Controlling Diastereodivergent Light-Driven Processes: The Impact of the Light Source and Steric Factors on the Paternò-Büchi Reaction

doi:10.21203/rs.3.rs-1676011/v1

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Controlling Diastereodivergent Light-Driven Processes: The Impact of the Light Source and Steric Factors on the Paternò-Büchi Reaction

https://doi.org/10.21203/rs.3.rs-1676011/v1

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By conducting in-depth mechanistic investigations to rationalize reaction manifolds, chemists can expand the generality of synthetic processes and discover novel reactivities. The challenge is to use the resulting information to control the selectivity of a given synthetic process. A particular challenge for organic chemists is to use an external stimulus to switch a reactivity on or off. Here, we mechanistically investigated light-driven [2+2] heterocycloadditions (Paternò-Büchi reactions) between indoles and ketones. We used ground-state UV-Vis absorption and transient absorption spectroscopy (TAS) at ns and fs timescale, together with DFT and TD-DFT calculations. We found that the reaction can proceed via an exciplex or electron-donor-acceptor (EDA) complex manifold, which are key intermediates in determining the reaction’s stereoselectivity. We used this discovery to control the reaction’s diastereoselectivity, gaining access to previously inaccessible diastereoisomeric variants. When moving from 370 to 456 nm irradiation, the EDA complex is increasingly favored, and the diastereomeric ratio dr (en-do:exo) moves from >99:<1 up to 47:53. In contrast, a simple Methyl-to-iPropyl favors the exciplex, reversing the dr from 89:11 to 16:84. Our study shows how light and steric parameters can be rationally used to control the diastereoselectivity of syn-thetically relevant photoreactions, creating new mechanistic pathways to previously inaccessible stereochemical variants.

Synthetic photochemistry has grown tremendously in the past decade¹. Radical species are no longer considered to be difficult-to-handle intermediates². Novel and selective visible-light synthetic methods have been rapidly developed alongside photoredox catalysis.³ More recently, milder visible-light sources have been used for popular light-driven reactions that were historically performed under UV-light irradiation^3-6. In this regard, the long-studied Paternò-Büchi (PB) reaction is a light-driven [2+2] heterocycloaddition reaction between an olefin and a carbonyl compound^{7, 8}. As first described by Paternò in 1909, the formidable light-driven reaction leads, in a single step, to a strained oxetane, which is often present in natural products and drugs⁹. This reaction and other light-driven processes have been the subject of intense mechanistic investigations (Fig. 1a), which identified diverse and divergent reaction manifolds^10-13. In 1954, Büchi reported that, in PB reactions, the ground-state olefin reacts with the triplet excited state (T₁) of the carbonyl counterpart, generating a 1,4 biradical intermediate (Fig. 1a, left)^{8, 15}.In 1972, Turro reported the possibility of generating an exciplex between the reagents, possibly leading to different product distributions.^{10, 12} A few years later, Mattay reported that, when a charge-transfer (CT) complex between the reagents takes place, the reaction proceeds through a more selective concerted mechanism¹¹.

The formation of a CT state follows either i) an exciplex between an electron-rich olefin and the excited ketone, or ii) the formation of an electron-donor-acceptor (EDA) complex, which is a ground-state association characterized by a red-shifted absorption with respect to the single reactants¹⁶. Importantly, the spatial arrangement of the reagents determines the geometries of the CT states and the final oxetane stereochemistry¹⁷. As hypothesized by Kochi¹⁸, different stereoisomers can emerge when the cycloaddition process passes through different CT states, which lead to different spatial arrangements (e.g. exciplex vs. EDA complex) (Fig. 1b). Here, the wavelength selection is relevant for the stereochemical outcome. This hypothesis is confirmed by considering the recently developed light-driven processes, which use new types of substrates that can generate EDA complexes (i.e. indoles)^{19, 20}. These scaffolds allow broad control over the electronic and steric parameters. By using different indole-derived heterocycles, it is thus possible to channel the reactivity towards the intended stereochemical variant²¹.

Based on detailed mechanistic investigations, we herein report how to control the stereochemical outcome of light-driven [2 + 2] heterocycloadditions. Our study includes biorelevant indole heterocycles, aromatic ketones, and a-ketoesters. We rationalized our experimental findings by using various spectroscopic techniques, ground state and transition absorption spectroscopy (TAS), emission spectroscopy, and DFT calculations (Fig. 1c). By manipulating specific physicochemical parameters (e.g. light source or steric factors), the reaction’s diastereoselectivity can be deliberately altered towards the activity of two stereodivergent reaction manifolds (exciplex vs. EDA complex), leading to opposite diastereomers. These findings were extended to different indole derivatives and implemented under continuous flow irradiation, allowing access to elusive stereochemical variants on a preparative scale.

Spectroscopic Identitication of Three Different Reaction Manifolds. We initiated our study by selecting as the mechanistic probe the [2 + 2] heterocycloaddition reaction between indoles 1a-b and aryl ketones 2a-b (Fig. 2), where no diastereoselection is envisaged due to the symmetric nature of the ketone (see Section E in SI). Interestingly, we discovered that according to our experimental findings, and in agreement with literature, the reaction can proceed through three alternative reaction manifolds (pathways i-iii in Fig. 2).

