Efficient labeling of organic molecules using 13C elemental carbon: universal access to 13C2-labeled synthetic building blocks, polymers and pharmaceuticals

Maria S. Ledovskaya a, Vladimir V. Voronin a, Konstantin S. Rodygin ab and Valentine P. Ananikov *ab
aInstitute of Chemistry, Saint Petersburg State University, Universitetsky prospect 26, Peterhof, 198504, Russia. E-mail: val@ioc.ac.ru
bN. D. Zelinsky Institute of Organic Chemistry Russian Academy of Sciences, Leninsky prospect 47, Moscow, 119991, Russia

Received 8th November 2019 , Accepted 18th December 2019

First published on 19th December 2019

Among different types of labeling, 13C-labeled compounds are the most demanding in organic chemistry, life sciences and materials design. However, 13C-labeled organic molecules are very difficult to employ in practice due to extreme cost. The rather narrow range of labeled organic starting materials and the absence of universal synthetic building units further complicate the problem and make utilization of 13C-labeled molecules hardly possible in many cases. Here we report a versatile approach for 13C2-labeling of organic molecules starting with 13C elemental carbon: 13C carbon is applied for the synthesis of calcium carbide (Ca13C2), which is subsequently used to generate acetylene – a universal 13C2 unit for atom-economic organic transformations. Syntheses of labeled alkynes, O,S,N-functionalized vinyl derivatives, polymers and pharmaceutical substances were demonstrated. Elemental 13C carbon, as the chemically most simple source for 13C2-labeling, here was successfully combined with universal synthetic applicability of alkynes.


Stable-isotope-labeled compounds are extensively used in chemical, biomedical and environmental research. The most common labels are isotopes of organogenic elements, notably 2H, 13C, 15N, 17O, 18O, 33S, 34S and 36S.1–5 Introduction of a stable label into a molecule facilitates its detection in a living organism by mass-spectrometry, nuclear magnetic resonance spectrometry (NMR) or magnetic resonance imaging (MRI). Besides being an observation target in itself, the label may increase the sensitivity of detection in favor of the neighboring atoms. This property underlies the principle of hyperpolarized NMR and MRI experiments6 and two-dimensional NMR applications.7 These techniques are especially useful in structural studies of polymeric materials and biomacromolecules including proteins, DNA, RNA and polysaccharides.2e,3b,8 A recent study demonstrated an interesting example of Raman microscopy application for distinguishing between various 13C-edited tags, with different Raman shifts for labeled, double-labeled and non-labeled molecules.9 However, tagging of particular groups in complex molecules, polymeric materials or living organisms for analytical purposes is just one of the applications involving stable labels. Kinetic studies of isotope effects represent an important mechanistic tool for modern chemistry.10 Isotopic substitutions significantly affect drug pharmacokinetics by modifying the balance of metabolic stability, activity and safety.11 Numerous applications of isotopic labeling in chemistry,12 biology,13 pharmacology,14 soil/agriculture15 and environmental studies13b,16 are very important. They are continuously upgraded by the enhancement of isotope detection techniques and labeling standards,17 development of which has become one of the top priorities for modern chemistry. Detection of polymer contaminants in the environment, so-called nanoplastics and microplastics, is another challenging topic.18 Incorporation of a stable label into a polymer chain makes its relation to nanoplastics and microplastics traceable. For environmental reasons, it is very important to use non-toxic, easily detectable labels, which do not alter the properties of polymeric materials. Indeed, carbon labeling with 13C is the most suitable and practical tool for a number of highly demanding applications.

Despite the paramount demand for labeled materials, the high prices of starting materials for chemical labeling severely limit the development and entail the following requirements to synthetic procedures: (1) the cheap source of label is preferable; (2) the reaction should be atom-economic to cut spending on the label. Labeling with 13C is notably difficult and expensive.19 Some of the previous investigations proposed the application of barium carbide-13C2[thin space (1/6-em)]20 or lithium carbide-13C2.21 By this way, a narrow range of organic compounds was obtained. The limitation of these methods is an exceptional complexity of the synthesis and handling with barium carbide-13C2 or lithium carbide-13C2. The other problem is the necessity to convert Ba13C2 and Li213C2 to acetylene-13C2, which then collected and redistilled prior to use20,21 due to metal oxides impurities formed according to described synthetic paths to Ba13C2 and Li213C2. In this study, we synthesize Ca13C2 from elemental 13C, which is cheap and most 13C-enriched source. We use labeled calcium carbide in situ to obtain 13C2-vinyl derivatives (Scheme 1, path a), which can be utilized as a label source in further syntheses. Designed here Ca13C2-based strategy enables efficient production of 13C2-labeled alkyne blocks, 13C2-bis(trimethylsilyl)acetylene (Scheme 1, path b), 1-bromo-2-trimethylsilylacetylene-13C2 (Scheme 1, path c) and dilithium acetylide-13C2 (Scheme 1, path d). We also use the synthesized Ca13C2 as a source of 13C2-acetylene for Diels–Alder – retro Diels–Alder sequence to obtain a 13C2-pyridazine core (Scheme 1, path e). In addition, its utility for incorporation of the label into polymeric chain is demonstrated by 13C2-vinyl derivative cationic polymerization (Scheme 1, path f).

image file: c9qo01357a-s1.tif
Scheme 1 Synthetic potential of 13C elemental carbon highlighted in this study.

Results and discussion

Synthesis of 13C-labeled calcium carbide (Ca13C2)

Calcium carbide is a well-known reagent in organic synthesis.22 It is widely used in organic synthesis due to the convenience of handling and better safety as compared to acetylene gas. The application of calcium carbide allows to reduce acetylene excess in the reaction vessel (stoichiometric or desired reagents ratio) and do not require special gas equipment: the reactions can be performed in a screw-cap tube22f,h,23 or two-chamber reactor.12e Practical methods to produce calcium carbide are based on thermal24 or microwave25 treatment of calcium and carbon sources. Limestone and coal are commonly used for carbide manufacturing.24a–c,26 In some cases, graphite,25,27 fine biochars28 or hydrocarbons29 are used as a source of carbon. Impurities from coal and lime usually interfere with the main process and contaminate the final product. Ultra-pure carbide for high-precision tasks should be therefore synthesized from the elements.30 In our setting for this study, calcium carbide-13C2 was synthesized using a modified procedure for better utilization of the valuable 13C carbon. Synthesis of 13C-labeled calcium carbide on ∼1 g scale and 5 g scales of 99% 13C-enriched carbon were performed (see ESI for description) (Scheme 2).
image file: c9qo01357a-s2.tif
Scheme 2 Synthesis of 13C-labeled calcium carbide (Ca13C2).

Examination of the synthesized labeled calcium carbide was done by scanning electron microscopy (SEM) and revealed its considerable morphological difference compared with commercially available unlabeled calcium carbide (cf.Fig. 1 and Fig. S1). The surface of the synthesized sample is highly developed, with numerous folds; its area is much larger than that of the commercially available reagent. Because of this feature, the synthesized carbide should be much more reactive with water and other substances.

image file: c9qo01357a-f1.tif
Fig. 1 SEM images of synthesized calcium carbide-13C2 samples (Ca13C2): a, b outer surface; c, d inner structural morphology revealed by ion beam cutting (FIB-SEM). Scale bars: 2 μm for 1a, 1 μm for 1b, 300 nm for 1c and 1d.

