Controlled Formation and Unusual Reactivity of Cyanohexatriyne (HC₇N), a Synthetically Challenging Interstellar Cyanopolyyne

ABSTRACT

Cyanohexatriyne (HC₇N), a highly unstable member of the interstellar cyanopolyyne family, has long resisted synthetic access. We report the first reproducible formation of HC₇N at the milligram scale, enabled by a cobalt–alkyne masking strategy that circumvents the intrinsic instability of extended sp‐carbon chains bearing a terminal nitrile. This approach overcomes the limitations of classical C_sp–C_sp coupling methods and provides enough material for chemical investigation. The formed HC₇N was characterized in solution and shown to undergo a rapid and stereoselective conjugate addition with diethylamine to the terminal C≡C triple bond.

First controlled formation of cyanohexatriyne (HC₇N) is achieved using a cobalt–alkyne masking strategy that overcomes the intrinsic instability of nitrile‐substituted polyynes. The approach enables spectroscopic validation of HC₇N and reveals its pronounced electrophilicity through a selective conjugate addition with diethylamine.

1. Introduction

The interstellar medium (ISM) hosts a remarkable chemical diversity: about 350 molecules have been identified to date [1], most of which bear at least one carbon atom [2]. Among these, several feature linear sp‐hybridized carbon chains, motifs that are both structurally demanding and chemically fragile. Of particular interest are the cyanopolyynes (H─(C≡C) _n ─CN, n = 1–5), a paradigmatic family of extended sp‐carbon systems. Their linear sp‐hybridized carbon backbone confers rigidity, while the terminal cyano group imparts a strong dipole moment, both features that facilitate their detection by radioastronomy [3, 4, 5, 6, 7, 8]. The smallest member, cyanoacetylene (1, n = 1), has long been considered a prebiotic molecule and invoked in scenarios for the emergence of life on the primitive Earth [9, 10, 11, 12, 13, 14, 15, 16]. First synthesized over a century ago by Moureu and Bongrand (Scheme 1a) [17], it is a liquid under ambient conditions and, despite slowly decomposing above 10°C when pure, has remained widely studied in laboratories worldwide [18, 19, 20].

The synthesis of the second member, cyanobutadiyne (2, n = 2), proved far more challenging. We first reported its preparation in 2005 via a tosylcyanide‐mediated exchange of a tributylstannyl group with a nitrile, a transformation developed specifically for this purpose [21]. Later, we introduced an alternative route via the corresponding amide precursor, which, upon dehydration with P₄O₁₀, afforded cyanobutadiyne in a modest yet reproducible 14% yield (Scheme 1b) [22]. The moderate efficiency reflects the notorious instability of the compound, which decomposes as soon as −40°C in the pure form.

SCHEME 1.

Reported synthetic routes to (a) cyanoacetylene 1, (b) cyanobutadiyne 2, and (c) cyanohexatriyne 3 (this work).

We next targeted the synthesis of cyanohexatriyne (3, n = 3), a long‐standing synthetic challenge within the series. While its formation has been inferred in complex product mixtures for spectroscopic studies [23, 24, 25], no reproducible chemical route to HC₇N has been established. The first mention of its preparation in a mixture dates back to 1980, when Kroto and coworkers formed it to record its microwave spectrum, but neither yield nor purity was reported [23]. Wakabayashi and coworkers managed to characterize trace amounts by ¹H and ¹³C NMR spectroscopy after generating them with laser ablation from ¹³C‐enriched carbon powder and liquid acetonitrile [26]. To date, however, no synthetic access to this compound has been reported. Our initial attempts to adapt the two strategies developed for cyanobutadiyne (2) proved unsuccessful, and Cadiot–Chodkiewicz couplings of bromocyanoacetylene (BrC₃N) [27] or bromocyanobutadiyne (BrC₅N) [28] with triisopropylsilylacetylene or triisopropylsilylbutadiyne led instead to cascade side reactions. These failures highlight a fundamental difficulty: direct conjugation of a cyano group with an extended C≡C triple‐bond chain profoundly reshapes acetylenic reactivity, making the controlled assembly of three consecutive triple bonds terminating in a nitrile group a significant synthetic challenge.