Conventional Triplet Mechanism – pathway i (Fig. 2, top). When indole 1a (R¹ = Me) and benzophenone 2a (R² = H) are involved, a conventional radical trapping mechanism is observed^{18, 19}. This is a PB process commonly mediated by a UV-light source (250–360 nm) that promotes, after intersystem crossing (ISC) from the singlet state, the generation of the long-lived triplet state (T₁). The T₁ is then trapped by the electron-rich 1a (triplet-state box in Fig. 2), generating the corresponding 1,4-biradical 4. This mechanism was confirmed by TAS-experiments at a ns scale (top-right 1,4-biradical box). In fact, by TAS, we observed the decay of the T₁ (max abs. at 525 nm) along with the concomitant appearance of the 1,4-biradical 4 (max abs. at 390 nm)²². This transient intermediate leads to the oxetane product 3a within a hundred ns (see Section C in SI). The experimental data clearly suggest a pure-triplet mechanism as the only operative pathway, as no traces of a radical ion-pair (IP) were detected. Additionally, a PET pathway can be excluded owing to its high endergonicity (ΔG_PET = 10.3 kcal·mol^-1). Importantly, it is well documented by several literature reports that when the ΔG_PET > 0 kcal·mol^-1, PET processes are prevented and the reaction proceeds through a radical-trapping mechanism^{23, 24}.

Exciplex-Based Pathway – pathway ii (Fig. 2, middle). In the presence of a more electron-deficient ketone such as 2b (R² = CF₃) and under diluted conditions ([2b] = 0.01M in Acetone) we observed an alternative mechanism. Analogously to pathway i, no ground state interactions between 1a and 2b were detected (see section C in SI). Nevertheless, TAS experiments revealed the appearance of the transient radical IP (5 + 6) upon T₁ decay, as supported by the spectral changes at λ = 780 nm characteristic of the benzophenone radical anion (Fig. 2, radical-ion-pair box, section C, D in SI). Additionally, no traces of the biradical 4 were observed at λ < 400 nm, indicating that the radical IP evolves through a concerted or quasi-concerted mechanism to the oxetane product 3. This data implies that after the ketone excitation, the T₁ state of 2b interacts with the indole generating the exciplex II²⁶, that possesses a charge transfer character consistent with the exergonicity of the photoinduced electron transfer (PET) process (ΔG_PET = − 9.7 kcal·mol^− 1).

EDA-Complex-Based Pathway – pathway iii (Fig. 2, bottom). This pathway foresees the interaction of the two reactants at the ground state level into an EDA complex under more concentrated conditions ([2b] = 0.1 M in Acetone). UV-Vis titration experiments with the electron-rich indole 1b and the electron-poor benzophenone 2b, revealed the appearance of a red-shifted CT band (Fig. 2, EDA complex box, bottom left). A modest binding constant (K_EDA = 0.47 M^-1, in acetone at 25°C) was extrapolated for the equilibrium of formation of the complex (see Section C in SI)^{27, 28}. Within an EDA-complex-based manifold, a stereochemically alternative radical IP (5 + 6) is directly produced upon PET (λ_max 723 nm). As monitored by TAS, a favorable PET process (ΔG_PET = -9.7 kcal·mol^-1) occurs delivering the radical IP, whose spectral assignment is confirmed by spectroelectrochemistry (Fig. 2, bottom-right box and Section C, D in SI). This species decays with a time-constant of 180 ns into the oxetane product.

We envisaged that the three diverse reaction manifolds observed by TAS are governed by alternative orbital interactions. For instance, the interactions within pathway iii differ from pathways i and ii lacking the π orbital overlap of the indole with the half-filled n_p orbital of the excited ketone. Indeed, it is well established that for EDA-complexes alternative p-p interactions are relevant¹⁶. Importantly, diverse orbital interactions may lead to diverse spatial orientations of the reagents and finally alter the stereoselectivity of the process. For this reason, we decided to gain insights into the diverse molecular orientations by using DFT methods.

The Exciplex vs. the EDA-complex Pathway. Computational Insights

Aiming at developing a novel stereodivergent process, we focused our attention on the exciplex-based pathway ii and the EDA-complex-based pathway iii, with 1b and 2b as reactants.

Under diluted conditions ([2b] = 0.01 M in Acetone), no EDA complex is detected, meaning that under these conditions the only active pathway is the exciplex-based pathway ii. Conversely, when more concentrated conditions ([2b] = 0.1 M in Acetone) are used the EDA-complex pathway iii starts to be competitive²⁷.

To gain insight into the two diverse arrangements involved in the PET-based pathways (exciplex vs. EDA complex), we employed DFT calculations at the (U)M06-2X/6-311 + + G(d,p)/ IEFPCM(acetone) level of theory (Fig. 3)¹⁷. This functional is a well-established method to describe charge transfer complexes both in singlet and triplet states^{28, 29}.

Excited-state (T ₁ ) – Exciplex arrangement, pathway ii (Fig. 3a). Upon direct excitation of the ketone 2b, the corresponding T₁ state is generated. At this juncture, the T₁ interacts with the ground state 1b¹⁰. In this case, the oxygen atom of the T₁ 2b and the C2 position of 1b are in close proximity (Fig. 3a, n_p-π interaction, 2.56 Å). Interestingly, the spin density map of the computed exciplex is almost equally distributed between the indole and the ketone (Fig. 3, 1.03 and 0.97 respectively). On the one hand, a large dipole moment is observed upon excitation (µ = 15.6 D). This altered charge distribution indicates a remarkable CT character as reflected by natural population analysis. In fact, a total of 0.90 charge unit is transferred from indole to the ketone, corroborating the PET-based pathway ii, where the radical ion-pair has been detected experimentally by LFP measurements.