Cutting the synthesized sample with an ion beam (FIB-SEM) reveals the complexity of its internal structure (Fig. 1, images c and d). The section encompasses numerous cavities of various shape and channels. The spongy internal texture of the obtained carbide samples can also accelerate the course of reactions by increasing the contact area between the reactants. The observed morphological differences between the commercially available carbide and the synthesized samples are explained by the difference in the methods of production. In industry, carbide is synthesized from calcium carbonate and coal, while the labeled carbide in this study is synthesized from the elements under vacuum. Cavities inside the samples result in developed internal structure and significantly increased surface area. Due to effect of moisture from the air, the samples are crusted with calcium hydroxide, a product of hydrolysis of the carbide with atmospheric moisture (Fig. 1, images a and b). This crust is very fragile, it cracks easily, and it crumbles under the action of the ion beam.

Due to such micro-structure the prepared Ca13C2 is very reactive and quantitatively releases the desired 13C2-labeled building block under regular organic synthesis conditions. Next, we evaluate the potential of Ca13C2 for a representative variety of key processes including the synthesis of 13C2-labeled alkynes, monomers, post-modification of pharmaceutically active compounds, construction of universal synthetic building blocks, drug labeling and labeled polymer synthesis.

Synthesis of 13C2-vinyl derivatives

In the beginning of the study, we explored the possibility of using Ca13C2 to generate acetylene-13C2 for vinylation reactions yielding 13C2-labeled O-, S- and N-vinyl derivatives, the versatile building blocks for organic synthesis and polymeric materials.23c,d,31 Vinylation with Ca13C2 by a carbide-based protocol proceeded exceptionally well. It afforded good to excellent yields of 13C2-vinyl ethers, vinyl sulfides and vinylated nitrogen compounds with 99% 13C content in the vinyl group (Table 1). For instance, 13C2-vinyl ethers of naturally occurring menthol (2b), cholesterol (2c), protected fructose (2f) and galactose (2e) were obtained in 81 to 87% yields. Reaction with antituberculosis drug ethambutol 1g produced the corresponding bis(vinyl-13C2) derivative 2g in 93% yield. Thiols 1h–j were transformed to 13C2-vinyl sulfides 2h–j in up to 99% yields. Vinylation of nitrogen compounds proceeded smoothly leading to 13C2-labeled products 2k–o in 67 to 95% yields. Moreover, 13C2-vinylation of antipsychotic drug olanzapine resulted with the derivative 2p obtained in 82% yield.
Table 1 The synthesis of 13C2-vinyl derivatives using calcium carbide
Reaction conditions: Sealed screw-cap tube, 1 (0.5 mmol), Ca13C2 (2.0 mmol), DMSO (1 ml), H2O (4.0 mmol); for 1a–g, 1k–p 0.5 mmol of KOtBu, 1.0 mmol of KF; for 1h–j 1.0 mmol of Et3N; for 1a–g 130 °C, 4 h; for 1h–j 100 °C, 4 h; for 1k–p 100 °C, 6 h.
image file: c9qo01357a-u1.tif

Synthesis of 13C2-alkynes and their use in transformations

At the next step of the study, the synthesized Ca13C2 was utilized in the synthesis of 13C2-labeled bis(trimethylsilyl)acetylene, a handy building block for various purposes. To minimize the losses of labeled substrate, we carefully adjusted the reaction conditions for the non-labeled substrate and optimized the procedure to achieve the maximal absorption of acetylene produced from CaC2.

In this study, we tested several approaches for gram-scale synthesis of labeled bis(trimethylsilyl)acetylene; the best of them involved the use of Grignard reagent. In this approach, the 13C-labeled calcium carbide reacted with water producing 13C2-acetylene, which was subsequently passed through an ice-cooled tetrahydrofuran solution of ethyl magnesium bromide. The resulting acetylenic Grignard reagent 3 reacted with chlorotrimethylsilane affording the desired bis(trimethylsilyl)acetylene-13C24 in 94% overall yield (Scheme 3).

image file: c9qo01357a-s3.tif
Scheme 3 Synthesis of bis(trimethylsilyl)acetylene-13C2. aOverall yield for 3 steps.

Transformations of symmetrical alkynes, e.g. bis(trimethylsilyl)acetylene-13C24, to asymmetrical derivatives is a challenging topic in organic chemistry with synthesis of halogenated alkynes being a special part of this topic.19a,32 A representative example is the transformation of bis (trimethylsilyl)acetylene-13C2 to its brominated derivative, 1-bromo-2-(trimethylsilyl)acetylene-13C25.

Sequential treatment of 13C2-labeled bis-substituted acetylene 4 by methyl lithium and bromine led to 1-bromo-2-(trimethylsilyl)acetylene-13C25 in 67% NMR yield (Scheme 4). 13C NMR spectrum of the reaction mixture comprised two doublets at 87.1 ppm and 61.5 ppm (J = 142.1 Hz) and the doublet of doublets of trimethylsilyl moiety at −0.1 ppm (J = 5.5, 1.9 Hz) identified as product 5.33 Formation of a side product, 1,1,2-tribromo-2-(trimethylsilyl)ethene-13C2, was indicated by two doublets at 130.8 ppm and 94.2 ppm (J = 72.0 Hz) and a doublet of trimethylsilyl moiety at 0.7 ppm (J = 3.8 Hz)33 observed in 13C NMR spectrum of the isolated mixture.

image file: c9qo01357a-s4.tif
Scheme 4 Synthesis of 1-bromo-2-(trimethylsilyl)acetylene-13C2.

Treatment of acetylene with organolithium reagents provides a convenient path to highly reactive lithium acetylide 6 (Li213C2, Scheme 5), which is excellent building block for variety of synthetic reactions.34 Practically, the experiment can be carried out in simple and convenient two-chamber reactors (Scheme 5, inserted picture). To estimate the suitability of the developed system for lithium acetylide-13C2 generation we have conducted a 13C NMR experiment by mixing methyl lithium with a benzene-d6 solution of 13C2-acetylene generated from the synthesized Ca13C2. The reaction of 13C2H2 with MeLi lead to the Li213C2 precipitation. Formation of 6 was confirmed by distortionless enhancement by polarization transfer (DEPT) spectroscopy. Solution of 13C2-acetylene produced a singlet at 71.9 ppm in the 13C NMR spectrum corresponding to 13CH group,35 which was also clearly visible in DEPT spectrum. The signal in DEPT spectrum disappeared upon formation of Li13C group in 6 (Fig. S24). The process was also monitored by 1H NMR: the labeled acetylene gave the picture of AA′XX′ system (δ = 1.36 ppm, JH–H = 9.5 Hz, 1JC–H = 249.0 Hz, 2JC–H = 49.0 Hz, JC–C = 173.0 Hz; Fig. S25),21a which disappeared upon lithiation. The formation of lithium acetylide was additionally confirmed by addition of water to the lithium carbide suspension: vigorous acetylene evolution was observed.

image file: c9qo01357a-s5.tif
Scheme 5 Production of 13C2-acetylene and lithium acetylide-13C2; inserted picture – convenient experimental setups using two-neck two-chamber (H-tube) or one-neck two-chamber reactors for one-vessel synthesis.

