbonyl C atoms of the N-carbamic acids [Figure 6 A and B].[17] The discernible low-field shifts of the C atoms next to the N atoms from d = 52–48 ppm for dipropylamine and from d = 46–44 ppm for benzylamine indicated the gain of electron density after the formation of the N-carbamic acids. The chemical shift at 39 ppm for both amines was due to the trace residue of normal DMSO in the [D6]DMSO solvent. The presence of the N-carbamic acid was again confirmed by 1 H NMR spectroscopy in [D6]DMSO. After the CO2 bubbling, the d(O¢H) of the N-carbamic acid appeared at 7.7 ppm, whereas the d(C¢H) of dipropylamine at 2.4 ppm was upshifted to 3.0 ppm (Figure 6 C), which was assigned to the d(C¢H) of the N-carbamic acid.[17] After the bubbling of CO2 into benzylamine, the d(C¢H) of the amine at 3.7 ppm shifted to 4.2 ppm, which was indicative of d(C¢H) of the N-carbamic acid. The newly formed d(O¢H) of the N-carbamic acid appeared at 8.7 ppm (Figure 6 D). Signals at d = 3.4 and 1.1 ppm were attributed to ethanol contamination from the tube for CO2 bubbling. The signal at d = 2.5 ppm originated from normal DMSO in [D6]DMSO. We then studied the solvent effect by 13C NMR spectroscopy (Figure 7). The addition of CO2 into a mixture of benzylamine and dipropylamine in [D6]DMSO and [D7]DMF at room temperature resulted in 100 % conversion to the N-carbamic acids. This was illustrated by the presence of two new C=O signals at d < 160 ppm (159 and 158 ppm in [D6]DMSO, 160 and 159 ppm in [D7]DMF, respectively), in good agreement with the results in Figure 6. In contrast, only a single signal appeared at d = 163 ppm in CDCl3, but it was stronger than the signals recorded in [D6]DMSO and [D7]DMF. The value was larger than the normal shift of the C atoms of carbamic acids (less than 160 ppm). This signal originated from ammonium carbamate [PhCH2NHCOO¢ (CH3CH2CH2)2NH2+], the adduct of the amine and CO2 in CDCl3 ; thus, only one signal was discerned.[17] The reaction of an amine and CO2 to form an N-carbamic acid (CA) is rapid and has a reaction rate k1 of 104 m¢1 s¢1. The reverse reaction is slow with k1’ = 101 m¢1 s¢1.[18] Previous studies mentioned that the C¢N bond might undergo an exchange reaction of the carboxyl group with CO2.[19] The formation of
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Figure 6. 13C and 1H NMR spectroscopy characterization of dipropylamine (A and C) and benzylamine (B and D) in Ar or CO2.
Figure 7. 13C NMR spectra of a mixture of benzylamine and dipropylamine in CDCl3, [D6]DMSO, or [D7]DMF after CO2 bubbling.
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CA was confirmed by 1H NMR, 13C NMR, and ATR-IR spectroscopy. The key reaction is that the CA further reacts with DMF to generate the formamide (FA) product and release CO2, which was also confirmed by IR and NMR spectroscopy. The reaction of DMF with CA may involve a C¢N bond-metathesis transient state. We isolated pure ammonium carbamate zwitterion (AC) and reacted it with DMF (Figure S6). As the reaction selectivity was > 99 %, we used the FA production rate as the reaction rate. The initial rate of 0 L mol¢1 s¢1 might infer that AC was converted to CA during this period. Further, the reaction rates decreased with time with an average rate k2 of 10¢6 L mol¢1 s¢1. This rate was much smaller than k1; therefore step 2 is the rate-determining step. Therefore, the initial reaction quickly generated CA and then AC, as an amine reservoir (Figure 8). The FA was generated from CA and DMF. The addition of a small amount of water irreversibly hydrolyzed CA to carbonate. A control reaction in a 1:1 volumetric ratio mixture of DMF and water at 100 8C for
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Figure 8. The possible reaction mechanism.
4 h gave 24 % conversion of benzylamine, in comparison with 92 % conversion in pure DMF. Moreover a reaction of the separated carbonate with DMF generated no product. These facts indicate that carbonate is not the reaction intermediate and its production is irreversible. The steric hindrance of the methyl groups (R1, R2) connected to the N atom of the amine interrupt the interaction of DMF with the amine and retard this reaction. The metathesis product dimethylamine, as the leaving group of DMF, has a pKa(N¢H) value of 10.6, which is large enough to form a stable carbamic acid product with CO2 under the reaction conditions and drive the reaction to the right. After the reaction, an increase in temperature or flushing with N2 would remove dimethylamine and CO2 gas; therefore, the reaction is clean and convenient.
Conclusions We have reported the use of CO2 as a mediator in the transformation of amines to their corresponding formamides in DMF. The metathesis reaction is conducted without the use of any metals. This will provide a useful method for the formylation and protection of amine groups in a simple, green, and economical way.