Ground-state (S ₀ ) – EDA-complex arrangement, pathway iii (Fig. 3b). As experimentally observed, when concentrated conditions are used ([2b] = 0.1 M in Ace) an EDA-complex is generated between the reagents. This complex is held together through a π-π stacking interaction between the electron-rich aromatic ring of indole 1b and the electron-poor aromatic ring of the ketone 2b (Fig. 3, interaction ~ 3.6 Å and corroborated by computed UV-Vis spectra in Fig. S.I.8.)^{30, 31}. Additionally, the analysis of the frontier molecular orbitals of the EDA-complex reveals that the HOMO is located on the indole moiety while the LUMO is distributed along the ketone resulting in a dipole moment (µ) of 4.8 D (Fig. 3). To better elucidate the photoinduced electron transfer observed after irradiation of the EDA complex, we performed vertical excitation calculations employing a TD-DFT method. This technique allowed us to analyze the corresponding excited state involved in the PET process. For the S₁ excited-state, a HOMO-LUMO contribution of 83.5% has been computed (3.66 eV), showing a remarkable charge transfer character (Fig. 3i, µ = 16.2 D). Indeed, natural population analysis of S₁ indicates that upon vertical excitation of the EDA complex a substantial charge (0.79) is transferred from the indole moiety 1b to the ketone 2b, which resembles the experimentally observed radical ion-pair system.

Exciplex vs. EDA complex. The impact of the light source on the diastereodifferenciation process

Based on the different geometries and orbital interactions obtained by DFT calculations, it is possible to represent the two alternative reaction manifolds by using a simplified potential energy surface diagram (Fig. 4)³¹. It is worth reminding, that the spatial arrangements of the molecules are retained and directly transferred to the final oxetane product due to the concerted-character of PET-based PB reactions^{11, 12}. For instance, when the reaction mixture is irradiated at 405 nm, the CT-band of the EDA complex is directly excited (Fig. 4 left, red lines). This irradiation leads to the formation of a radical IP with a preferred π−π interaction. On the other hand, 2b can be directly excited at 370 nm. In this case the n_p-π interaction will govern the spatial arrangement of the IP (Fig. 4 right, green lines). Thus, a light stereodifferentiation processes can occur when switching the irradiation source from UV- to visible-light.

As per the DFT calculations, there are two alternative sets of interactions, which do not result in any product diversification when using symmetric benzophenones. These are crucial when moving to prochiral carbonyls. We therefore evaluated benzil 7, which is a class of synthetically relevant prochiral carbonyls used in several polar and radical reactions (Fig. 5)^{32, 33}. We hypothesized that the endo:exo selectivity²⁴ of the reaction would depend on the competition between the two alternative reaction manifolds (exciplex vs. EDA complex). The conventional pure-triplet mechanism (pathway i) was ruled out by the LFP experiments of 7 with 1b (see Section F in SI), which instead confirmed the photogeneration of the CT state, in agreement with the favorable ΔG_PET (-5.8 kcal·mol^-1). Thus, by altering the irradiation wavelength and the parameters that influence the EDA complex formation, the endo/exo selectivity can be deliberately altered in a diastereodivergent light-driven process (see Section E and F in SI). Specifically, 8-endo will be the preferred product in an exciplex-based mechanism, while 8-exo will be favored following an EDA complex pathway (Fig. 5, left). Remarkably, we observed the formation of 8-endo as a single diastereoisomer when running the reaction at 370 nm (> 99:<1 dr, 370 nm Fig. 5b). The endo selectivity results from the direct excitation of the free ketone 7, participating in an exciplex with 1b.¹⁹ As hypothesized, when moving to less energetic 405 and 456 nm irradiation wavelengths, the exo selectivity increases, with the dr moving to 77:23 (456 nm Fig. 5b). This is in line with the activity of the excited EDA complex between benzil 7 and the indole 1b, whose presence was confirmed by the UV-Vis absorption spectra (Fig. 5c). Increasing the concentration from 0.01 to 0.1 M favors the EDA complex pathway, resulting in a dr of 93:7 and 68:32 upon irradiation at 370 and 405 nm, respectively. No significant variation was observed at 456 nm, indicating that 64:36 dr is the limit value under these reaction conditions. Following previous experimental observations, we reasoned that performing the reaction under reduced temperature should inhibit the interconversion between the two reaction manifolds, thus magnifying the observed light stereodifferentiation process.³⁵. Indeed, when running the reaction at -78°C, the dr moved from > 99:<1 at 370 nm to 52:48 at 456 nm. This dr variation is the highest ever registered for PB light-diastereodifferentiation processes, and it confirmed our initial working hyphothesis^{36 − 38}. Furthermore, these experimental data reveal that the choice of the light is crucial. Reproducibility issues in diastereoselective PB processes involving heterocyclic systems can be now rationalized and possibly solved by selecting the appropriate irradiation wavelength³⁹. As a control experiment, we performed a reaction in an aromatic solvent, which interferes with the π−π interactions in the EDA complex. Accordingly, when using C₆D₆ as solvent, we observed reduced activity of the EDA-complex pathway, resulting in a dr no lower than 80:20 at 465 nm (Fig. 5b, right column).