13C2-Pyridazine core construction

We tested if 13C2-acetylene generated from the synthesized Ca13C2 is suitable for obtaining 13C2-pyridazine cores. For this purpose, 3,6-dichloro-1,2,4,5-tetrazine 7 was synthesized and used as a starting material. After optimization, 4,5-13C2-3,6-dichloropyridazine 8 was for the first time obtained from Ca13C2 in an almost quantitative yield using two-chamber reactor (Scheme 6, for the setup see inserted picture on Scheme 5). Compound 8 reacted with sodium hydrosulfide to afford 4,5-13C2-6-chloropyridazine-3-thiol 9 in 87% yield. Compound 9 subsequently reacted with 2-chloro-N,N-diethylacetamide producing 13C2-labeled choleretic drug Azintamide 10 in 91% yield (Scheme 6).
image file: c9qo01357a-s6.tif
Scheme 6 Synthesis of 13C2-azintamide.

It should be emphasized that for reactions with acetylene we propose simple and efficient experimental setups based on two-chamber reactors (Scheme 5, inserted picture). Generation of labeled acetylene and subsequent transformations are carried out in one vessel. Such setups minimize losses of labeled acetylene and avoid contact with atmosphere (for controlled release of acetylene water can be slowly added to the corresponding tube via septum).

Labeled polymer synthesis

Also, we investigated cationic polymerization of vinyl derivatives. For this purpose, 13C2-vinyl derivative 2d and, for comparison, its non-labeled analog (see ESI for details) were exposed to cationic polymerization conditions (Scheme 7). 13C-Labeled polymer 11d and its unlabeled analog were isolated in good yields by using a conventional protocol, without specific optimization of the reaction conditions.
image file: c9qo01357a-s7.tif
Scheme 7 Cationic polymerization of 13C2-vinyl derivative.

The properties of the polymeric products were characterized by NMR spectroscopy and size exclusion chromatography (see ESI for details). With the correction for 13C, molecular weights of 13C-labeled and non-labeled polymers were similar: 14[thin space (1/6-em)]000 g mol−1 and 12[thin space (1/6-em)]600 g mol−1, respectively. Thus, 13C-labeled polymers can be readily obtained by using standard reaction conditions and this finding opens a new path to labeled polymeric materials.

Improved spectral detection

To estimate the level of supposed improvement in detectability of compounds after the labeling, we conducted a comparative NMR study. 13C NMR spectra of 13C2-Azintamide 10 and non-labeled Azintamide were recorded (both at 30 mM concentration). The peaks for 10 were clearly detectable from a single scan with an excellent signal-to-noise ratio (S/N ≥ 40, Fig. 2A). At the same concentration, non-labeled Azintamide gave no detectable signal in this spectral region (Fig. 2B). To highlight the difference in spectral detection, non-labeled Azintamide produced a detectable signal at 256 scans with S/N ratio of only ≈7 (see Fig. S2–S5).
image file: c9qo01357a-f2.tif
Fig. 2 Fragments of 13C NMR spectra of 5 mg samples of 13C-labeled (A) and non-labeled (B) Azintamide (10) recorded with 1 scan (101 MHz, CDCl3, 298 K).

Thus, high intensity NMR signal can be rapidly detected for 13C2-labeled compounds (1 scan, 3 s; Fig. 2A). Noticeably, under the same conditions detection for unlabeled compound was impossible (no signal, Fig. 2B) and much lower signal intensity was recorded even after significantly longer measurements time (256 scans, ∼15 min; Fig. S4 and S5). Using a labeled drug molecule is an important model study since NMR/MRI studies of drugs action and metabolism is one of the most demanding problems in biochemistry and medicine. With natural 13C abundance such studies are literally impossible due to negligible signal intensity, whereas 13C-labeled probes provide outstanding opportunity.


To summarize, a functional and cost efficient way of introducing 13C2-unit into organic molecules has been proposed. Calcium carbide-13C2 is a multipurpose compound that can be applied as an in situ source of 13C2-acetylene by using a tube, two-chamber reactor or a separate vessel for gas generation.

Using calcium carbide-13C2, we have successfully obtained building blocks with 13C2-vinyl and 13C2-alkyne moieties. The scope of afforded products includes vinyl ethers, vinyl sulfides, vinylated nitrogen compounds and bis(trimethylsilyl)acetylene-13C2. A convenient milligram-scale path to 1-bromo-2-(trimethylsilyl)acetylene-13C2 was described. The possibility of construction of 13C2-pyridazine core from Ca13C2 has been demonstrated; the approach has been successfully applied for 13C2-Azintamide synthesis as an example of 13C-labeled drug molecule. Paramount increase in the NMR signals intensity was observed, highlighting promising perspectives to enhance medicinal and pharmacological studies of 13C-labeled drugs. Cationic polymerization of 13C2-vinylated compounds proceeds straightforwardly yielding polymers of normal length with the highest possible content of the label in the carbon chain.

In overall, development of efficient synthetic methodology was achieved starting from elemental carbon as chemically most simple source for 13C labeling. Highly diverse and well-developed chemistry of acetylene undoubtedly favors usage of this 13C labeled alkyne as a universal synthetic building block.

Experimental section

General information

Chemicals were purchased from Sigma Aldrich, Alfa Aesar and Acros Organics in reagent grade or better quality and checked by NMR and GC before use. Granulated calcium carbide of technical grade (≥75% purity) was purchased from Sigma Aldrich. The synthesis of 13C2-labeled calcium carbide is described in ESI. Ca13C2 should be stored in a closed vessel in a dry place to avoid undesirable contact with moisture. Handling of Ca13C2 does not require special equipment; the one recommendation is to limit air exposure to Ca13C2 by around 1 min to minimise its contact with accidental moisture. NMR spectra were recorded on a Bruker Avance 400 spectrometer (1H 400 MHz; 13C 101 MHz). Chemical shifts δ are reported in ppm relative to residual CHCl3 (1H, δ = 7.26), C6H6 (1H, δ = 7.16) or DMSO (1H, δ = 2.50) and CDCl3 (13C, δ = 77.16), C6D6 (13C, δ = 128.06) or DMSO-d6 (13C, δ = 39.52) as internal standards. High-resolution mass spectra (HRMS) were recorded on a Bruker micrOTOF spectrometer using electrospray ionization (ESI). Size-exclusion chromatography (SEC) was carried out using an Agilent 1260 Infinity GPC-SEC system equipped with a PLgel 5 μm MIXED-D 300 × 7.5 mm column and a differential refractive index detector. Average molar mass (Mn,SEC) and molar mass distribution (Mw/Mn) values were determined using SEC in tetrahydrofuran (THF) at 40 °C (flow rate = 1.0 mL min−1) vs. polystyrene standards. The unit calibration was conducted using commercially available narrow molecular-weight-distribution polystyrene standards (Polystyrene High Easivials PL2010-0201 and PL2010-0202). The chromatograms were processed using the Aglient GPC-SEC software. The polymer samples were initially filtered through a PLgel 10 μm Guard 50 × 7.5 mm column. Reactions were monitored by TLC analysis using Merck UV-254 plates. Preparative column chromatography was performed on Merck silica gel 60 (230–400 Mesh) pretreated with triethylamine.

