1. Straight and Crossed Modes Correspond to Different Regiochemical Connectivity Patterns

1.1 Two Alkenes Can Form Different Regiochemical Connectivities

In an intramolecular [2+2] photocycloaddition, two alkenes are connected by a tether. Depending on how the reactive carbon atoms of the two alkenes are paired, two types of regiochemical connectivity can be formed: straight and crossed.[2]

Following the labeling convention used by Rigotti et al., the four reactive carbon atoms of the two alkenes can be designated α, β and α′, β′, respectively. The two typical connectivity patterns can be represented as follows:

Straight and crossed describe different regiochemical connectivity patterns between the reactive carbon atoms of the two alkenes. In intramolecular reactions, changing the way the termini are paired leads to different ring-system connectivities and can therefore generate structurally distinct polycyclic products.[2]

Crossed [2+2] photocycloadditions can establish combinations of C–C bonds that are difficult to form directly through thermal reactions and can therefore be used to construct polycyclic frameworks with bridged-ring connectivity.[2]

1.2 Regioselectivity Is Related to Stepwise C–C Bond Formation

For the triplet-state, stepwise intramolecular [2+2] photocycloadditions discussed in this article, regioselectivity is associated with the sequence of the two C–C bond-forming events.

The first C–C bond-forming event establishes the regiochemical connectivity between the two alkenes and generates a 1,4-diradical intermediate. The two remaining radical centers must then form the second C–C bond to complete construction of the cyclobutane unit.[2]

Accordingly, the experimentally observed regioselectivity involves two consecutive processes:

1. Which regiochemical connectivity of the 1,4-diradical is generated by the first C–C bond-forming event; 

2. Whether the resulting 1,4-diradical can proceed to form the second C–C bond. 

The first bond-forming event establishes the regiochemical connectivity of the intermediate, while subsequent ring closure or competitive reverse cleavage of the 1,4-diradical further determines whether that connectivity is converted into the final product.[2]

2. Triplet-State Intramolecular [2+2] Photocycloadditions Can Proceed by Stepwise Bond Formation via a 1,4-Diradical

2.1 The First C–C Bond-Forming Event Has the Character of a Radical-Type Addition

For triplet-state intramolecular [2+2] photocycloadditions, Rigotti et al. described the first C–C bond-forming event as a radical-type addition to the tethered alkene. This process first forms one new C–C bond and generates a 1,4-diradical intermediate.[2]

This stepwise bond-forming feature is fundamental to understanding the relationship between tether length and regioselectivity. Tether length changes the cyclization geometry associated with different modes of initial bond formation, thereby affecting the tendency to generate 1,4-diradicals with different regiochemical connectivities.[2]

In the chiral rhodium Lewis acid-mediated reaction studied by Rigotti et al., the substrate forms a coordination complex with the chiral rhodium complex. The experimentally observed stereoconvergence supports a triplet-state pathway for the photocycloaddition, and on this basis the authors proposed that intersystem crossing (ISC) occurs before formation of the first C–C bond. The first C–C bond then forms to generate the corresponding 1,4-diradical.[2]

The process can be summarized as follows:

Photoexcitation of the substrate within the catalyst–substrate coordination complex → intersystem crossing → entry into the triplet-state reaction pathway → first C–C bond formation → 1,4-diradical → subsequent reactions

The stepwise bond-forming pathway and 1,4-diradical mechanism described here apply to systems for which corresponding evidence for triplet-state reactivity is available. Other types of intramolecular [2+2] photocycloadditions should be analyzed separately according to their specific excited states and mechanistic evidence.

2.2 Subsequent Reactions of the 1,4-Diradical Affect Product Formation

The first C–C bond-forming event can generate 1,4-diradicals with different regiochemical connectivities or different spatial configurations. These intermediates do not necessarily have the same ability to form the second C–C bond.

Rigotti et al. proposed that when the two remaining radical centers in a 1,4-diradical have a spatial relationship favorable for bond formation, they can form the second C–C bond and complete construction of the cyclobutane unit. Constitutional or configurational isomeric intermediates that cannot efficiently undergo the second bond-forming event because of spatial constraints can instead undergo reverse cleavage to regenerate the starting structure; certain nonproductive intermediates may also enter side-reaction pathways.[2]

This process can be summarized as follows:

For this type of triplet-state stepwise reaction, the experimentally observed regioselectivity results from the combined effects of the first C–C bond-forming event and the subsequent reactions of the 1,4-diradical. The first bond-forming event establishes straight or crossed regiochemical connectivity, while the second bond-forming event, reverse cleavage, and other competing processes further influence the final product distribution.[2]

3. Effect of Tether Length on Straight and Crossed Regioselectivity

For the substrate connectivity examined in the studies by Rigotti et al., the length of the tether between the two alkenes changes the ring size generated during the first C–C bond-forming event and thereby affects the relative preference for the straight and crossed reaction pathways.[1,2]

3.1 A Three-Atom Tether Favors Formation of a Five-Membered Ring Along the Straight Pathway

The carbon atoms of the two alkenes proximal to the tether are designated α and α′, respectively. When the tether contains three atoms, formation of the first C–C bond between α and α′ causes the newly formed α–α′ bond and the pre-existing three-atom tether to constitute a five-membered ring.