Experimental Section Methods: All chemicals were analytical grade and used as purchased without further purification. Most of the chemicals were purchased from Aladdin Chemicals, except DMF, aniline, and diethylamine, which were purchased from Tianjin Kemiou Chemical Reagent Co., Ltd., n-butylamine and cyclohexylamine were purchased from Sinopharm Chemical Reagent Co., Ltd., and 2,6-dimethylpyrazine was purchased from J&K chemicals. Catalytic reactions: The reactions were conducted in a 50 mL glass batch reactor (heavy wall, maximum pressure: 0.6 MPa, Synthware Glass). Typically, benzylamine (1.5 mmol), DMF (2 mL), and a stirring bar were placed in the reactor, which was then charged with CO2 gas (1 bar) from a gas cylinder. The reaction solution changed gradually into a thick white gel over several minutes. The reactor was sealed tightly with a Teflon stopper and then immersed in an oil bath preheated at the desired temperature. The ChemSusChem 2015, 8, 2066 – 2072
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gradual disappearance of the gel indicated the end of reaction, which was also tracked by GC (Agilent 7890A). The reaction solution was cooled to room temperature, and then a sample of the reaction mixture ( 0.2 mL) was analyzed by GC–MS (Agilent 7890A5975C). In most cases, the reaction was very clean and, thus, the conversion of amine and the selectivity for formamide were obtained from the normalized GC integration peak areas. General characterizations and analyses: All liquid NMR spectroscopy experiments were performed with a Bruker Avance III-400 spectrometer with [D6]DMSO, [D7]DMF, or CDCl3 as the deuterated solvent for locking. 1H and 13C NMR spectroscopy experiments with proton decoupling were conducted at 100.62 MHz with 200 scans and a 2 s recycle delay. The chemical shifts were referenced to tetramethylsilane (TMS). In situ ATR-IR spectra were recorded with a Mettler Toledo React IR 4000 spectrometer with a DiCom probe. The IR spectra were recorded with [benzylamine] = 0.75 m in DMF after CO2 degassing for at least 2 min under continuous stirring. Bovine serum albumin (BSA) digestion: The BSA was denatured with 8 m urea/100 mm tetraethylammonium bromide (TEAB, pH 8.0), reduced by 10 mm dithiothreitol at 60 8C for 1 h, and alkylated with 20 mm iodoacetamide in darkness at room temperature for 30 min, followed by dilution with 100 mm TEAB buffer (pH 8.0) and digestion with trypsin at 37 8C for 16 h. Finally, the BSA digests were desalted with C18 solid-phase extraction (SPE) columns and lyophilized for use. MALDI-TOF MS analysis: The MALDI-TOF MS experiments were performed using an AB Sciex 5800 MALDI-TOF/TOF mass spectrometer (AB Sciex) equipped with a pulsed Nd–YAG laser at 355 nm in reflective positive-ion mode. The sample ( 0.5 mL) and matrix (0.5 mL; 25 mg mL¢1 2,5-dihydroxybenzoic acid in 50 % acetonitrile/ H2O) were spotted on the MALDI plate for MS analysis. The liquid chromatography coupled with mass spectrometry/mass spectrometry (LC–MS/MS) experiments were performed using a Thermo Q Exactive mass spectrometer (Thermo) with a nanospray ion source and a U3000 RSLCnano system (Thermo). After lyophilization, the samples were redissolved with 0.1 % formic acid solution and loaded on a C18 capillary trap column (200 mm i.d., 4 cm) packed with C18 AQ beads (5 mm, 120 æ, Daison) and separated by a capillary analysis column (75 mm i.d.) with C18 AQ beads (3 mm, 120 æ, Daison). The buffers used for the online analysis were 0.1 % (v/v) formic acid in water and 0.1 % (v/v) formic acid in acetonitrile, the flow rate was 300 nL min¢1 for nanoflow LC–MS/MS analysis. A gradient from 5 to 35 % (v/v) acetonitrile was achieved in 15 min for arginine samples and 90 min for BSA samples. The MS and MS/MS spectra were collected by higher-energy collision-induced dissociation (HCD) at 28 % energy in a data-dependent mode with one MS scan followed by 10 MS/MS scans. The RAW files collected by Xcalibur 2.1 were converted to MGF files by Proteome Discoverer (v1.2.0.208, Thermo) and searched with Mascot (version 2.3.0, Matrix Science). Cysteine carboxamidomethylation was set as a static modification of 57.0215 Da, and formylation and methionine oxidation were set as variable modifications of 27.9949 Da and 15.9949 Da, respectively. The mass tolerances were 10 ppm and 0.5 Da for the parent and fragment ions, respectively. A maxi-
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Full Papers mum of two missed cleavages was allowed, and the false discovery rate for peptide identifications was controlled to < 1 %.
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Received: March 3, 2015 Revised: April 3, 2015 Published online on June 3, 2015
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