General procedure for the synthesis of 13C2-vinyl derivatives 2a–p

A reaction tube equipped with screw-cap was loaded with 1 (0.5 mmol), calcium carbide-13C2 (2 mmol), 1.0 mmol of KOtBu, and 0.5 mmol of KF for 1a–h and 1l–q or 1.0 mmol of Et3N for 1i–k. Then 1.0 ml of DMSO-d6 and 4.0 mmol of H2O were added and the tube was immediately sealed; the mixture was stirred at 130 °C for 4 h in the case of 1a–h, 100 °C for 4 h in the case of 1i–k and 100 °C for 6 h in the case of 1l–q. After that, the reaction mixture was cooled to room temperature and extracted with hexane. The solvent from hexane extract was evaporated, and the residue was purified by column chromatography with hexane as an eluent.

Conflicts of interest

There are no conflicts to declare.


The authors express their gratitude to the Resource Centres of Saint Petersburg State University: Magnetic Resonance Research Centre, Chemical Analysis and Materials Research Centre, and Educational Resource Centre. We express a special gratitude to the Resource Centre for Nanotechnology of Saint Petersburg State University and, personally, to Vladimir U. Mikhailovsky.

Notes and references

  1. (a) S. L. Harbeson and R. D. Tung, in Annu. Rep. Med. Chem., ed. J. E. Macor, Academic Press, 2011, vol. 46, pp. 403–417 Search PubMed; (b) K. Park, T. Matsuda, T. Yamada, Y. Monguchi, Y. Sawama, N. Doi, Y. Sasai, S.-I. Kondo, Y. Sawama and H. Sajiki, Direct Deuteration of Acrylic and Methacrylic Acid Derivatives Catalyzed by Platinum on Carbon in Deuterium Oxide, Adv. Synth. Catal., 2018, 360, 2303–2307 CrossRef CAS.
  2. (a) J. A. M. Lummiss, A. G. G. Botti and D. E. Fogg, Isotopic probes for ruthenium-catalyzed olefin metathesis, Catal. Sci. Technol., 2014, 4, 4210–4218 RSC; (b) K. A. Moore, J. S. Vidaurri-Martinez and D. M. Thamattoor, The Benzylidenecarbene–Phenylacetylene Rearrangement: An Experimental and Computational Study, J. Am. Chem. Soc., 2012, 134, 20037–20040 CrossRef CAS PubMed; (c) Z. Pan, S. M. Pound, N. R. Rondla and C. J. Douglas, Intramolecular Aminocyanation of Alkenes by N-CN Bond Cleavage, Angew. Chem., Int. Ed., 2014, 53, 5170–5174 CAS; (d) S. Scheller, M. Goenrich, S. Mayr, R. K. Thauer and B. Jaun, Intermediates in the Catalytic Cycle of Methyl Coenzyme M Reductase: Isotope Exchange is Consistent with Formation of a σ-Alkane–Nickel Complex, Angew. Chem., Int. Ed., 2010, 49, 8112–8115 CrossRef CAS; (e) A. R. Galiakhmetov, E. A. Kovrigina, C. Xia, J.-J. P. Kim and E. L. Kovrigin, Application of methyl-TROSY to a large paramagnetic membrane protein without perdeuteration: 13C-MMTS-labeled NADPH-cytochrome P450 oxidoreductase, J. Biomol. NMR, 2018, 70, 21–31 CrossRef CAS PubMed.
  3. (a) J. Kremser, E. Strebitzer, R. Plangger, M. A. Juen, F. Nußbaumer, H. Glasner, K. Breuker and C. Kreutz, Chemical synthesis and NMR spectroscopy of long stable isotope labelled RNA, Chem. Commun., 2017, 53, 12938–12941 RSC; (b) Y. Liu, E. Holmstrom, P. Yu, K. Tan, X. Zuo, D. J. Nesbitt, R. Sousa, J. R. Stagno and Y.-X. Wang, Incorporation of isotopic, fluorescent, and heavy-atom-modified nucleotides into RNAs by position-selective labeling of RNA, Nat. Protoc., 2018, 13, 987 CrossRef CAS PubMed; (c) P. S. Nadaud, J. J. Helmus, S. L. Kall and C. P. Jaroniec, Paramagnetic Ions Enable Tuning of Nuclear Relaxation Rates and Provide Long-Range Structural Restraints in Solid-State NMR of Proteins, J. Am. Chem. Soc., 2009, 131, 8108–8120 CrossRef CAS PubMed.
  4. (a) S. H. Brewer, B. Song, D. P. Raleigh and R. B. Dyer, Residue Specific Resolution of Protein Folding Dynamics Using Isotope-Edited Infrared Temperature Jump Spectroscopy, Biochemistry, 2007, 46, 3279–3285 CrossRef CAS PubMed; (b) D. Grekov, Y. Bouhoute, I. del Rosal, L. Maron, M. Taoufik, R. M. Gauvin and L. Delevoye, 17O MAS NMR studies of oxo-based olefin metathesis catalysts: a critical assessment of signal enhancement methods, Phys. Chem. Chem. Phys., 2016, 18, 28157–28163 RSC; (c) P. Guga, K. Domański and W. J. Stec, Oxathiaphospholane Approach to the Synthesis of P-Chiral, Isotopomeric Deoxy(ribonucleoside phosphorothioate)s and Phosphates Labeled with an Oxygen Isotope, Angew. Chem., Int. Ed., 2001, 40, 610–613 CrossRef CAS; (d) S. Hanashima, N. Fujiwara, K. Matsumoto, N. Iwasaki, G.-Q. Zheng, H. Torigoe, K. Suzuki, N. Taniguchi and Y. Yamaguchi, A solution 17O-NMR approach for observing an oxidized cysteine residue in Cu,Zn-superoxide dismutase, Chem. Commun., 2013, 49, 1449–1451 RSC.
  5. (a) N. Jehmlich, F.-D. Kopinke, S. Lenhard, C. Vogt, F.-A. Herbst, J. Seifert, U. Lissner, U. Völker, F. Schmidt and M. von Bergen, Sulfur-36S stable isotope labeling of amino acids for quantification (SULAQ), Proteomics, 2012, 12, 37–42 CrossRef CAS; (b) S. Ren, P. S. Fier, H. Ren, A. J. Hoover, D. Hesk, R. Marques and I. Mergelsberg, 34S: A New Opportunity for the Efficient Synthesis of Stable Isotope Labeled Compounds, Chem. – Eur. J., 2018, 24, 7133–7136 CrossRef CAS PubMed; (c) V. L. Sushkevich, A. G. Popov and I. I. Ivanova, Sulfur-33 Isotope Tracing of the Hydrodesulfurization Process: Insights into the Reaction Mechanism, Catalyst Characterization and Improvement, Angew. Chem., Int. Ed., 2017, 56, 10872–10876 CrossRef CAS.