In addition to the experimental data, we used DFT and TD-DFT calculations to compute the two different geometries for the EDA complex between ketone 7 and indole 1b (see section K in SI). Notably, the excited state (S₂, HOMO-LUMO contribution = 98.4%) of this complex in the exo configuration has a larger dipole moment (µ = 18.6 D) than in the endo geometry (µ = 15.4 D). This indicates a substantial charge-transfer character and is in accordance with the experimental trend.

Spectroscopical characterization of the exciplex intermediate, pathway ii (Fig. 6).

In order to confirm the key reactivity of an exciplex between substrates 1b and 7, we performed transient absorption spectrometry (TAS) measurements at a fs timescale. These experiments allowed investigating the dynamics of the systems within the first nanosecond after photoexcitation with a time resolution of about 150 fs (see SI, section F). We compared the photophysics of the single benzil 7 in the absence and in the presence and of indole 1b (Fig. 6a and b, respectively). All the experiments were conducted under the reaction conditions ([1b] = [7] = 0.1M in Ace).

For 7, the excitation at 400 nm results in the formation of positive excited state absorption features (ESA). At early time, we recorded a broad absorption band centered at about 560 nm, which gradually evolved into a sharper feature with a maximum at about 525 nm. While the literature contains few reports of the ultrafast dynamics of 7, which are typically performed at longer time resolution, it is reasonable to assign the early time signal at 560 nm to the ESA from the instantaneously photoexcited S₁ state (S₁®S_n transition)^{41, 43}. This signal quickly decays (0.3 ps) while the band at 525 nm rises with the same time constant. Once formed, this band decays over a longer timeframe than the explored 600 ps. This behavior is in agreement with a fast S₁®T₁ ISC that moves the population from S₁ to T₁ on a sub-ps timescale, followed by the long-lived T₁®T_n absorption at 525 nm⁴⁴.

The TAS spectra of the mixture 7-1b (Fig. 6.b) are qualitatively similar to the TAS spectra of 7. This is not surprising, given that the excitation at 400 nm preferentially excites 7 and therefore its spectral features are expected to prevail in the mixture response. However, the dynamic behavior is significantly different, with the ESA band at 525 nm decaying much quicker in the mixture than in 7 (Fig. 6c-d). The time trace of 7 alone could be fitted with a bi-exponential model characterized by a fast rise (t_rise=0.3 ps) assigned to the S₁®T₁ ISC the and a slow t_decay (> 500ps) assigned to all the relaxation processes from the T₁ state to the S₀ ground state. Interestingly, an additional relaxation pathway is observed for the triplet state in the presence of 1b, with a time constant of about 50 ps, which is associated with the formation of triplet exciplex species as depicted in Fig. 6e. Indeed, the formation of the triplet state is known to lead to a planarization of the benzil molecule,⁴⁴ which favors the exciplex formation, as confirmed by our TD-DFT calculations (see section K in SI). We can exclude that the 50 ps time constant corresponds to the direct formation of a 7-1b CT state. This is because TAS experiments performed on the 7-1b mixture confirmed that this species gives rise to a characteristic ESA signal at significantly longer wavelengths (ca 600 nm) and has much longer dynamics.

Adding to previous experimental evidence and supported by DFT calculations, the findings support the existence of an exciplex between substrates 1b and 7 under these experimental conditions, while offering a rare report of the activity of this elusive and fleeting intermediate.

Exciplex vs. EDA complex. The impact of the electronic and steric factors on the diastereodifferenciation process

Having verified the key activity of the exciplex under the light-driven stereodifferentiation processes, we next investigated how steric and electronic parameters can be used to rationally control the stereodifferentiation events. Specifically, we selected α-ketoesters 9 as a molecular probe⁴⁵ to monitor the impact of steric and electronic parameters on the reaction outcome, while keeping constant a visible-light source set at 405 nm (Fig. 8). Interestingly, the steric repulsion between the R group and the substituent at the C-2 of the indole 1b (OTBS) will favor a carbonyl perpendicular orientation in the exciplex, leading to 10-exo (Fig. 8, exciplex box). However, the 10-endo selectivity will be preferred when favoring a p-p interaction between the aryl group of 9 and the aromatic indole core (Fig. 8, EDA-complex box).

Evaluation of the electronic factors (Fig. 8b). We began by evaluating the impact of the electronic factors on the reaction outcome. First, we selected various α-ketoesters 9 recording the corresponding UV-Vis spectra in the presence of 1b, thus assessing their ability to generate an EDA complex. In the case of α-ketoester with Ar = 3,5-CF₃Ph, we observed a red-shifted CT band (see Fig. 5a and Section G in SI). Additionally, the highly negative ΔG_PET = − 17.1 kcal·mol^− 1 measured was consistent with the formation and activity of an EDA complex. No spectral variations were registered for the other α-ketoesters. We next examined the experimental outcome for all the substates under a 405 nm irradiation (Fig. 5b).

