Domino reactions are defined as two or more consecutive transformations under identical reaction conditions, in which the subsequent reactions take place at the functionalities formed in the previous steps without the addition of further reagents or catalysts1,2,3. This type of reaction is represented in the biosynthesis of lanosterol from (S)-2,3-oxidosqualene4, in which sequential intramolecular cyclisations occur as a result of the organised and proximal reaction sites of the intermediate in each step. Given that domino reactions proceed without the isolation of any intermediates, judicious planning is required to predict the reaction pathways by combination of known transformations. Nevertheless, domino reactions sometimes bring about unprecedented transformations. For example, a 1,3-diyne with a tethered alkynyl diynophile undergoes an intramolecular hexadehydro-Diels–Alder reaction5 to form a highly reactive benzyne intermediate, which is quickly trapped by a cycloalkane solvent6,7. This trap reaction is an intermolecular double hydrogen atom transfer from the cycloalkane 2H-donor to the benzyne 2H-acceptor, and produces the corresponding cycloalkene and substituted benzene. If the benzyne intermediate is trapped intramolecularly by another tethered 1,3-diyne, a naphthyne is formed as a second aryne intermediate8. The intramolecular aryne formations are repeated until the intermediate is trapped by an external arynophile.

To clarify the mechanism of a domino process that involves an unprecedented transformation, direct isolation of the key intermediates is required. However, this is challenging because the intermediates are usually unstable and highly reactive. We envisage that if each step in the domino process proceeds under identical external stimuli, thermally stable intermediates could be isolated by removing the applied stimuli. Consequently, we would be able to directly visualise and discuss the whole process without having to make any assumptions, as if taking a snapshot of the intermediate at a given reaction time9.

Here, we perform a photoinduced domino reaction consisting of three photochemical steps (Fig. 1). First, the oxidative photocyclisation of stilbene derivative 1 bearing a tetrafluorobenzene ring at the terminal affords 1,2,3,4-tetrafluoro[7]helicene (F4-[7]helicene; 2), which readily undergoes a formal intramolecular Diels–Alder reaction induced by photoirradiation. Then, resulting product 3 undergoes a double fluorine atom transfer to afford 4 under the same photochemical conditions. As a result, the four neighbouring fluorine atoms on the same benzene ring of 1 are separated into two fluorine pairs in a single photochemical operation. In this triple photochemical domino process, intermediates 2 and 3 are thermally stable and can thus be characterised by X-ray crystallography, which allows the elucidation of the otherwise putative domino process.

Fig. 1
figure 1

Triple photochemical domino reaction. i E/Z-Photoisomerisation. ii [6π]-Electrocyclisation followed by dehydrogenation (oxidative photocyclisation). iii [4π + 2π]-Cycloaddition (photoinduced Diels–Alder reaction). iv [2σ + 2σ + 2π]-Double group transfer reaction (photoinduced dyotropic rearrangement). The number of participating orbital electrons is shown in square brackets. In the oxidative photocyclisation from 1 to 1′, the (E,Z) and (Z,Z) isomers of 1 are also present but not shown for simplicity


Photoirradiation of tetrafluorostilbene 1

Photochemical electrocyclisation of stilbene derivatives followed by thermal in situ dehydrogenation with iodine is the standard protocol for synthesising a variety of helicene homologues10,11,12,13,14. Previously, we have demonstrated that an elongated stilbene derivative with six vinylene spacers undergoes oxidative photocyclisation at six separate positions to afford [16]helicene, the longest known carbohelicene15. We applied the same protocol to a toluene solution of F4-stilbene 1 (0.20 mM) using a high-pressure Hg lamp (Fig. 2a). After 30 min irradiation at 30 °C, the starting material was completely consumed. However, intended F4-[7]helicene 2 was not obtained, and instead, bridged compound 4 was isolated in 20% yield. Even when the reaction was conducted at 0 °C for 30 min, 2 was not obtained (4; 14% yield). The product yield of 4 was increased to 40% by irradiation for 10 min at 50 °C.

Fig. 2
figure 2

Synthesis and characterisation of 4. a Transformation of 1 to 4 under UV light irradiation in the presence of I2 (oxidant, 2.2 equiv.). b ORTEP drawing of the X-ray crystal structure of 4 (thermal ellipsoids at the 50% probability level). Only one enantiomer is shown here but the crystal structure contains both enantiomers. Selected interatomic distances (Å) and torsion angles (°): C17–F1, 1.407(2); C18–F2, 1.398(2); C3–F3, 1.356(2); C4–F4, 1.348(2); C1–C2, 1.378(2); C15–C16, 1.336(3); C16–C17, 1.507(3); C17–C18, 1.555(2); F1–C17–C18–F2, 2.3(2); C15–C16–C17–F1, 83.7(2). c 1H NMR spectrum (500 MHz, 298 K, CDCl3) of 4. The characteristic signal region (5.0–5.4 ppm) is highlighted in the inset. Note that the endo proton Hi appears as a doublet of triplets with a large geminal coupling constant of 51.0 Hz at 5.14 ppm