  6. (a) R. V. Shchepin, D. A. Barskiy, A. M. Coffey, I. V. Manzanera Esteve and E. Y. Chekmenev, Efficient Synthesis of Molecular Precursors for Para-Hydrogen-Induced Polarization of Ethyl Acetate-1-13C and Beyond, Angew. Chem., Int. Ed., 2016, 55, 6071–6074 CrossRef CAS; (b) J. A. M. Bastiaansen, H. A. I. Yoshihara, A. Capozzi, J. Schwitter, R. Gruetter, M. E. Merritt and A. Comment, Probing cardiac metabolism by hyperpolarized 13C MR using an exclusively endogenous substrate mixture and photo-induced nonpersistent radicals, Magn. Reson. Med., 2018, 79, 2451–2459 CrossRef CAS; (c) R. R. Flavell, C. von Morze, J. E. Blecha, D. E. Korenchan, M. Van Criekinge, R. Sriram, J. W. Gordon, H.-Y. Chen, S. Subramaniam, R. A. Bok, Z. J. Wang, D. B. Vigneron, P. E. Larson, J. Kurhanewicz and D. M. Wilson, Application of Good's buffers to pH imaging using hyperpolarized 13C MRI, Chem. Commun., 2015, 51, 14119–14122 RSC.
  7. (a) H. M. De Feyter, R. I. Herzog, B. R. Steensma, D. W. J. Klomp, P. B. Brown, G. F. Mason, D. L. Rothman and R. A. de Graaf, Selective proton-observed, carbon-edited (selPOCE) MRS method for measurement of glutamate and glutamine 13C-labeling in the human frontal cortex, Magn. Reson. Med., 2018, 80, 11–20 CrossRef CAS; (b) F. Bhinderwala, S. Lonergan, J. Woods, C. Zhou, P. D. Fey and R. Powers, Expanding the Coverage of the Metabolome with Nitrogen-Based NMR, Anal. Chem., 2018, 90, 4521–4528 CrossRef CAS; (c) M. P. Schätzlein, J. Becker, D. Schulze-Sünninghausen, A. Pineda-Lucena, J. R. Herance and B. Luy, Rapid two-dimensional ALSOFAST-HSQC experiment for metabolomics and fluxomics studies: application to a 13C-enriched cancer cell model treated with gold nanoparticles, Anal. Bioanal. Chem., 2018, 410, 2793–2804 CrossRef; (d) L. E. S. F. Machado, R. Page and W. Peti, 1H, 15N and 13C sequence specific backbone assignment of the vanadate inhibited hematopoietic tyrosine phosphatase, Biomol. NMR Assignments, 2018, 12, 5–9 CrossRef CAS; (e) R. Schnieders, A. C. Wolter, C. Richter, J. Wöhnert, H. Schwalbe and B. Fürtig, Novel 13C-detected NMR Experiments for the Precise Detection of RNA Structure, Angew. Chem., Int. Ed., 2019, 58, 9140–9144 CrossRef CAS PubMed.
  8. (a) J. C. Meza-Contreras, R. Manriquez-Gonzalez, J. A. Gutiérrez-Ortega and Y. Gonzalez-Garcia, XRD and solid state 13C-NMR evaluation of the crystallinity enhancement of 13C-labeled bacterial cellulose biosynthesized by Komagataeibacter xylinus under different stimuli: A comparative strategy of analyses, Carbohydr. Res., 2018, 461, 51–59 CrossRef CAS PubMed; (b) L. Ramirez, A. Shekhtman and J. Pande, Nuclear Magnetic Resonance-Based Structural Characterization and Backbone Dynamics of Recombinant Bee Venom Melittin, Biochemistry, 2018, 57, 2775–2785 CrossRef CAS PubMed; (c) K. S. O'Connor, J. R. Lamb, T. Vaidya, I. Keresztes, K. Klimovica, A. M. LaPointe, O. Daugulis and G. W. Coates, Understanding the Insertion Pathways and Chain Walking Mechanisms of α-Diimine Nickel Catalysts for α-Olefin Polymerization: A 13C NMR Spectroscopic Investigation, Macromolecules, 2017, 50, 7010–7027 CrossRef.
  9. Z. Chen, D. W. Paley, L. Wei, A. L. Weisman, R. A. Friesner, C. Nuckolls and W. Min, Multicolor Live-Cell Chemical Imaging by Isotopically Edited Alkyne Vibrational Palette, J. Am. Chem. Soc., 2014, 136, 8027–8033 CrossRef CAS.
  10. (a) S. Scheller, M. Goenrich, R. K. Thauer and B. Jaun, Methyl-Coenzyme M Reductase from Methanogenic Archaea: Isotope Effects on Label Exchange and Ethane Formation with the Homologous Substrate Ethyl-Coenzyme M, J. Am. Chem. Soc., 2013, 135, 14985–14995 CrossRef CAS PubMed; (b) S. K. Wright, M. S. DeClue, A. Mandal, L. Lee, O. Wiest, W. W. Cleland and D. Hilvert, Isotope Effects on the Enzymatic and Nonenzymatic Reactions of Chorismate, J. Am. Chem. Soc., 2005, 127, 12957–12964 CrossRef CAS PubMed; (c) T. W. Schneider, M. T. Hren, M. Z. Ertem and A. M. Angeles-Boza, [RuII(tpy)(bpy)Cl]+-Catalyzed reduction of carbon dioxide. Mechanistic insights by carbon-13 kinetic isotope effects, Chem. Commun., 2018, 54, 8518–8521 RSC.
  11. (a) A. Mullard, Deuterated drugs draw heavier backing, Nat. Rev. Drug Discovery, 2016, 15, 219 CrossRef CAS; (b) C. Schmidt, First deuterated drug approved, Nat. Biotechnol., 2017, 35, 493 CrossRef CAS PubMed.
  12. (a) M. B. Richardson, D. G. M. Smith and S. J. Williams, Quantitation in the regioselectivity of acylation of glycosyl diglycerides: total synthesis of a Streptococcus pneumoniae α-glucosyl diglyceride, Chem. Commun., 2017, 53, 1100–1103 RSC; (b) J. Emsermann, A. J. Arduengo and T. Opatz, Synthesis of Highly Substituted 2-13C-Imidazolium Salts and Metal NHC -Complexes for the Investigation of Electronic Unsymmetry by NMR, Synthesis, 2013, 45, 2251–2264 CrossRef CAS; (c) L. Barra, B. Schulz and J. S. Dickschat, Pogostol Biosynthesis by the Endophytic Fungus Geniculosporium, ChemBioChem, 2014, 15, 2379–2383 CrossRef CAS; (d) M. S. Ledovskaya, K. S. Rodygin and V. P. Ananikov, Calcium-mediated one-pot preparation of isoxazoles with deuterium incorporation, Org. Chem. Front., 2018, 5, 226–231 RSC; (e) V. V. Voronin, M. S. Ledovskaya, E. G. Gordeev, K. S. Rodygin and V. P. Ananikov, [3+2]-Cycloaddition of in Situ Generated Nitrile Imines and Acetylene for Assembling of 1,3-Disubstituted Pyrazoles with Quantitative Deuterium Labeling, J. Org. Chem., 2018, 83, 3819–3828 CrossRef CAS; (f) M. S. Ledovskaya, V. V. Voronin, K. S. Rodygin, A. V. Posvyatenko, K. S. Egorova and V. P. Ananikov, Direct Synthesis of Deuterium-Labeled O-, S-, N-Vinyl Derivatives from Calcium Carbide, Synthesis, 2019, 51, 3001 CrossRef CAS.