Using a visible-light source was crucial because it enabled the activity of the exciplex and the EDA complex pathways (see section G in SI). This meant that the electronic and steric parameters were the key features in governing the selectivity of these photoreactions⁴⁶. In fact, both the EDA complex and free α-ketoesters absorb light under these conditions. Only the PB reaction with the electron-deficient 3,5-CF₃Ph α-ketoester was highly endo-selective (84:16 dr, Fig. 8b). The other α-ketoesters showed no ground-state association with 1b, while maintaining a high level of exergonicity (ΔG_PET in the range of -6.0 to -9.5 kcal·mol^− 1, Fig. 8b) and resulting in similar dr of about 70:30.^{11, 24}

We depicted the differences in reactivity by plotting the obtained experimental dr against the E_red of 9 and highlighting the different behavior of the 3,5-CF₃Ph α-ketoester (Fig. 8b, right).

Evaluation of the steric factors (Fig. 8c). We then investigated the role of the steric factors, tuning the R group within 9. The Charton analysis allowed us to compare the sensitivities (ψ) of the two different manifolds (EDA complex vs exciplex).⁴⁷ When increasing the R size (from Me to iPr), the endo/exo selectivity was reversed, passing from 74:26 to 43:57 dr for Ar = Ph (exciplex manifold), and from 84:16 to 45:55 dr for Ar = 3,5-CF₃Ph (EDA complex manifold). We rationalize this trend as reflecting an increased steric repulsion between the R group and the OTBS, favoring the perpendicular approach. Nevertheless, the EDA complex manifold experiences a 1.5 increased sensitivity (ψ = -1.51 vs ψ = -2.23 for the exciplex and EDA manifolds, respectively), in agreement with a greater dependence of the parallel approach (π−π interactions) towards steric variations. Finally, we sought to use these findings to deliberately alter the diastereoselective outcome of the PB process by manipulating the steric factors.⁴⁷ We selected the 3,5-CF₃Ph α-ketoester because it is the only substrate that formed an EDA complex with 1b (ψ = -2.23). We observed an initial dr of 84:16 in favor of the endo product. The endo selectivity increased slightly at 40°C (89:11).^{48, 37} When passing from R = Me to R = iPr, the endo:exo selectivity was reversed with a dr of 45:55 and further magnified to 16:84 when lowering the temperature (-78°C). We thus isolated and characterized the elusive exo-isomer of oxetane 10 in synthetically useful isolated yield (58%). These results demonstrate that simple structural variations (Me versus iPr) in the starting material can dramatically alter the stereochemical outcome of light-driven processes. The importance of the proper light-source selection is also key. No variations were observed when running the reaction at 370 nm. Moreover, these results indicate that overlooked minor modifications of a substrate can have a tremendous impact on the reaction outcome of [2 + 2] photocycloadditions.

Following the rational approach used for the previous reaction partners, computational analysis was performed (see section K in SI). We computed the EDA complexes and the corresponding vertical excitations between the α-ketoester (9, R = Me) and indole 1b. Remarkably, the corresponding excited state (S₁, HOMO-LUMO contribution = 94.4%) of the EDA complex in the endo configuration (major diastereoisomer) has a larger charge-transfer character (µ = 15.8 D) than the exo geometry (µ = 14.3 D). This trend is in agreement with previous data on the benzil-indole couple. Moreover, similarly to the 1b-2b exciplex, the complex in the triplet state between 1b and 9 (R = Me) possesses a large dipole moment (m = 15.9 D), as reflected by the charge transferred (0.95) from indole to the ketone, which supports the PET-based pathway.

Generality and Synthetic Potential of the developed diastereodifferentiation processes

Having established two alternative yet complementary methods to govern the stereochemical outcome of the PB reaction, we sought to extend our findings to different carbonyl precursors and to other types of indole derivatives (Table 1). We selected different indoles characterized by various steric and electronic modifications at C-5 and C-6. These new substrates were then subject to a) the light-driven and b) the steric factor diastereodifferentiation process under the developed conditions. When changing the light source from UV (370 nm) to visible (456 nm), a significant variation in the dr was observed in all cases (Fig. 8a). In particular, the presence of an EDG (OMe) stabilized the EDA complex, resulting in higher exo-selectivity (53:47). However, the presence of an EWG (CF₃) did not particularly alter the reaction outcome, demonstrating the robustness of our findings.

In terms of the steric parameters, switching from Me- to iPr-α-ketoester dramatically changed the stereochemical outcomes, with the dr inverted in all cases. Specifically, the electron-rich OMe group induces an EDA-complex manifold prevalence, while the CF₃ group favors the exciplex manifold by disfavoring the π−π interactions with the electron-deficient α-ketoester 9.

After evaluating alternative indole derivatives, we explored the preparative potential of the developed light diastereodifferen-tiation process. The reaction between benzil 8 and indole 1b was readily implemented into a flow reactor (Fig. 8 and section I in the SI).⁴⁹ The reaction in flow furnished identical results with a shorter residence time (40 min).⁵⁰ Furthermore, under the flow conditions, we ran the reaction at 1 mmol scale, isolating both the endo-9 and the exo-9 product with an overall yield as high as 88% and 0.57 g in a single strike. This unprecedented light stereodifferentiation flow process lays the foundation for the use of our protocol in semipreparative medicinal chemistry settings.