The structure of 4 was unambiguously determined by X-ray crystallographic analysis (Fig. 2b and Supplementary Figure 3). The bottom bicyclooctane framework is fused with the lateral benzene ring and the vertical [4]helicene moiety, generating a spiro-carbon at the centre. Intriguingly, two fluorine atoms, which were originally located on the terminal benzene ring of 1, were transferred to the bicyclooctane ring with syn-stereochemistry. On the basis of the crystal structure, we next investigated the solution structure of 4 by NMR spectroscopy (Fig. 2c). The NMR signal of the endo proton Hi (δ = 5.14 ppm) is a doublet of triplets with a large geminal F2–Hi coupling (2JFH = 51.0 Hz) and small vicinal Hj–Hi and F1–Hi couplings (gauche 3JHH = 3JFH = 3.4 Hz), whereas the signal of the bridgehead proton Hj (δ = 5.34 ppm) is a doublet of triplets with small Hi–Hj and F2–Hj couplings. The cis-vicinal F1–F2 coupling (cis 3JFF = 20.2 Hz) was recorded by 19F NMR spectroscopy.

Clearly, multi-step transformations occurred to generate 4 from 1 under photoirradiation. To closely follow the progress of the photochemical process, we strictly controlled the irradiation time (Supplementary Figure 4). A shorter irradiation time (2 min, 50 °C) allowed us to isolate F4-[7]helicene 2 in 7% yield, together with unreacted 1 (75% yield). Another intermediate, 3, was obtained by irradiation for 5 min at 50 °C (isolated yields of 1: 13%; 2: 18%; 3: 14%; 4: 8%). Intermediates 2 and 3 were thermally stable even in refluxing toluene (~120 °C). These results clearly demonstrate that, in addition to the first (1 → 2) step, the second (2 → 3) and third (3 → 4) steps proceed photochemically and successively under the same conditions (Fig. 1). The triple photochemical domino reaction starts with the photochemical [6π]-electrocyclisation of 1 through facile E/Z-photoisomerisation at two separate positions to give an unstable dihydrophenanthrene intermediate. In the absence of iodine, the domino process does not start because the dihydrophenanthrene intermediate returns to 1 without being oxidised. The phenanthrene formation at the F4-styryl terminal was slower than that at the unsubstituted styryl terminal: [5]helicene bearing the F4-styryl group 1′ was isolated (~15%) from the reaction mixture after 5 min irradiation (Supplementary Figure 5).

The structures of domino intermediates 2 and 3 were also confirmed by X-ray crystallographic analysis. Despite our extensive efforts to optimise the crystallisation conditions for 2, crystal twinning inevitably occurred. Intermediate 2 formed racemic crystals in the triclinic space group P1̄ with four independent molecules (i.e., two P and two M enantiomers) in the asymmetric unit (Fig. 3a and Supplementary Figure 1). In the crystal, the P and M enantiomers are alternatively arranged without intermolecular aromatic–aromatic interactions. The C–C bonds in the inner helix have single bond character (e.g., C25–C26, 1.455–1.467 Å), whereas those in the outer helix have double bond character (e.g., C18–C19, 1.344–1.355 Å); these are typical characteristics of helicene-like molecules. The shortest C···C contact is found between C1 and C26 (2.901–2.935 Å) in the inner helix, and these atoms are connected by the subsequent transformation. The centroid distance between the two terminal benzene rings in crystalline F4-[7]helicene 2 (3.57–3.70 Å) is shorter than that in crystalline unsubstituted [7]helicene (3.78–3.89 Å)16,17,18,19,20, which indicates favourable stacking interactions between the upper F4-benzene and the lower unsubstituted benzene moieties at the terminals21,22,23,24.