  13. (a) R. Riclea, C. A. Citron, J. Rinkel and J. S. Dickschat, Identification of isoafricanol and its terpene cyclase in Streptomyces violaceusniger using CLSA-NMR, Chem. Commun., 2014, 50, 4228–4230 RSC; (b) M.-T. Chung, C. N. Trueman, J. A. Godiksen, M. E. Holmstrup and P. Grønkjær, Field metabolic rates of teleost fishes are recorded in otolith carbonate, Commun. Biol., 2019, 2, 24 CrossRef PubMed; (c) C. Tominski, T. Lösekann-Behrens, A. Ruecker, N. Hagemann, S. Kleindienst, C. W. Mueller, C. Höschen, I. Kögel-Knabner, A. Kappler and S. Behrens, Insights into Carbon Metabolism Provided by Fluorescence In Situ Hybridization-Secondary Ion Mass Spectrometry Imaging of an Autotrophic, Nitrate-Reducing, Fe(II)-Oxidizing Enrichment Culture, Appl. Environ. Microbiol., 2018, 84, e02166–e02117 CAS.
  14. (a) A. E. Mutlib, Application of Stable Isotope-Labeled Compounds in Metabolism and in Metabolism-Mediated Toxicity Studies, Chem. Res. Toxicol., 2008, 21, 1672–1689 Search PubMed; (b) Y. Gong, D. C. Hoerr, L. E. Weaner and R. Lin, Synthesis of [2H, 13C] and [14C] labeled vasopressin V1a/V2 receptor antagonist RWJ-676070 and its stable labeled N-des-benzoyl metabolite, J. Labelled Compd. Radiopharm., 2008, 51, 268–272 CrossRef CAS; (c) M. I. Abboud, M. Kosmopoulou, A. P. Krismanich, J. W. Johnson, P. Hinchliffe, J. Brem, T. D. W. Claridge, J. Spencer, C. J. Schofield and G. I. Dmitrienko, Cyclobutanone Mimics of Intermediates in Metallo-β-Lactamase Catalysis, Chem. – Eur. J., 2018, 24, 5734–5737 CrossRef CAS PubMed.
  15. (a) A. R. Johnsen, A. Winding, U. Karlson and P. Roslev, Linking of Microorganisms to Phenanthrene Metabolism in Soil by Analysis of 13C-Labeled Cell Lipids, Appl. Environ. Microbiol., 2002, 68, 6106 CrossRef CAS; (b) E. Liu, J. Wang, Y. Zhang, D. A. Angers, C. Yan, T. Oweis, W. He, Q. Liu and B. Chen, Priming effect of 13C-labelled wheat straw in no-tillage soil under drying and wetting cycles in the Loess Plateau of China, Sci. Rep., 2015, 5, 13826 CrossRef PubMed.
  16. (a) B. J. Peterson and B. Fry, Stable Isotopes In Ecosystem Studies, Annu. Rev. Ecol. Syst., 1987, 18, 293–320 CrossRef; (b) J. Hoefs, in Stable Isotope Geochemistry, ed. J. Hoefs, Springer Berlin Heidelberg, Berlin, Heidelberg, 2009, pp. 1–227 Search PubMed.
  17. (a) R. Wu, S. N. Lodwig, J. G. Schmidt, R. F. Williams and L. A. Silks, Synthesis of 13C labeled sulfur and nitrogen mustard metabolites as mass spectrometry standards for monitoring and detecting chemical warfare agents, J. Labelled Compd. Radiopharm., 2012, 55, 211–222 CrossRef CAS; (b) S. Schatschneider, S. Abdelrazig, L. Safo, A. M. Henstra, T. Millat, D.-H. Kim, K. Winzer, N. P. Minton and D. A. Barrett, Quantitative Isotope-Dilution High-Resolution-Mass-Spectrometry Analysis of Multiple Intracellular Metabolites in Clostridium autoethanogenum with Uniformly 13C-Labeled Standards Derived from Spirulina, Anal. Chem., 2018, 90, 4470–4477 CrossRef CAS.
  18. (a) C. M. Rochman, J. M. Parnis, M. A. Browne, S. Serrato, E. J. Reiner, M. Robson, T. Young, M. L. Diamond and S. J. Teh, Direct and indirect effects of different types of microplastics on freshwater prey (Corbicula fluminea) and their predator (Acipenser transmontanus), PLoS One, 2017, 12, e0187664 CrossRef; (b) M. T. Zumstein, A. Schintlmeister, T. F. Nelson, R. Baumgartner, D. Woebken, M. Wagner, H.-P. E. Kohler, K. McNeill and M. Sander, Biodegradation of synthetic polymers in soils: Tracking carbon into CO2 and microbial biomass, Sci. Adv., 2018, 4, eaas9024 CrossRef CAS; (c) R. C. Thompson and I. E. Napper, in Plastics and the Environment, The Royal Society of Chemistry, 2019,  10.1039/9781788013314-00060, pp. 60–81; (d) J. S. Hanvey, P. J. Lewis, J. L. Lavers, N. D. Crosbie, K. Pozo and B. O. Clarke, A review of analytical techniques for quantifying microplastics in sediments, Anal. Methods, 2017, 9, 1369–1383 RSC; (e) O. S. Alimi, J. Farner Budarz, L. M. Hernandez and N. Tufenkji, Microplastics and Nanoplastics in Aquatic Environments: Aggregation, Deposition, and Enhanced Contaminant Transport, Environ. Sci. Technol., 2018, 52, 1704–1724 CrossRef CAS PubMed; (f) A. J. Underwood, M. G. Chapman and M. A. Browne, Some problems and practicalities in design and interpretation of samples of microplastic waste, Anal. Methods, 2017, 9, 1332–1345 RSC.
  19. (a) T. Müller, J. Hulliger, W. Seichter, E. Weber, T. Weber and M. Wübbenhorst, A New Organic Nanoporous Architecture: Dumb-Bell-Shaped Molecules with Guests in Parallel Channels, Chem. – Eur. J., 2000, 6, 54–61 CrossRef; (b) D. van Harskamp, J. B. van Goudoever and H. Schierbeek, in Mass Spectrometry and Stable Isotopes in Nutritional and Pediatric Research, ed. H. Schierbeek, Wiley, 2017, ch. 2, pp. 45–66 Search PubMed; (c) A. T. L. Wotherspoon, M. Safavi-Naeini and R. B. Banati, Microdosing, isotopic labeling, radiotracers and metabolomics: relevance in drug discovery, development and safety, Bioanalysis, 2017, 9, 1913–1933 CrossRef CAS PubMed.