Here we report controlled synthetic access to cyanohexatriyne 3 (Scheme 1c), overcoming the longstanding limitations of classical C_sp‐C_sp coupling strategies. Our approach relies on a cobalt–alkyne masking strategy, which has proven effective for stabilizing highly reactive linear and cyclic oligoynes, including cyclo[n]carbons [29, 30, 31, 32]. However, this strategy has never been applied to the cyanopolyyne family. By temporarily deconjugating the cyano group from the sp‐carbon chain, this strategy enables the use of conventional transformations to assemble the cyanohexatriyne fragment, while avoiding the decomposition pathways that plagued prior attempts. Beyond its synthesis, this work reveals the unusual reactivity of HC₇N, notably a rare conjugate addition of diethylamine to the terminal C≡C triple bond.

2. Results and Discussion

The synthesis began from triisopropylsilylcyanobutadiyne 4, previously described in the literature [28, 33]. Treatment of 4 with dicobaltoctacarbonyl Co₂(CO)₈ in hexane, followed by addition of bis(diphenylphosphino)methane (dppm), selectively afforded complex 5 in 66% yield. As observed in related systems [29, 30], the triisopropylsilyl (TIPS) substituent directs complexation to the most remote C≡C triple bond for steric reasons, here the one bearing the cyano group. It is worth noting that the presence of the nitrile group does not interfere with the complexation, although it could, in principle, coordinate to cobalt and alter the course of the reaction. Interestingly, a minor product 5′, containing two dppm ligands, was also isolated and unambiguously characterized by NMR spectroscopy and X‐ray diffraction (Figure S3). Deprotection of the TIPS group in 5 with tetrabutylammonium fluoride (TBAF) furnished complex 6 in 82% yield. Without the cobalt‐masking group, this step would generate unstable cyanobutadiyne 2, precluding further chain elongation for stability reasons. A Cadiot–Chodkiewicz coupling of 6 with either triisopropylsilylbromoacetylene 7 [34] or triethylsilylbromoacetylene 8 [35] under standard conditions delivered complexes 9 and 10 in 82% and 78% yields, respectively. Notably, cobalt masking effectively stabilized a nitrile‐substituted polyyne fragment, allowing it to be purified by silica gel chromatography without decomposition. Finally, oxidative decomplexation with I₂ in dichloromethane provided the silyl‐protected cyanohexatriynes 11 and 12 in 15% and 43% yields, respectively (Scheme 2). To the best of our knowledge, this route represents the first isolation of silyl‐protected cyanohexatriynes.

SCHEME 2.

Cobalt–alkyne masking strategy that overcomes the intrinsic instability of nitrile‐substituted polyynes, allowing the first isolation of cyanohexatriyne derivatives 11 and 12.

To enable characterization of cyanohexatriyne 3, the final transformation was conducted in deuterated chloroform under vacuum‐line conditions, allowing both the solvent and any volatile products to be condensed onto a cold finger at the end of the reaction. In this way, cyanohexatriyne 3 was never isolated as a pure substance but remained in solution, from which its NMR spectrum could be immediately recorded. This setup thus required the use of only non‐volatile reagents.

Our first attempt involved desilylation of compound 11 with 1 equiv of TBAF on alumina (15 equiv) at −20°C under nitrogen. After condensation of volatiles, no traces of cyanohexatriyne 3 were observed, and only starting material 11 was recovered from the residue, suggesting that the TIPS group was too resistant under these conditions. We then applied the same procedure to compound 12. In this case, after only 3 min, condensation of the volatiles revealed the formation of cyanohexatriyne 3, confirmed by NMR spectroscopy. Because 3 could not be isolated at room temperature, its yield was quantified by the addition of anisole in the NMR tube as an internal standard, giving 4%. Alternative desilylation using TBAF in THF (1 M) led to immediate decomposition (black solution, no 3 detected). However, treatment of 12 with alumina alone (20 equiv, r.t., 1.5 h) afforded cyanohexatriyne 3 in 5% yield (Table 1). This procedure was independently reproduced by two operators, who obtained product 3 in comparable yields.

TABLE 1.

Different attempts to generate cyanohexatriyne 3 from silyl precursors.