Fig. 3
figure 3

Isolated intermediates 2 and 3 in the triple photochemical domino reaction. a ORTEP drawing of the X-ray crystal structure of 2 (thermal ellipsoids at the 50% probability level). Although four crystallographically independent molecules are present in the asymmetric unit (Supplementary Figure 1), only the molecule with the shortest C1···C26 contact (2.901 Å) is shown here. Selected interatomic distances (Å) and torsion angles (°): C1–F1, 1.349(5); C2–F2, 1.350(5); C3–F3, 1.337(6); C4–F4, 1.342(6); C1–C2, 1.348(8); C17–C18, 1.422(9); C18–C19, 1.344(7); C25–C26, 1.467(7); C17–C26, 1.416(7); C1–C26, 2.901(6); C2–C19, 3.791(8); C24–C25–C26–C27, −17.2(8); C28–C29–C30–C1, −25.2(8). b ORTEP drawing of the X-ray crystal structure of 3 (thermal ellipsoids at the 50% probability level). Only one enantiomer is observed in the crystal structure owing to spontaneous resolution into the P21 non-centrosymmetric space group. Selected interatomic distances (Å) and torsion angles (°): C1–F1, 1.403(3); C2–F2, 1.401(2); C3–F3, 1.345(2); C4–F4, 1.355(2); C17–F1, 2.947(2); C18–F2, 2.726(2); C1–C2, 1.572(3); C17–C18, 1.340(3); C18–C19, 1.511(2); C17–C26, 1.525(2); C1–C26, 1.552(2); C2–C19, 1.551(3); F1–C1–C2–F2, 9.5(2); F1–C1–C26–C17, −67.9(2); F2–C2–C19–C18, 56.5(2)

Intermediate 3 exhibited spontaneous resolution of enantiomers and crystallised in the non-centrosymmetric space group, monoclinic P21 (Fig. 3b and Supplementary Figure 2). The X-ray structure of 3 clearly illustrates that an intramolecular [4π + 2π]-cycloaddition of 2 takes place between the second distal benzene ring as a diene and the terminal electron-deficient F4-benzene ring as a dienophile to generate the C1–C26 and C2–C19 bonds. As a result of this cycloaddition, the bottom C17–C18 bond gains double bond character (1.340 Å). The vicinal F1 and F2 atoms of 3 are in close contact to the subjacent C=C bond (C17–F1, 2.947 Å; C18–F2, 2.726 Å, which are less than the sum of the van der Waals radii25 of C and F, 3.17 Å) and ready to be transferred. As described above, X-ray visualisation of the domino process is thus possible for sequential photochemical reactions that go through thermally stable intermediates.

Photoirradiation of F4-[7]helicene 2

With thermally stable intermediate 2 in hand, we next performed a double photochemical domino reaction and monitored the process by NMR spectroscopy (Supplementary Figures 68). The photochemical domino process at 50 °C in acetone-d6 was faster than that in toluene-d8, which suggests that the acetone solvent probably functions as a triplet sensitiser and promotes the substrate into the ππ* triplet state26. Although acetone is a better solvent for the double photochemical domino reaction starting from 2, it is not suitable for the triple photochemical domino reaction starting from 1 owing to its reaction with 1 under photoirradiation to form an oxetane. Similar to photoinduced Diels–Alder reactions between anthracenes and dienophiles27,28, the stepwise formation of two C–C bonds should occur in 2 as follows: the first C–C bond formation takes place in the inner helix between atoms with a shorter C···C distance (C1–C26, 2.901–2.935 Å; Fig. 3a and Supplementary Figure 1), then the second C–C bond formation closes the ring to afford 3.

The observed photochemical Diels–Alder reactivity is specific to F4-[7]helicene 2. Neither F4-[6]helicene24 nor F4-[8]helicene showed Diels–Alder reactivity under thermal or photochemical conditions (Supplementary Figures 10 and 11). It is known that intramolecular thermal Diels–Alder reactions of [7]helicene homologues require in situ generation of a benzyne intermediate29, Lewis acid activation19,30, or annealing at an extremely high temperature (~250 °C) on a metal surface31.

Photoirradiation of Diels–Alder product 3

Using intermediate 3, we verified the photoinduced double fluorine atom (2F) transfer from 3 to 4. The syn-stereospecific 2F-transfer was swift and clean in acetone-d6, and no further photochemical transformation occurred from 4 (Fig. 4). Because two C–F σ bonds and one C–C π bond participate in the 2F-transfer, it can be regarded as a formal [2σ + 2σ + 2π]-pericyclic reaction, known as a dyotropic rearrangement32,33,34,35,36, which is an intramolecular process involving double group transfer reactions. Although the synthetic usefulness of 2H-dyotropic transfers is widely recognised and a photochemical 2H-dyotropic transfer37 by triplet sensitisation is known, the corresponding 2F-dyotropic transfers have not yet been reported. Usually, thermal dyotropic rearrangements require high temperatures and proceed through a concerted pathway via a six-membered ring transition state with in-plane aromaticity38,39. However, considering that C–F bonds are markedly stronger than C–H bonds, overcoming the high energy penalty required to break two C–F bonds at the same time to form a six-membered ring transition state is unrealistic. In contrast, photochemical rearrangements proceed through a stepwise pathway with a biradical intermediate37,40,41,42. Aromatisation of the upper F2-diene ring of 3 is the driving force for the stepwise 2F transfer; the first F transfer is somewhat advantageous for the outer F atom because of its shorter C···F migration distance (C18–F2, 2.726 Å; Fig. 3b).