  20. (a) B. R. Arnold and J. Michl, Ultraviolet and polarized infrared spectroscopy of matrix-isolated cyclobutadiene and its isotopomers, J. Phys. Chem., 1993, 97, 13348–13354 CrossRef CAS; (b) W. Sakami, W. E. Evans and S. Gurin, The Synthesis of Organic Compounds Labelled with Isotopic Carbon1, J. Am. Chem. Soc., 1947, 69, 1110–1112 CrossRef CAS PubMed; (c) M. Saunders, R. M. Jarret and P. Pramanik, Nortricyclyl-norbornenyl cation. Isotopic perturbation and isotopic scrambling, J. Am. Chem. Soc., 1987, 109, 3735–3739 CrossRef CAS; (d) R. M. Jarret and M. Saunders, Di-carbon-13 labeling: a means to measure carbon-12-carbon-13 isotopic equilibria in 2-norbornyl cation, J. Am. Chem. Soc., 1987, 109, 3366–3369 CrossRef CAS; (e) R. M. Jarret and M. Saunders, Carbon scrambling and carbon-13-carbon-13 coupling constants in carbon-13 NMR spectra of 2-norbornyl chloride, J. Am. Chem. Soc., 1987, 109, 647–649 CrossRef CAS; (f) T. Yamamoto, I. Wataru, T. Kanbara, Y. Nakamura, M. Kikuchi and I. Ando, Preparation of 13C-Poly(p-phenylene). IR, 13C-NMR, and ESR Spectra of the Polymer, Chem. Lett., 1992, 21, 2001–2004 CrossRef.
  21. (a) T. W. Whaley and D. G. Ott, Syntheses with stable isotopes: Acetylene-13C2 and lithium acetylide-13C2 ethylenediamine complex, J. Labelled Compd. Radiopharm., 1974, 10, 461–468 CrossRef CAS; (b) H. Barker, Radiocarbon Dating: Large-scale Preparation of Acetylene from Organic Material, Nature, 1953, 172, 631 CrossRef CAS.
  22. (a) M. Turberg, K. J. Ardila-Fierro, C. Bolm and J. G. Hernández, Altering Copper-Catalyzed A3 Couplings by Mechanochemistry: One-Pot Synthesis of 1,4-Diamino-2-butynes from Aldehydes, Amines, and Calcium Carbide, Angew. Chem., Int. Ed., 2018, 57, 10718–10722 CrossRef CAS; (b) K. J. Ardila-Fierro, C. Bolm and J. G. Hernández, Mechanosynthesis of Odd-Numbered Tetraaryl[n]cumulenes, Angew. Chem., Int. Ed., 2019, 58, 12945 CrossRef CAS PubMed; (c) R. Fu and Z. Li, Direct Synthesis of 2-Methylbenzofurans from Calcium Carbide and Salicylaldehyde p-Tosylhydrazones, Org. Lett., 2018, 20, 2342–2345 CrossRef CAS PubMed; (d) S. P. Teong, J. Lim and Y. Zhang, Vinylation of Aryl Ether (Lignin β-O-4 Linkage) and Epoxides with Calcium Carbide through C–O Bond Cleavage, ChemSusChem, 2017, 10, 3198–3201 CrossRef CAS PubMed; (e) A. Hosseini, D. Seidel, A. Miska and P. R. Schreiner, Fluoride-Assisted Activation of Calcium Carbide: A Simple Method for the Ethynylation of Aldehydes and Ketones, Org. Lett., 2015, 17, 2808–2811 CrossRef CAS PubMed; (f) K. S. Rodygin, G. Werner, F. A. Kucherov and V. P. Ananikov, Calcium Carbide: A Unique Reagent for Organic Synthesis and Nanotechnology, Chem. – Asian J., 2016, 11, 965–976 CrossRef CAS PubMed; (g) K. S. Rodygin, Y. A. Vikenteva and V. P. Ananikov, Calcium-Based Sustainable Chemical Technologies for Total Carbon Recycling, ChemSusChem, 2019, 12, 1483–1516 CrossRef CAS PubMed; (h) M. Fakharian, A. Keivanloo and M. R. Nabid, Using Calcium Carbide as an Acetylene Source for Cascade Synthesis of Pyrrolo[2,3-b]quinoxalines via Copper-Free Sonogashira Coupling Reaction, Helv. Chim. Acta, 2018, 101, e1800004 CrossRef; (i) N. Kaewchangwat, R. Sukato, V. Vchirawongkwin, T. Vilaivan, M. Sukwattanasinitt and S. Wacharasindhu, Direct synthesis of aryl substituted pyrroles from calcium carbide: an underestimated chemical feedstock, Green Chem., 2015, 17, 460–465 RSC.
  23. (a) R. Fu and Z. Li, Direct Synthesis of Symmetric Diarylethynes from Calcium Carbide and Arylboronic Acids/Esters, Eur. J. Org. Chem., 2017, 6648–6651 CrossRef CAS; (b) A. Hosseini, A. Pilevar, E. Hogan, B. Mogwitz, A. S. Schulze and P. R. Schreiner, Calcium carbide catalytically activated with tetra-n-butyl ammonium fluoride for Sonogashira cross coupling reactions, Org. Biomol. Chem., 2017, 15, 6800–6807 RSC; (c) R. Matake, Y. Adachi and H. Matsubara, Synthesis of vinyl ethers of alcohols using calcium carbide under superbasic catalytic conditions (KOH/DMSO), Green Chem., 2016, 18, 2614–2618 RSC; (d) K. S. Rodygin and V. P. Ananikov, An efficient metal-free pathway to vinyl thioesters with calcium carbide as the acetylene source, Green Chem., 2016, 18, 482–486 RSC.
  24. (a) J. M. Wilson, Proceedings of the institute, stated meeting held Wednesday, March 20, 1895, J. Franklin Inst., 1895, 139, 321–341 CrossRef; (b) J. J. Mu and R. A. Hard, A rotary kiln process for making calcium carbide, Ind. Eng. Chem. Res., 1987, 26, 2063–2069 CrossRef CAS; (c) G. Li, Q. Liu and Z. Liu, CaC2 Production from Pulverized Coke and CaO at Low Temperatures—Influence of Minerals in Coal-Derived Coke, Ind. Eng. Chem. Res., 2012, 51, 10748–10754 CrossRef CAS; (d) J. Guo, D. Zheng, X. Chen, Y. Mi and Z. Liu, Chemical Reaction Equilibrium Behaviors of an Oxy-Thermal Carbide Furnace Reaction System, Ind. Eng. Chem. Res., 2013, 52, 17773–17780 CrossRef CAS; (e) L. Ji, Q. Liu and Z. Liu, Thermodynamic Analysis of Calcium Carbide Production, Ind. Eng. Chem. Res., 2014, 53, 2537–2543 CrossRef CAS; (f) G. Li, Q. Liu and Z. Liu, Kinetic Behaviors of CaC2 Production from Coke and CaO, Ind. Eng. Chem. Res., 2013, 52, 5587–5592 CrossRef CAS.
  25. R. C. Pillai, E. M. Sabolsky, S. L. Rowan, I. B. Celik and S. Morrow, Solid-State Synthesis of Calcium Carbide by Using 2.45 GHz Microwave Reactor, Ind. Eng. Chem. Res., 2015, 54, 11001–11010 CrossRef CAS.
  26. R. Wang, Z. Liu, L. Ji, X. Guo, X. Lin, J. Wu and Q. Liu, Reaction kinetics of CaC2 formation from powder and compressed feeds, Front. Chem. Sci. Eng., 2016, 10, 517–525 CrossRef CAS.
  27. M. H. El-Naas, R. J. Munz and F. Ajersch, Modelling of a Plasma Reactor for the Synthesis of Calcium Carbide, Can. Metall. Q., 1998, 37, 67–74 CrossRef CAS.
  28. G. Li, Q. Liu, Z. Liu, Z. C. Zhang, C. Li and W. Wu, Production of Calcium Carbide from Fine Biochars, Angew. Chem., Int. Ed., 2010, 49, 8480–8483 CrossRef CAS PubMed.