In a triplet-state stepwise [2+2] photocycloaddition, this step can be regarded as a radical-type intramolecular addition that generates a 1,4-diradical intermediate. A three-atom tether therefore generally favors initial α–α′ bond formation and subsequently the formation of a straight product.[1,2]

Early studies of photosensitized diene cyclization observed regioselectivity consistent with a five-membered-ring-forming pathway, providing experimental evidence for this tether-length effect.[1,2]

The five-membered ring described here is formed by the first C–C bond-forming event together with the pre-existing tether. Subsequent formation of the second C–C bond generates the cyclobutane unit and completes the [2+2] cycloaddition.

3.2 With a Two-Atom Tether, the Initial Straight Bond-Forming Event Involves Formation of a Four-Membered Ring

When the tether is shortened to two atoms, if α and α′ still form the first bond, the newly formed C–C bond together with the two-atom tether constitutes a four-membered ring.

Rigotti et al. noted that systems containing a two-atom tether avoid this four-membered-ring formation, and the straight pathway corresponding to α–α′ bond formation is therefore suppressed.[2]

When the tether is shortened from three atoms to two, the ring formed during the first bond-forming event along the straight pathway changes from a five-membered ring to a four-membered ring. This change alters the relative preference among the different regiochemical bond-forming modes.

3.3 A Two-Atom Tether Can Form a Five-Membered Ring Through Crossed Bond Formation

A system containing a two-atom tether can adopt another mode of initial bond formation, namely formation of an α–β′ bond or an α′–β bond.

Taking α–β′ bond formation as an example, the first ring closure includes α, the two tether atoms, α′, and β′, for a total of five atoms, and therefore still forms a five-membered ring.

Through initial α–β′ or α′–β bond formation, a two-atom tether can avoid the four-membered-ring formation involved in the straight pathway and establish crossed regiochemical connectivity. Subsequent formation of the second C–C bond from the resulting 1,4-diradical gives the crossed [2+2] photocycloaddition product.[2]

This tether-length effect can be summarized as follows:

Thus, in this type of triplet-state stepwise intramolecular [2+2] photocycloaddition, tether length affects the relative favorability of the straight and crossed pathways by changing the ring size generated during the first radical-type bond-forming event. A three-atom tether favors α–α′ bond formation to generate a five-membered ring; when the tether is shortened to two atoms, α–β′ or α′–β bond formation can still generate a five-membered ring, resulting in a preference for crossed regiochemical connectivity.[2]

4. Application of Crossed [2+2] Photocycloaddition to the Construction of Bicyclo[2.1.1]hexanes

Crossed [2+2] photocycloaddition can establish bridged-ring connectivities that are difficult to obtain directly through conventional bond-forming reactions. The synthesis of bicyclo[2.1.1]hexanes is a representative application of this reaction mode.

In 2022, Rigotti and Bach reported a visible-light-driven intramolecular crossed [2+2] photocycloaddition of styrene derivatives. Triplet energy transfer places the substrate in a reactive triplet state, after which intramolecular cycloaddition occurs to afford bicyclo[2.1.1]hexane derivatives. The study reported 19 examples, with yields ranging from 61% to quantitative yield.[3]

According to the triplet-state stepwise [2+2] mechanistic model adopted in this article, the reaction process can be summarized as follows:

Photosensitizer absorbs visible light → triplet energy transfer → substrate forms a reactive triplet state → first crossed C–C bond formation → 1,4-diradical → second C–C bond formation → bicyclo[2.1.1]hexane framework

Triplet energy transfer provides the substrate with the reactive excited state required for photocycloaddition. Once the substrate enters the triplet state, the position of the first C–C bond-forming event determines whether straight or crossed regiochemical connectivity is established. For the stepwise reactions discussed here, tether length and the corresponding geometry of the first cyclization are important factors affecting regioselectivity.[2,3]

Thus, the photosensitizer and triplet energy transfer primarily affect formation of the reactive triplet state, whereas straight or crossed regiochemical connectivity is associated with the subsequent intramolecular bond-forming mode of the excited substrate. For the substrate types discussed above, the geometry of the first bond-forming event imposed by the tether is an important structural factor in the formation of crossed regiochemical connectivity.[2,3]

5. The Effect of Tether Length on Regioselectivity Must Be Analyzed in the Context of the Specific Reaction System

For the intramolecular [2+2] photocycloadditions discussed in references [1,2], there is a clear relationship between tether length and regioselectivity: a three-atom tether generally favors straight bond formation, whereas a two-atom tether can form a five-membered-ring intermediate through crossed bond formation.[1,2]

This relationship is associated with the specific substrate connectivity and stepwise bond-forming mechanism involved. Other intramolecular [2+2] photocycloaddition systems may also be influenced by alkene substitution patterns, substrate conformation, electronic structure, and the nature of the excited state.