In conclusion, we have been able to gain control over the stereochemical outcome of light-driven [2 + 2] heterocycloaddition reactions involving diverse types of carbonyls and indole derivatives. Our results are based on experimental results and corroborated by in-depth investigations of the reaction mechanisms performed by photodynamic analyses, TAS-experiments and supported by spectroelectrochemistry and DFT calculations. With a rational approach, we have revealed the major role of a visible-light-driven EDA complex manifold that can channel the reactivity towards unconventional diastereoselectivity. The often-overlooked effect of the light-source variation was exploited to the development of new light-stereodifferentiation reactions (dr endo / exo passing from > 99:<1 up to 43:57, Table 1a). On the other hand, the punctual modulation of the steric parameters of the starting ketone allows access to unprecedented diastereoinversion events under visible-light irradiation (dr endo / exo passing from 89:11 to 16:84, Table 1b). The generality and synthetic utility of our findings was further proved for a series of structurally diverse indoles (Table 1) and by implementing the light stereodifferentiation process in flow (Fig. 10).

Our study demonstrates how the mechanistic understanding of light-driven processes can increase their synthetic potential to previously inaccessible structural targets. Further, we envisage a widespread utilization of our approach to the development of novel and selective photoreactions as well as to the mechanistic elucidation of unconventional light-driven reactivity.

General. For the 1H NMR, 13C NMR spectra and HPLC traces of compounds in this Article, details of synthetic procedures and details of the computational study, see the Supplementary Information.

Online content

The Supporting Information is available free of charge on the ACS Publications website. Experimental procedures and characterization data, cyclic voltammetry, UV-Vis spectra, TAS experiments, 1D and 2D-NMR-spectra (PDF).

Data availability

All relevant data supporting the findings of this study, including experimental procedures and compound characterization, NMR and other spectroscopic analysis are available within the article and its Supplementary Information.

Acknowledgements

P.C. thanks the Seal of Excellence@UNIPD, QuantaCOF for a postdoctoral fellowship. Pietro Franceschi, Philip Andreetta, and Gianluca Simionato are acknowledged for preliminary experiments. Dr Sara Bonacchi is acknowledged for insightful discussions.

Author contributions

J. M. and L.D. wrote the manuscript with contributions from all the authors. J. M. and L. D. conceived the project and devised the experiments. J. M. and A. V. carried out the reactions and isolated and characterized the products. J. M., L. D., M. B. and A. S. rationalized the experimental results. F. R., M. N, E. C. and E. F. performed the spectroscopic investigations using TAS. P.C. and A. S. performed the DFT calculations.

Competing interests

All the authors declare no competing interests.

Additional information

Supplementary information The online version contains supplementary material available at

Correspondence and requests for materials should be addressed to Luca Dell’Amico.