Entry	Substrate	Conditions	Observation	Yield of 3 a
1	11	TBAF/Al2O3, −20°C, 10 min	11 recovered	—
2	12	TBAF/Al2O3, −20°C, 3 min	Formation of 3 (NMR)	4%
3	12	TBAF (1 M, THF, r.t.)	Immediate decomposition (black solution)	—
4	12	Al2O3, r.t., 1.5 h	Formation of 3 (NMR)	5%

^a Yield determined by the addition of anisole as an internal standard.

The ¹³C NMR spectrum of compound 3 is in excellent agreement with the data reported by Wakabayashi and coworkers, displaying a resonance at 105 ppm corresponding to the cyano carbon and six resonances between 49 and 70 ppm attributable to the acetylenic carbons (Figure 1). The intense resonance at 70 ppm can be attributed to the terminal acetylenic carbon, while the unusually high‐field signal at 49 ppm is characteristic of carbons adjacent to a cyano group, as already observed in 1 and 2 and related compounds [36, 37]. Minor signals below 10 ppm are also observed, most likely arising from residual silylated impurities (Figure S15). Importantly, no additional resonances were detected above 10 ppm, confirming that no other acetylenic or ethylenic species were trapped onto the cold finger. This conclusion was further supported by the ¹H NMR spectrum.

FIGURE 1.

¹³C NMR spectrum of cyanohexatriyne 3 from 48 to 107 ppm (CDCl₃, 101 MHz, 298 K).

With reproducible access to HC₇N 3, we sought to probe its intrinsic reactivity toward a nucleophile. Given the well‐established conjugate addition observed for the shorter homologues 1 and 2 at the terminal C≡C triple bond, we questioned how the extension of the sp‐carbon chain would influence the regioselectivity [21, 38, 39, 40, 41]. Treatment of cyanohexatriyne 3 with 1.2 equivalents of diethylamine in an NMR tube resulted in the complete disappearance of the acetylenic proton within 10 min and the appearance of two doublets at 4.20 and 7.04 ppm (J = 13.3 Hz). These data, closely matching those reported for the parent (E)‐adduct obtained from HC₅N and dimethylamine [21], support the exclusive formation of the (E)‐adduct 13 corresponding to the addition to the terminal C≡C triple bond (Scheme 3) in 46% yield. While no other product from the reaction of HC₇N could be identified by NMR spectroscopy, we cannot rule out the partial decomposition of substrate 3 or product 13 over time in the NMR tube or during the reaction, thus explaining the observed yield. This result not only underscores the pronounced electrophilic character of HC₇N but also reveals a rare conjugate addition pathway. Notably, the most reactive carbon is the terminal carbon, that is, the carbon atom most remote from the nitrile group. This regioselectivity parallels that previously observed for HC₃N and HC₅N, despite the substantially extended conjugated chain [42, 43]. The exclusive formation of the E‐isomer is also noteworthy. In contrast to previously reported amine additions to shorter cyanopolyynes, no E/Z mixture was detected by NMR spectroscopy. The steric demand of the two ethyl substituents may contribute to this selectivity. Further studies with other nucleophiles will be conducted in the future to explore the generality of this reactivity.

SCHEME 3.

Reactivity of cyanohexatriyne 3 with diethylamine.

3. Conclusion

In conclusion, we report the first reproducible access to cyanohexatriyne (HC₇N), enabled by a cobalt‐masking strategy that overcomes the intrinsic instability of extended cyanopolyynes. Whereas earlier studies afforded only trace amounts insufficient for chemical interrogation, our approach provides a few milligrams of this compound in solution, thereby allowing its reactivity to be explored for the first time. HC₇N undergoes a rapid and stereoselective conjugate addition with diethylamine, furnishing exclusively the E‐adduct corresponding to an addition to the terminal C≡C triple bond. Beyond its astrochemical relevance, this work establishes cobalt masking as an effective strategy for the controlled synthesis of highly reactive sp‐carbon chains bearing strongly electron‐withdrawing termini, paving the way to longer homologues such as HC₉N and HC₁₁N.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Supporting File: chem71321‐sup‐0001‐SuppMat.pdf

Data Availability Statement

The data that support the findings of this study are available in the Supporting Information of this article.