A 2024 study reported the visible-light intramolecular [2+2] cycloaddition of bis(cinnamoyl) ketene dithioacetals.[4] This reaction system can form two different types of cycloaddition products:

① Crossed cycloaddition affords bridged bicyclo[3.1.1]heptane-2,4-diones;

② Straight cycloaddition affords fused bicyclo[3.2.0]heptane-2,4-diones.

Mechanistic studies indicated that the substrates can directly absorb visible light and undergo excitation; the authors further used density functional theory to investigate the reaction pathway of the crossed [2+2] cycloaddition.[4]

This study demonstrates that different regiochemical bond-forming pathways can coexist within the same intramolecular [2+2] reaction system. Accordingly, when analyzing a new reaction system, the following factors can be examined in sequence:

1. How the reactive excited state is generated; 

2. The possible positions of the first C–C bond-forming event; 

3. The ring sizes and conformational requirements associated with the different bond-forming modes; 

4. When mechanistic evidence supports stepwise bond formation, whether the intermediate can proceed to form the second C–C bond. 

Tether length reflects the geometric constraints imposed on intramolecular bond formation, but the actual regioselectivity also depends on substrate structure and the operative excited-state reaction pathway.

6. Mechanistic Relationship Between Straight and Crossed Regioselectivity

For the triplet-state stepwise intramolecular [2+2] photocycloadditions that are the primary focus of this article, regioselectivity can be summarized as the following sequence:

Tether length and substrate conformation → spatial relationship for the first C–C bond-forming event → competition between different regiochemical connectivities → formation of the corresponding 1,4-diradical → second C–C bond formation or reverse cleavage → straight or crossed product

The tether first constrains the relative conformations accessible to the two alkenes and affects the ring size generated during the first C–C bond-forming event. The first bond-forming event establishes the regiochemical connectivity and generates the corresponding 1,4-diradical; the spatial configuration of the intermediate then determines whether it can proceed to form the second C–C bond. A 1,4-diradical that does not satisfy the geometric requirements for subsequent bond formation can undergo reverse cleavage.[2]

7. Representative Chemicals Related to Studies of Straight/Crossed Regioselectivity and Stepwise C–C Bond Formation in Intramolecular [2+2] Photocycloadditions

Table 1. Triplet Sensitizers and Visible-Light Photosensitizers

Table 2. Model Substrates, Reaction Units, and Reagents for Substrate Construction

Table 3. Photoreaction Media and Auxiliary Reagents for Substrate Preparation

Note: The products listed above are representative Aladdin products relevant to scientific research. Specific applications should be determined with reference to the product specifications, batch COA, and the intended reaction or evaluation system. Additional information on product specifications, grades, and COAs can be retrieved from the Aladdin official website using the product name/CAS number/catalog number.

References

[1] Liu, R. S. H.; Hammond, G. S. Photosensitized Internal Addition of Dienes to Olefins. Journal of the American Chemical Society, 1967, 89, 4936–4944. DOI: 10.1021/ja00995a019.

[2] Rigotti, T.; Schwinger, D. P.; Graßl, R.; Jandl, C.; Bach, T. Enantioselective crossed intramolecular [2+2] photocycloaddition reactions mediated by a chiral chelating Lewis acid. Chemical Science, 2022, 13, 2378–2384. DOI: 10.1039/D2SC00113F.

[3] Rigotti, T.; Bach, T. Bicyclo[2.1.1]hexanes by Visible Light-Driven Intramolecular Crossed [2 + 2] Photocycloadditions. Organic Letters, 2022, 24, 8821–8825. DOI: 10.1021/acs.orglett.2c03606.

[4] Sang, Y.; Zhou, X.; Jin, C.; Pan, L.; Liu, Q.; Yuan, H.; Li, Y. Visible-light-driven, catalyst-free intramolecular crossed and straight [2 + 2] cycloaddition. Organic Chemistry Frontiers, 2024, 11, 3478–3484. DOI: 10.1039/D4QO00647J.

[5] Graßl, R.; Jandl, C.; Bach, T. Visible Light-Mediated Photochemical Reactions of 2-(2′-Alkenyloxy)cycloalk-2-enones. The Journal of Organic Chemistry, 2020, 85, 11426–11439. DOI: 10.1021/acs.joc.0c01501.

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