Fig. 4
figure 4

Monitoring the photoinduced double fluorine atom transfer from 3 to 4. An acetone-d6 solution of 3 (2.2 mM) in an NMR tube was photoirradiated at 50 °C. 1H NMR spectra (500 MHz, 298 K, acetone-d6) of the sample solution are shown (3: blue squares, 4: red circles). a Before irradiation. b After 5 min irradiation


Using F4-stilbene 1, we performed a photoinduced domino reaction consisting of three photochemical steps: oxidative photocyclisation/photoinduced Diels–Alder reaction/photoinduced double group transfer reaction. Multiple photochemical domino reactions remain undeveloped43,44,45 because domino reactions initiated by photoirradiation conventionally consist of consecutive thermal steps after the first photochemical step. One advantage of a photochemical domino process over a thermal one is that the domino process can be suspended and restarted at will simply by controlling the irradiation time. Therefore, we can confirm the domino process based on the X-ray crystal structures of isolated intermediates. The reaction sites generated at each domino step were highly organised and therefore smoothly brought about the subsequent intramolecular transformations under identical reaction conditions. Through the domino process from 1 to 4, two vicinal fluorine atoms located on the terminal benzene ring of 1 were transferred onto the bicyclooctane framework of 4.

Recently, the development of non-photochemical methods for the preparation of helicenes has attracted increasing attention14,46. However, if we had not applied the conventional oxidative photocyclisation method to prepare F4-[7]helicene 2, we would not have observed the unprecedented photoinduced 2F-transfer. It is worth further investigating this clean 2F-transfer in acetone from both practical and theoretical points of view.


General procedure for photochemical domino reaction

A toluene solution (500 mL) of F4-stilbene 1 (45.4 mg, 0.0999 mmol, 0.20 mM), iodine (oxidant; 64.3 mg, 0.253 mmol, 2.5 equiv.) and propylene oxide (acid scavenger; 0.35 mL, 5.0 mmol, 50 equiv.) was bubbled with nitrogen gas for 15 min. A high-pressure Hg lamp (HB400X-15 400 W; SEN LIGHTS CORP) in a quartz water-cooling jacket was placed at the centre of a 500-mL reaction vessel containing the sample solution for internal irradiation. After sealing, the reaction vessel was immersed into an oil bath (PEG400) and the sample solution was heated at 50 °C with magnetic stirring. After UV light irradiation (the most prominent and efficient peak: 313 nm) at 50 °C for 10 min, the sample solution was cooled to room temperature and washed with an aqueous Na2S2O3 solution to remove residual iodine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford a black oily residue. The crude product was directly purified by recycling preparative HPLC (GPC, eluent: CHCl3) to afford pure product 4 (17.9 mg, 0.0397 mmol, 40%) as a light brown solid.

Intermediates 2 and 3 were obtained using the above procedure with a shorter irradiation time. After 2 min irradiation of 1 (46.1 mg, 0.101 mmol) in toluene (500 mL) at 50 °C, F4-[7]helicene 2 was isolated as a light yellow solid (3.23 mg, 7.17 × 10−3 mmol) in 7% yield. Unreacted starting material 1 was recovered (34.6 mg, 0.0768 mmol, 75%) and used for another irradiation. After 5 min irradiation of 1 (45.6 mg, 0.100 mmol) in toluene (500 mL) at 50 °C, Diels–Alder product 3 was isolated as a yellow solid (6.33 mg, 1.41 × 10−2 mmol) in 14% yield. Unreacted 1, F4-[7]helicene 2 and 2F-transferred compound 4 were also obtained in 13, 18 and 8% yields, respectively.

Synthesis of 1–4, F4-[6]helicene and F4-[8]helicene

See Supplementary Methods.

X-ray crystallographic analyses

See Supplementary Methods and Supplementary Figures 13. The CIF and checkCIF files for compounds 24 are available as Supplementary Data 1-3 and 4-6 respectively.

Monitoring photochemical reactions

The 1H NMR spectra for the triple photochemical domino reaction from 1 to 4 are shown in Supplementary Figures 4 and 5. The 1H NMR spectra for the double photochemical domino reaction from 2 to 4 are shown in Supplementary Figures 68. The 1H NMR spectra for the photoinduced double fluorine atom transfer from 3 to 4 are shown in Fig. 4 and Supplementary Figure 9. The 1H NMR spectra of F4-[6]helicene and F4-[8]helicene after UV light irradiation are shown in Supplementary Figures 10 and 11, respectively.

Detailed NMR characterisation

See Supplementary Figures 1219 for the precursor of 1, Supplementary Figures 2032 for (E,Z)-1, Supplementary Figures 3336 for (E,E)-1, Supplementary Figures 3750 for 2, Supplementary Figures 5165 for 3, Supplementary Figures 6681 for 4, Supplementary Figures 8298 for F4-[6]helicene, and Supplementary Figures 99111 for F4-[8]helicene.