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.


Introduction

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.

Conclusions

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.

Acknowledgements

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

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Footnote

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

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