Yoon, T. P., Ischay, M. A. & Du, J. Visible light photocatalysis as a greener approach to photochemical synthesis. Nat. Chem. 2, 527–532 (2010).
For examples of how to tame radical selectivity see: Minisci, F. et al. Additions and Corrections Polar Effects in Free-Radical Reactions Selectivity and Reversibility in the Homolytic Benzylation of Protonated Heteroaromatic Bases (Journal of Organic Chemistry (1986) 51(22) (4326)). Journal of Organic Chemistry vol. 51 4326 (1986).
Shaw, M. H., Twilton, J. & MacMillan, D. W. C. Photoredox Catalysis in Organic Chemistry. Journal of Organic Chemistry vol. 81 6898–6926 (2016).
Mateos, J. et al. A visible-light Paternò-Büchi dearomatisation process towards the construction of oxeto-indolinic polycycles. Chem. Sci. 11, 6532–6538 (2020).
Franceschi, P.; Mateos, J.; Vega-Peñaloza, A.; Dell’Amico, L. Microfluidic Visible‐Light Paternò–Büchi Reaction of Oxindole Enol Ethers. Eur. J. Org. Chem. 2020, 43, 6718–6722.
Zheng, J., Dong, X. & Yoon, T. P. Divergent Photocatalytic Reactions of α-Ketoesters under Triplet Sensitization and Photoredox Conditions. Org. Lett. 22, 6520–6525 (2020).
Paternò, E.; Chieffi, G. Sintesi in Chimica Organica per Mezzo Della Luce. Nota II. Composti Degli Idrocarburi Non Saturi Con Aldeidi e Chetoni. Gazz. Chim. Ital., 39, 341, (1909).
Büchi, G., Inman, C. G. & Lipinsky, E. S. Light-catalyzed Organic Reactions. I. The Reaction of Carbonyl Compounds with 2-Methyl-2-butene in the Presence of Ultraviolet Light. J. Am. Chem. Soc. 76, 4327–4331 (1954).
Bull, J. A., Croft, R. A., Davis, O. A., Doran, R. & Morgan, K. F. Oxetanes: Recent Advances in Synthesis, Reactivity, and Medicinal Chemistry. Chemical Reviews vol. 116 12150–12233 (2016).
Turro, N. J. et al. Molecular photochemistry of alkanones in solution: α-cleavage, hydrogen abstraction, cycloaddition, and sensitization reactions. Acc. Chem. Res. 5, 92–101 (1972).
Mattay, J., Gersdorf, J. & Buchkremer, K. Photoreactions of biacetyl with electron-rich olefins. An extended mechanism. Chem. Ber. 120, 307–318 (1987).
Fréneau, M. & Hoffmann, N. The Paternò-Büchi reaction—Mechanisms and application to organic synthesis. Journal of Photochemistry and Photobiology C: Photochemistry Reviews, 33, 83–108 (2017).
Mateos, J., Cuadros, S., Vega-Peñaloza, A. & Dell’amico, L. Unlocking the Synthetic Potential of Light-Excited Aryl Ketones: Applications in Direct Photochemistry and Photoredox Catalysis. Synlett. 33, 116–128 (2022).
Salem, L. Surface Crossings and Surface Touchings in Photochemistry. J. Am. Chem. Soc. 96, 3486–3501 (1974).
Griesbeck, A. G., Abe, M. & Bondock, S. Selectivity control in electron spin inversion processes: Regio- and stereochemistry of Paternò-Büchi photocycloadditions as a powerful tool for mapping intersystem crossing processes. Acc. Chem. Res. 37, 919–928 (2004).
Crisenza, G. E. M., Mazzarella, D. & Melchiorre, P. Synthetic Methods Driven by the Photoactivity of Electron Donor-Acceptor Complexes. Journal of the American Chemical Society vol. 142 5461–5476 (2020).
Matsumura, K., Mori, T. & Inoue, Y. Wavelength control of diastereodifferentiating Paternó-Büchi reaction of chiral cyanobenzoates with diphenylethene through direct versus charge-transfer excitation. J. Am. Chem. Soc. 131, 17076–17077 (2009).
Sun, D., Hubig, S. M. & Kochi, J. K. Oxetanes from [2 + 2] cycloaddition of stilbenes to quinone via photoinduced electron transfer. J. Org. Chem. 64, 2250–2258 (1999).
Zhang, Y., Xue, J., Gao, Y., Fun, H. K. & Xu, J. H. Photoinduced [2 + 2] cycloadditions (the Paterno–Büchi reaction) of 1-acetylisatin with enol ethers—regioselectivity, diastereoselectivity and acid catalysed transformations of the spirooxetane products. J. Chem. Soc. Perkin 1 2, 345–353 (2002).
Kandukuri, S. R. et al. X-ray characterization of an electron donor-acceptor complex that drives the photochemical alkylation of indoles. Angew. Chemie - Int. Ed. 54, 1485–1489 (2015).
Buzzetti, L., Crisenza, G. E. M. & Melchiorre, P. Mechanistic Studies in Photocatalysis. Angewandte Chemie - International Edition vol. 58 3730–3747 (2019).
Freilich, S. C. & Peters, K. S. Observation of the 1,4-Biradical in the Paterno-Buchi Reaction. J. Am. Chem. Soc. 103, 6255–6257 (1981).
Rehm, D. & Weller, A. Kinetics of Fluorescence Quenching by Electron and H-Atom Transfer. Isr. J. Chem. 8, 259–271 (1970).
The ∆G_ET was calculated by using the modified Rehm-Weller equation for PET as reported in the SI (section H, page S93). For examples of the application of this method see: Mattay, J., Runsink, J., Rumbach, T., Ly, C. & Gersdorf, J. Selectivity and Charge Transfer in Photoreactions of α, α, α-Trifluorotoluene with Olefins. J. Am. Chem. Soc. 107, 2557–2558 (1985).
Mattay, J.; Gersdorf, J.; Buchkremer, K. Photoreactions of Biacetyl with Electron-Rich Olefins. An Extended Mechanism. Chem. Ber. 1987, 120, 307–318.
The direct spectroscopic signature of the exciplex was investigated for benzil 7 and indole 1b. This because the low visible-light absorption of benzophenone 2b at 405 nm led to the selective excitation of EDA complex with a negligible contribution of the ketone direct excitation.
Due to the modest binding constant registered (K_EDA = 0.47 M^{– 1}), we can assume that most of the ketone 2b is not involved into the EDA complex, thus allowing also the direct excitation of the free species resulting in the exciplex-based manifold.
Mieres-Perez, J., Costa, P., Mendez-Vega, E., Crespo-Otero, R. & Sander, W. Switching the Spin State of Pentafluorophenylnitrene: Isolation of a Singlet Arylnitrene Complex. J. Am. Chem. Soc. 140, 17271–17277 (2018).
Gutiérrez-Hernández, A. et al. Deep Eutectic Solvent Choline Chloride/ p-toluenesulfonic Acid and Water Favor the Enthalpy-Driven Binding of Arylamines to Maleimide in Aza-Michael Addition. J. Org. Chem. 86, 223–234 (2021).