  29. C. S. Kim, R. F. Baddour, J. B. Howard and H. P. Meissner, CaC2 Production from CaO and Coal or Hydrocarbons in a Rotating-Arc Reactor, Ind. Eng. Chem. Process Des. Dev., 1979, 18, 323–328 CrossRef CAS.
  30. (a) S. M. Hick, C. Griebel and R. G. Blair, Mechanochemical Synthesis of Alkaline Earth Carbides and Intercalation Compounds, Inorg. Chem., 2009, 48, 2333–2338 CrossRef CAS PubMed; (b) R. J. Harris and R. A. Widenhoefer, Synthesis and Characterization of a Gold Vinylidene Complex Lacking π-Conjugated Heteroatoms, Angew. Chem., Int. Ed., 2015, 54, 6867–6869 CrossRef CAS PubMed; (c) D. K. Hsu, M. D. Freeberg and R. W. Duerst, Synthesis of acetylene-13C2, J. Labelled Compd. Radiopharm., 1981, 18, 1549–1550 CrossRef CAS; (d) B. Nitsche, H.-P. Köst, E. Cmiel and S. Schneider, A new synthesis and NMR-spectroscopy of [15N-,5,4-13C]-aminolevulinic acid, J. Labelled Compd. Radiopharm., 1987, 24, 623–630 CrossRef CAS.
  31. (a) M. S. Ledovskaya, V. V. Voronin and K. S. Rodygin, Methods for the synthesis of O-, S- and N-vinyl derivatives, Russ. Chem. Rev., 2018, 87, 167–191 CrossRef CAS, and references therein; (b) E. Rattanangkool, T. Vilaivan, M. Sukwattanasinitt and S. Wacharasindhu, An Atom-Economic Approach for Vinylation of Indoles and Phenols Using Calcium Carbide as Acetylene Surrogate, Eur. J. Org. Chem., 2016, 4347–4353 CrossRef CAS; (c) K. S. Rodygin, A. S. Bogachenkov and V. P. Ananikov, Vinylation of a Secondary Amine Core with Calcium Carbide for Efficient Post-Modification and Access to Polymeric Materials, Molecules, 2018, 23, 648 CrossRef PubMed; (d) K. S. Rodygin, I. Werner and V. P. Ananikov, A Green and Sustainable Route to Carbohydrate Vinyl Ethers for Accessing Bioinspired Materials with a Unique Microspherical Morphology, ChemSusChem, 2017, 11, 292–298 CrossRef PubMed; (e) S. P. Teong, A. Y. H. Chua, S. Deng, X. Li and Y. Zhang, Direct vinylation of natural alcohols and derivatives with calcium carbide, Green Chem., 2017, 19, 1659–1662 RSC; (f) V. V. Voronin, M. S. Ledovskaya, A. S. Bogachenkov, K. S. Rodygin and V. P. Ananikov, Acetylene in Organic Synthesis: Recent Progress and New Uses, Molecules, 2018, 23, 2442 CrossRef PubMed; (g) G. Werner, K. S. Rodygin, A. A. Kostin, E. G. Gordeev, A. S. Kashin and V. P. Ananikov, A solid acetylene reagent with enhanced reactivity: fluoride-mediated functionalization of alcohols and phenols, Green Chem., 2017, 19, 3032–3041 RSC; (h) V. Bühler, Polyvinylpyrrolidone Excipients for Pharmaceuticals: Povidone, Crospovidone and Copovidone, Springer, 2005 Search PubMed; (i) B. A. Trofimov, L. A. Oparina, O. A. Tarasova, A. V. Artem'ev, V. B. Kobychev, Y. V. Gatilov, A. I. Albanov and N. K. Gusarova, Tuneable superbase-catalyzed vinylation of α-hydroxyalkylferrocenes with alkynes, Tetrahedron, 2014, 70, 5954–5960 CrossRef CAS; (j) Y. Maki, H. Mori and T. Endo, Xanthate-Mediated Controlled Radical Polymerization of N-Vinylindole Derivatives, Macromolecules, 2007, 40, 6119–6130 CrossRef CAS; (k) K. Nakabayashi, Y. Abiko and H. Mori, RAFT Polymerization of S-Vinyl Sulfide Derivatives and Synthesis of Block Copolymers Having Two Distinct Optoelectronic Functionalities, Macromolecules, 2013, 46, 5998–6012 CrossRef CAS.
  32. (a) C. D. Campbell, R. L. Greenaway, O. T. Holton, P. R. Walker, H. A. Chapman, C. A. Russell, G. Carr, A. L. Thomson and E. A. Anderson, Ynamide Carbopalladation: A Flexible Route to Mono-, Bi- and Tricyclic Azacycles, Chem. – Eur. J., 2015, 21, 12627–12639 CrossRef CAS PubMed; (b) S. J. Hein, D. Lehnherr and W. R. Dichtel, Rapid access to substituted 2-naphthyne intermediates via the benzannulation of halogenated silylalkynes, Chem. Sci., 2017, 8, 5675–5681 RSC.
  33. M. A. Fox, A. M. Cameron, P. J. Low, M. A. J. Paterson, A. S. Batsanov, A. E. Goeta, D. W. H. Rankin, H. E. Robertson and J. T. Schirlin, Synthetic and structural studies on C-ethynyl- and C-bromo-carboranes, Dalton Trans., 2006, 3544–3560 RSC.
  34. (a) J. Barluenga, P. J. Campos and G. Canal, A Novel Synthesis of N-(2-Alkynyl)arylamines, Synthesis, 1989, 33–35 CrossRef CAS; (b) R. Gleiter and D. B. Werz, Alkynes Between Main Group Elements: From Dumbbells via Rods to Squares and Tubes, Chem. Rev., 2010, 110, 4447–4488 CrossRef CAS PubMed; (c) K. R. Martin, C. W. Kamienski, M. H. Dellinger and R. O. Bach, Ethynylation of ketones using dilithium acetylide, J. Org. Chem., 1968, 33, 778–780 CrossRef CAS; (d) T. A. Schaub, J. T. Margraf, L. Zakharov, K. Reuter and R. Jasti, Strain-Promoted Reactivity of Alkyne-Containing Cycloparaphenylenes, Angew. Chem., Int. Ed., 2018, 130, 16586–16591 CrossRef; (e) O. Shynkaruk, Y. Qi, A. Cottrell-Callbeck, W. Torres Delgado, R. McDonald, M. J. Ferguson, G. He and E. Rivard, Modular Synthesis of Diarylalkynes and Their Efficient Conversion into Luminescent Tetraarylbutadienes, Organometallics, 2016, 35, 2232–2241 CrossRef CAS; (f) W. B. Sudweeks and H. S. Broadbent, Generalized syntheses of .gamma.-diketones. I. Addition of dimetalloacetylides to aldehydes. II. Dialkylation of bisdithianes, J. Org. Chem., 1975, 40, 1131–1136 CrossRef CAS; (g) L. Brandsma, Preparative Acetylenic Chemistry, Elsevier, Amsterdam, 2nd edn, 1988 Search PubMed.
  35. J. M. A. Al-Rawi and A.-H. Khuthier, Studies in tertiary amine oxides. III—carbon-13 NMR assignment of N-alkynyl cyclic amines, Org. Magn. Reson., 1981, 15, 285–287 CrossRef CAS.


Electronic supplementary information (ESI) available: General procedures and spectral data. See DOI: 10.1039/c9qo01357a

This journal is © the Partner Organisations 2020