The modelling of the EDA-complex and exciplex was also accomplished with a simplified model involving 3,5-CF₃benzophenone as the ketone 2b and an N-Moc indole where R² = R³ = Me. For this model system, several conformers of the EDA were obtained with slightly different energies (0.1 to 0.2 kcal·mol^-1, Section I in SI). For the real case study, involving indole 1b (N-Boc, R² = OTBS, R³ = Bn), we considered the EDA complex having a proper orientation of the functional groups matching with the observed experimental results.
Mori, T. & Inoue, Y. Charge-transfer excitation: Unconventional yet practical means for controlling stereoselectivity in asymmetric photoreactions. Chem. Soc. Rev. 42, 8122–8133 (2013).
Trost, B. M., Dong, G. & Vance, J. A. Cyclic 1,2-Diketones as Core Building Blocks: A Strategy for the Total Synthesis of (–)-Terpestacin. Chem. – A Eur. J. 16, 6265–6277 (2010).
Samanta, S., Roy, D., Khamarui, S. & Maiti, D. K. Ni(ii)-salt catalyzed activation of primary amine-sp3Cα-H and cyclization with 1,2-diketone to tetrasubstituted imidazoles. Chem. Commun. 50, 2477–2480 (2014).
The endo/exo selectivity notation has been widely used in the Paternò-Büchi transformation. It refers to the initial approach of the aryl group of the carbonyl to the alkene. For an example see: Buschmann, H., Scharf, H. -D, Hoffmann, N. & Esser, P. The Isoinversion Principle—a General Model of Chemical Selectivity. Angew. Chemie Int. Ed. English 30, 477–515 (1991).
For the effect of temperature variation in light stereodifferentiation processes see e.g.: Matsumura, K., Mori, T. & Inoue, Y. Solvent and temperature effects on diastereodifferentiating paternó-büchi reaction of chiral alkyl cyanobenzoates with diphenylethene upon direct versus charge-transfer excitation. J. Org. Chem. 75, 5461–5469 (2010).
aito, H., Mori, T., Wada, T. & Inoue, Y. Diastereoselective [2 + 2] Photocycloaddition of Stilbene to Chiral Fumarate. Direct versus Charge-Transfer Excitation. J. Am. Chem. Soc. 126, 1900–1906 (2004).
Aoki, Y., Matsuki, N., Mori, T., Ikeda, H. & Inoue, Y. Exciplex ensemble modulated by excitation mode in intramolecular charge-transfer dyad: Effects of temperature, Solvent polarity, and wavelength on photochemistry and photophysics of tethered naphthalene-dicyanoethene system. Org. Lett. 16, 4888–4891 (2014).
Nagasaki, K., Inoue, Y. & Mori, T. Entropy-Driven Diastereoselectivity Improvement in the Paternò–Büchi Reaction of 1-Naphthyl Aryl Ethenes with a Chiral Cyanobenzoate through Remote Alkylation. Angew. Chemie - Int. Ed. 57, 4880–4885 (2018).
D’Auria, M. The Paternò-Büchi reaction-a comprehensive review. Photochemical and Photobiological Sciences vol. 18 2297–2362 (2019).
D’Auria, M. The Paternò-Büchi reaction-a comprehensive review. Photochemical and Photobiological Sciences vol. 18 2297–2362 (2019).
Harris, C.B.; Ippen, E.P.; Mourou, G. & Zewail A.H., Ultrafast Phenomena VIII, (Eds.; Springer: Berlin, Heidelberg, 1993.)
Ikeda, N., Koshioka, M., Masuhara, H. & Yoshihara, K. Picosecond dynamics of excited singlet states in organic microcrystals: Diffuse reflectance laser photolysis study. Chem. Phys. Lett. 150, 452–456 (1988).
Singh, A. K., Palit, D. K. & Mittal, J. P. Conformational relaxation dynamics in the excited electronic states of benzil in solution. Chem. Phys. Lett. 360, 443–452 (2002).
Fang, T. S. & Singer, L. A. Variable temperature studies on the luminescence from Benzil in a polymethylmethacrylate glass. An example of matrix controlled photorotamerism. Chem. Phys. Lett. 60, 117–121 (1978).
The ketoesters were selected avoiding any relevant variations in the absorption and ε extinction molar coefficient. See section G in SI for details.
Interestingly, a light-diastereodifferection process was also observed for the reaction between the α-ketoester 9 (Ar = 3,5-CF₃Ph) and the indole 1b, with the dr endo:exo passing from 84:16 under 370 nm irradiation to 57:43 under a 427 nm irradiation at -78°C. The lower dr variation registered with respect to the reaction performed with benzil 8 is likely due to the very similar absorption profile between the EDA complex and the single substrate. See Section G in SI for more details.For examples of the application of the Charton analysis see: Sigman, M. S. & Miller, J. J. Examination of the role of Taft-type steric parameters in asymmetric catalysis. J. Org. Chem. 74, 7633–7643 (2009).
Harper, K. C., Bess, E. N. & Sigman, M. S. Multidimensional steric parameters in the analysis of asymmetric catalytic reactions. Nature Chemistry vol. 4 366–374 (2012).
Extensive studies performed by Inoue, Mori and Abe have demonstrated that the use of high temperature (> 40°C) generally favors more strongly interacting e.g. p-p stacked EDA complexes over more flexible structures such as an exciplexes. This observation agrees with our experimental observations. See e.g. J. Org. Chem. 75, 5461–5469, (2010).
Cambié, D., Bottecchia, C., Straathof, N. J. W., Hessel, V. & Noël, T. Applications of Continuous-Flow Photochemistry in Organic Synthesis, Material Science, and Water Treatment. Chem. Rev. 116, 10276–10341 (2016).
Mateos, J. et al. A microfluidic photoreactor enables 2-methylbenzophenone light-driven reactions with superior performance. Chem. Commun. 54, 6820–6823 (2018).

Table 1 is available in the Supplementary Files section.

There is NO Competing Interest.

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Controlling Diastereodivergent Light-Driven Processes: The Impact of the Light Source and Steric Factors on the Paternò-Büchi Reaction
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Table 1. Generality of the developed light-driven and steric factors diastereodifferetiation processes. *The reaction was performed in PhH, the same reaction in Ace gave inferior endo: exo selectivity with a dr of 40:60. All the yields refer to a reaction time of 2h – no attempts were made to optimize the yield values. The reported dr values refer to endo:exo dr.

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Controlling Diastereodivergent Light-Driven Processes: The Impact of the Light Source and Steric Factors on the Paternò-Büchi Reaction

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The Exciplex vs. the EDA-complex Pathway. Computational Insights

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